Статті в журналах: "Pancreatic neuroendocrine tumour, genomic alterations"

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Mafficini, Andrea, and Aldo Scarpa. "Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium." Journal of Endocrinology 236, no. 3 (March 2018): R161—R167. http://dx.doi.org/10.1530/joe-17-0560.

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Neuroendocrine tumours (NETs) may arise throughout the body and are a highly heterogeneous, relatively rare class of neoplasms difficult to study also for the lack of disease models. Despite this, knowledge on their molecular alterations has expanded in the latest years, also building from genetic syndromes causing their onset. Pancreatic NETs (PanNETs) have been among the most studied, and research so far has outlined a series of recurring features, as inactivation of MEN1, VHL, TSC1/2 genes and hyperactivation of the PI3K/mTOR pathway. Next-generation sequencing has added new information by showing the key role of alternative lengthening of telomeres, driven in a fraction of PanNETs by inactivation of ATRX/DAXX. Despite this accumulation of knowledge, single studies often relied on few cases or were limited to the DNA, RNA, protein or epigenetic level with lack of integrative analysis. The International Cancer Genome Consortium aimed at removing these barriers through a strict process of data and samples collection, to produce whole-genome integrated analyses for many tumour types. The results of this effort on PanNETs have been recently published and, while confirming previous observations provide a first snapshot of how heterogeneous is the combination of genetic alterations that drive this tumour type, yet converging into four pathways whose alteration has been enriched by newly discovered mechanisms. While calling for further integration of genetic and epigenetic analyses, these data allow to reconcile previous findings in a defined frame and may provide clinical research with markers for patients stratification and to guide targeted therapy decisions.

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Hofving, Tobias, Yvonne Arvidsson, Bilal Almobarak, Linda Inge, Roswitha Pfragner, Marta Persson, Göran Stenman, Erik Kristiansson, Viktor Johanson, and Ola Nilsson. "The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines." Endocrine-Related Cancer 25, no. 3 (March 2018): 367–80. http://dx.doi.org/10.1530/erc-17-0445.

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Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing theSMAD4gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss ofCDKN2AandCDKN2B, and QGP-1 harboured amplifications ofMDM2andHMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g.ATRXmutation in QGP-1) and, for patient tumours, rare genetic events (e.g.TP53mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

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Patel, Rishi, R. Joseph Bender, Quanlin Li, Dana Pan, Richard Tuli, Michael J. Pishvaian, and Andrew Eugene Hendifar. "Multi-omic molecular profiling of pancreatic neuroendocrine tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15685-e15685. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15685.

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e15685 Multi-omic Molecular profiling of Pancreatic Neuroendocrine Tumors Authors: Rishi R Patel, Joseph Bender, Quanlin, Dana Pan, Lynn Matrisian, David Halverson, Emanuel Petricoin, Subha Madhavan, Richard Tuli, Michael Pishvaian, Andrew Hendifar; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA Background: Pancreatic Neuroendocrine Tumors (pNETs) are a rare malignancy with an incidence of 2 per 1,000,000. In 2016, the Pancreatic Cancer Action Network and Perthera initiated the Know Your Tumor (KYT) initiative in an effort to improve coordination across clinical spectrums in regards to multi-omic molecular profiling and clinical outcomes data pertaining to pancreatic tumors. We used data collected as part of the KYT effort to describe demographic, clinical and genomic data for pNETs. Methods: From 2015 - 2016, 15 patients with pNET were enrolled in the KYT program, which helped facilitate tissue acquisition, clinical data collection, and multi-omic molecular profiling. Using the data collected, we performed Fisher’s Exact to assess for statistical significance between genetic alterations and histology. Results: 11/15 of our patients were female. 8/15 had metastatic disease at the time of diagnosis, while 5/15 had locally advanced disease at the time of diagnosis. 29 genetic alterations were pathogenic. KMT2D and MEN1 were jointly found in 6/15 of our patients. 5/15 with pathogenic alterations in p53, 2/15 with DAXX, 5/15 with alteration in RB1, and 2/15 with alterations in PTEN and TSC2. 2 patients had pathologic alterations in mismatch repair genes, MLH1 and MSH1. Two genes had a statistically significant relationship to pNET histology. Alterations in MEN1 (p = 0.0097) and SPTA1 (p = 0.0333) were associated with high grade tumors (p = 0.0097). Of note, both of the patients under the age of 35 shared an alteration in ATR, which none of the other enrollees expressed. Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.

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Starr, Jason Scott, Kabir Mody, Ali Roberts, and Pashtoon Murtaza Kasi. "Circulating tumor DNA analysis of neuroendocrine tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15698-e15698. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15698.

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e15698 Background: Neuroendocrine tumors (NETs) and carcinomas (NECs) are a diverse group of tumors with an equally diverse biology and clinical behavior. Data on tissue-based genomic profiling of NETs exists, however, there is limited data using circulating tumor DNA (ctDNA) technology. We sought out to characterize NETs via ctDNA to identify genomic alterations. Methods: 27 patients with metastatic NET/NEC with 32 total plasma samples were analyzed using Guardant360 ctDNA assay. Breakdown of NET/NEC by location: 14 pancreatic NET (pNET), 11 NEC, 1 small bowel NET, 1 lung NET. The ctDNA test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: Of the 27 patients, 19 (70%) had a detectable genomic alteration. The detectable (non-synonymous) alterations are as follows: TP53 (n = 14, 70%), NF1 (n = 8, 40%), EGFR (n = 5, 25%), BRCA2 (n = 4, 20%), KRAS (n = 4, 20%), ARID1A (n = 3, 15%), CDK6 (n = 3, 15%), ALK (n = 3, 15%), MET (n = 2, 10%), PTEN (n = 2, 10%), BRAF (n = 2, 10%), MTOR (n = 2, 10%) AKT1 (n = 1), BRCA1 (n = 1), CCND2 (n = 1), CCNE1 (n = 1), CTNNB1 (n = 1), ESR1 (n = 1), FGFR2 (n = 1), HRAS (n = 1), IDH1 (n = 1), KIT (n = 1), MYC (n = 1), NOTCH1 (n = 1), NRAS (n = 1), PDGFRA (n = 1), RAF1 (n = 1), RB1 (n = 1), SMAD4 (n = 1), STK11 (n = 1), TSC1 (n = 1), ERBB2 (n = 1), PIK3CA (n = 1). Conclusions: This experience highlights the feasibility of ctDNA to help identify genomic alterations in this patient population. Further studies incorporating ctDNA testing in this patient population are warranted.

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Garralda, Elena, Antonio Calles, Fernando López-Ríos, Siân Jones, Lisa M. Kann, Samuel V. Angiuoli, Luis A. Diaz, et al. "Integrated next-generation sequencing and patient-derived xenografts to personalized cancer treatment." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3068. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3068.

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3068 Background: The knowledge of actionable somatic genomic alterations present in each tumor is making possible the era of personalized cancer treatment. Methods: Using massively parallel sequencing we performed whole exome sequencing analysis of tumor and matched normal blood samples of 8 patients (2 pancreatic adenocarcinoma, 1 neuroendocrine tumor, 1 glioblastoma, 1 uveal melanoma, 1 colon cancer) to identify putatively actionable tumor specific genomic alterations. We used 2 in silico methods (Polyphen and SIFT) to estimate the functional significance of a given confirmed mutation. Primary xenografts (PDX), generated by direct engraftment of tumor samples from the patients into immunocompromised mice, were used as an in vivo platform that provided the opportunity to test proposed personalized medicine strategies. Results: At this time exome sequencing analyses have been performed for 5 patients (1 patient died prematurely, 1 tumor sample was insufficient, 1 result is pending). More than 30 million bases of target DNA were analyzed in the tumor and normal samples in every case, with at least 70 distinct reads at each base. Tumor specific mutations (Muts) and copy number variations (CNVs) were identified: 5 Muts in the neuroendocrine tumor; 62Muts/6CNVs and 38Muts/10CNVs in the pancreatic tumors; 63Muts/23CNVs in the glioblastoma; 5 Muts in the melanoma. All samples profiled contained actionable alterations with the most relevant mutations affecting NF1, PTPN11, EPHA3, CDKN2A, FAS (glioblastoma); PI3KCA, ARID1A, ARID1B, DDR2, SMAD4, TP53, KRAS, PTCHD3 (pancreatic); CREB3L3, ITPR2 (neuroendocrine); GNA11, TAOK3 (melanoma). PDX from the pancreatic cancer patient was treated with a PI3K inhibitor and dasatinib, reported to be effective in discodin domain receptor 2 (DDR2) mutant cancer with no effect. Accordingly treatment of that patient with dasatinib was not effective and the level of this mutation in the tumor was observed to be low. Conclusions: Detection of actionable tumor-specific genomic alterations in the clinical setting is feasible. In silico methods and primary xenografts can help in the challenge of linking confirmed mutations to protein function and ultimately to clinical utility.

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Azar, Ibrahim, Omid Yazdanpanah, Shiva Swaroop Bongu, Mohammed Najeeb Al Hallak, W. Michael Korn, Anthony Frank Shields, and Philip Agop Philip. "Molecular profiling of pancreatic neuroendocrine neoplasms (panNENs): A single-institution experience." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e16207-e16207. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16207.

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e16207 Background: PanNENs are rare with a heterogeneous pathophysiology and widely differing clinical course. Despite a recent update of the grading system, prognostication and prediction of response to therapy remain challenging. Somatostatin receptor aside, there are currently no predictive biomarkers or targeted agents for panNENs. Molecular profiling offers an opportunity to develop new drugs and personalize treatments. Methods: We compiled data from patients diagnosed with panNENs from Karmanos Cancer Institute between 2014 and 2020. Of the 35 patients with panNENs, 33 underwent Next Generation Sequencing (Caris Molecular Intelligence). Two tumor biopsies were insufficient for molecular analysis. Results: Of the 35 tumors analyzed, 11 were grade 1, 18 were G2, 2 were well-differentiated G3 and 4 were poorly differentiated pancreatic neuroendocrine carcinomas (panNEC). Median age at diagnosis was 61. 21 patients identified as White, 6 as Black and 8 as other. 21 were men. 28 patients were metastatic at diagnosis. The most frequently detected molecular alteration was MEN1 mutations (11 G1, 1 G1 and 1 G3). 3 G2 and 2 G3 tumors expressed PTEN mutations. All 3 p53 mutations were G3, 2 of them panNEC. An FGFR3 amplification was detected in a single G1 panNEN. Her2/Neu amplification was detected in a G2 tumor. Other frequent alterations were MGMT (4), TOP2A (4), ARID1A (3), TUBB3 (3) and TSC2 (3). 3 tumors were PD-L1 positive. All tumors were TMB non-high and MMR-proficient. Conclusions: Molecular profiling of panNEN can detect targetable alterations with currently validated commercial agents. panNENs are immunologically cold. Further genomic and epigenomic profiling studies can help understand the molecular underpinnings of pathophysiology and aid in the development of biology-driven targeted therapies.

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Martin, David R., Elisa LaBauve, Joseph M. Pomo, Vi K. Chiu, Joshua A. Hanson, and Rama R. Gullapalli. "Site-Specific Genomic Alterations in a Well-Differentiated Pancreatic Neuroendocrine Tumor With High-Grade Progression." Pancreas 47, no. 4 (April 2018): 502–10. http://dx.doi.org/10.1097/mpa.0000000000001030.

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Yao, James, Abhishek Garg, David Chen, Jaume Capdevila, Paul Engstrom, Rodney Pommier, Eric Van Cutsem, et al. "Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials." Endocrine-Related Cancer 26, no. 4 (April 2019): 391–403. http://dx.doi.org/10.1530/erc-18-0332.

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Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

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Raj, Nitya, Ronak Shah, Zsofia Stadler, Semanti Mukherjee, Joanne Chou, Brian Untch, Janet Li, et al. "Real-Time Genomic Characterization of Metastatic Pancreatic Neuroendocrine Tumors Has Prognostic Implications and Identifies Potential Germline Actionability." JCO Precision Oncology, no. 2 (November 2018): 1–18. http://dx.doi.org/10.1200/po.17.00267.

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Purpose We assessed the usefulness of real-time molecular profiling through next-generation sequencing (NGS) in predicting the tumor biology of advanced pancreatic neuroendocrine tumors (panNETs) and in characterizing genomic evolution. Methods Patients with metastatic panNETs were recruited in the routine clinical practice setting (between May 2014 and March 2017) for prospective NGS of their tumors as well as for germline analysis using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing platform. When possible, NGS was performed at multiple time points. Results NGS was performed in 96 tumor samples from 80 patients. Somatic alterations were identified in 76 of 80 patients (95%). The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). Alterations could be defined in pathways that included chromatin remodeling factors, histone methyltransferases, and mammalian target of rapamycin pathway genes. Somatic loss of heterozygosity was particularly prevalent (55 of 95 tested samples [58%]), and the presence of loss of heterozygosity resulted in improved overall survival (P = .06). Sequencing of pre- and post-treatment samples revealed tumor-grade progression; clonal evolution patterns were also seen (molecular resistance mechanisms and chemotherapy-associated mutagenesis). Germline genetic analysis identified clinically actionable pathogenic or likely pathogenic variants in 14 of 88 patients (16%), including mutations in high-penetrance cancer susceptibility genes ( MEN1, TSC2, and VHL). Conclusion A clinical NGS platform reveals pertubations of biologic pathways in metastatic panNETs that may inform prognosis and direct therapies. Repeat sequencing at disease progression reveals increasing tumor grade and genetic evolution, demonstrating that panNETs adopt a more aggressive behavior through time and therapies. In addition to frequent somatic mutations in MEN1 and TSC2, germline mutations in these same genes underlie susceptibility to panNETs and highlight the need to re-evaluate whether germline genetic analysis should be performed for all patients with panNETs.

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Cowzer, Darren, Ronak H. Shah, Sippy Punn, Laura Fiedler, April DeMore, Joanne F. Chou, Marinela Capanu, Michael F. Berger, Diane Reidy-Lagunes, and Nitya Prabhakar Raj. "Next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) in advanced pancreatic neuroendocrine neoplasms (PanNENs)." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 653. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.653.

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653 Background: PanNENs represent 1-2% of all pancreatic neoplasms. The genomic landscape derived from PanNEN tumor tissue has been described previously. There are little data detailing the frequency of genetic alterations identified in cfDNA in an advanced PanNEN population, the plasma-tissue concordance of detected alterations, and the clinical utility of cfDNA. Methods: Patients (pts) with metastatic PanNENs underwent collection of cfDNA for NGS using the MSK-IMPACT 505 gene assay between March 2017 and April 2020. Matched tissue based NGS with the FDA authorized MSK-IMPACT gene assay was completed when tumor tissue was available. For some pts, plasma and tumor tissue were sequenced at multiple time points. Clinical actionability of sequence variants was annotated by OncoKB. Clinicopathologic characteristics were extracted, and data are herein reported. Results: 25 unique pts with metastatic PanNENs had 32 plasma samples analyzed. The majority had well differentiated (22/25; 88%), intermediate grade disease (13/25; 52%). 6 (24%) pts had well differentiated high grade disease and 3 (12%) had poorly differentiated neuroendocrine carcinomas. After extraction, median cfDNA yield per sample was 23.98ng (range: 3.2 to 500.1). Mutations were detected in 21(66%) of 32 samples (10 pre systemic therapy, 10 at progression, 12 post response to therapy or while stable on therapy). The most frequently mutated genes occurring in >10% of patients were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%) and ATRX (12%). 23 (92%) pts underwent tumor tissue sequencing with MSK-IMPACT with a median time of 6.9 (range: 0.5-33.4) months between tissue collection and time of plasma analysis. NGS of cfDNA identified the most common mutations observed in tumor tissue for: DAXX (5/6; 83%), TSC2 (3/6; 50%), MEN1 (5/12; 42%), ARID1A (3/5; 60%) and ATRX (3/6; 50%). In 21/23 (91%) paired samples, additional mutations not seen in tissue were detected in plasma and included TSC2, TP53, EGFR, VHL, and BRCA2. Potentially actionable mutations were identified in sequenced cfDNA in 8/25 (32%) patients including 4 TSC2 mutations (level 3b), 1 ATM mutation (level 3b), 2 ARID1A mutations (level 4) and 1 KRAS mutation (level 4). One patient who was treated with larotrectinib for an ETV6:NTRK3 fusion detected on tumor sequencing ultimately developed resistance with a NRTK3 G623R alteration identified through sequencing of cfDNA at radiographic disease progression. Conclusions: NGS of cfDNA in metastatic PanNENs, across the spectrum of WHO-defined tumor grade/differentiation, revealed tumor-associated genetic alterations in 66% of plasma samples. Clonal evolution, actionable alterations, and resistance mechanisms can be detected through circulating cfDNA genotyping and may serve as a powerful tool to better understand disease biology of a disease that often changes over time and through therapy.

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Guan, Michelle, Jun Gong, Andrew Eugene Hendifar, Richard Tuli, Veronica Placencio-Hickok, Joseph Bender, Edik Matthew Blais, and Emanuel Petricoin. "Multiplatform profiling of pancreatic neuroendocrine tumors (PanNETs) identifies novel co-occurring pathogenic alterations and associations with clinicopathologic factors." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 211. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.211.

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211 Background: We correlated genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identified novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management through multi-omic profiling. Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. PanNETs having undergone molecular profiling for precision matched therapeutic purposes were screened. We performed correlative analyses by pairwise comparisons between pathogenic alterations or altered molecular pathways and clinicopathologic variables. Hierarchical clustering was used to visualize associations. The Kaplan-Meier method was used to estimate overall survival (OS) and survival differences across variables were analyzed by the log-rank test. Results: We included 33 patients with predominantly locally advanced and metastatic PanNETs from 12/2014-1/2018. Chromatin remodeling pathway and MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs, while MEN1 alterations were also less associated with metastatic disease at diagnosis (all Fisher’s exact two-tailed p ≤ 0.05). Several molecular pathway or pathogenic alterations correlated with worse OS: DNA repair pathway (log-rank p = 0.0022), RB1 alterations by NGS (p = 0.018), and TP53 alterations by NGS (p = 0.01). There were several significant co-occurring alterations (Fisher’s exact p ≤ 0.05): ERCC1 expression by immunohistochemistry (IHC) and DAXX (NGS), RB1 (NGS) and DNA repair pathway (NGS), and TS (IHC) and cyclin-dependent kinase pathway (NGS). Having an altered chromatin remodeling pathway was less associated with having an altered receptor tyrosine kinase (RTK) signaling pathway (Fisher’s exact p ≤ 0.05). Conclusions: We identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs.

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Vandamme, T., M. Beyens, G. Boons, A. Schepers, K. Kamp, K. Biermann, P. Pauwels, et al. "Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms." Endocrine-Related Cancer 26, no. 1 (January 2019): 1–12. http://dx.doi.org/10.1530/erc-18-0120.

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Mutations in DAXX/ATRX, MEN1 and genes involved in the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway have been implicated in pancreatic neuroendocrine neoplasms (pNENs). However, mainly mutations present in the majority of tumor cells have been identified, while proliferation-driving mutations could be present only in small fractions of the tumor. This study aims to identify high- and low-abundance mutations in pNENs using ultra-deep targeted resequencing. Formalin-fixed paraffin-embedded matched tumor-normal tissue of 38 well-differentiated pNENs was sequenced using a HaloPlex targeted resequencing panel. Novel amplicon-based algorithms were used to identify both single nucleotide variants (SNVs) and insertion-deletions (indels) present in >10% of reads (high abundance) and in <10% of reads (low abundance). Found variants were validated by Sanger sequencing. Sequencing resulted in 416,711,794 reads with an average target base coverage of 2663 ± 1476. Across all samples, 32 high-abundance somatic, 3 germline and 30 low-abundance mutations were withheld after filtering and validation. Overall, 92% of high-abundance and 84% of low-abundance mutations were predicted to be protein damaging. Frequently, mutated genes were MEN1, DAXX, ATRX, TSC2, PI3K/Akt/mTOR and MAPK-ERK pathway-related genes. Additionally, recurrent alterations on the same genomic position, so-called hotspot mutations, were found in DAXX, PTCH2 and CYFIP2. This first ultra-deep sequencing study highlighted genetic intra-tumor heterogeneity in pNEN, by the presence of low-abundance mutations. The importance of the ATRX/DAXX pathway was confirmed by the first-ever pNEN-specific protein-damaging hotspot mutation in DAXX. In this study, both novel genes, including the pro-apoptotic CYFIP2 gene and hedgehog signaling PTCH2, and novel pathways, such as the MAPK-ERK pathway, were implicated in pNEN.

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Raj, Nitya Prabhakar, Tara Soumerai, Emily Valentino, Jaclyn Frances Hechtman, Michael F. Berger, and Diane Lauren Reidy. "Next-generation sequencing (NGS) in advanced well differentiated pancreatic neuroendocrine tumors (WD pNETs): A study using MSK-IMPACT." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 246. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.246.

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246 Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in chromatin modeling genes (MEN1, DAXX, and ATRX), and in the mTOR pathway. NGS brings this technology to the clinic but its relevance in practice has been questioned. In this prospective, IRB-approved study (NCT01775072), we used the MSK-IMPACT assay to perform NGS on WD pNETs in a routine practice setting. MSK-IMPACT, performed in a CLIA-compliant laboratory, is a multiplexed assay (Illumina HiSeq) providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements. Methods: After written consent, tumor and germline DNA were analyzed. Genomic alterations were catalogued. Results: MSK-IMPACT results are available in 39 patients (pts). Actionable alterations were identified in 13/39 pts (33.3%). These actionable alterations included BRAF V600E (2 pts; 5.1%), and mutations in TSC1 (1 pt; 2.6%), TSC2 (5 pts; 12.8%), PTEN (4 pts; 10.3%), CDKN1B (2 pts; 5.1%), CDKN2A (2 pts; 5.1%), CDKN2B (2 pts; 5.1%), CDKN2C (1 pt; 2.6%), and ARID1A (5 pts; 12.8%). Other recurrently altered genes included MEN1 (23 pts, 59.0%), DAXX (13 pts, 33.3%), and ATRX (10 pts, 25.6%). Notably, 7 pts (17.9%) had alterations in the histone methyltransferase SETD2. All 7 pts presented with metastatic liver disease. No tumors were low grade; 6/7 (85.7%) were intermediate grade and 1/7 (14.3%) were high grade. All 7 pts received capecitabine/temozolomide (cape/tem); 6 pts (85.7%) had disease shrinkage and 1 pt (14.3%) had stable disease. Conclusions: The mutational landscape in our study was in line with prior work in pNET whole exome sequencing. In one-third of our cohort, potentially actionable alterations were identified through NGS but have not yet been shown to be therapeutically relevant. An exploratory analysis to identify responses to different therapies is ongoing. In addition, we report a novel finding of SETD2 alterations in pNETs. All pts with SETD2 alterations had intermediate to high grade tumors that responded to cape/tem. The clinical significance of SETD2 in pNETs is unknown, and evaluation using tissue microarrays is ongoing.

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Samsom, K. G., L. M. van Veenendaal, G. D. Valk, M. R. Vriens, M. E. T. Tesselaar, and J. G. van den Berg. "Molecular prognostic factors in small-intestinal neuroendocrine tumours." Endocrine Connections 8, no. 7 (July 2019): 906–22. http://dx.doi.org/10.1530/ec-19-0206.

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Background Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis. Aim We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs. Method A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019. Results The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44–100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs. Conclusion SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.

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Takahashi, Kenta, Yasuyuki Gen, Kousuke Tanimoto, Atsushi Kudo, Noriko Oshima, Daisuke Ban, Akira Takemoto, et al. "Clinical impact of hemizygous deletion detection and panel-size in comprehensive genomic profiling." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15671-e15671. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15671.

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e15671 Background: Comprehensive genomic profiling (CGP) identified single nucleotide variants (SNVs), copy number alteration (CNA), indels, and rearrangements in cancer-related genes. Only limited CGP detects hemizygous deletion. Also panel size differs among CGPs. Clinical impact of hemizygous deletion and panel-size are not well characterized. Methods: Formalin-fixed paraffin-embedded tissues from 10 cancer patients were analyzed by two CGPs: 1) test A (ACT Onc+) that interrogates SNVs, indels, rearrangement, and CNA including amplification, hemizygous and homozygous deletions in 440 genes, 2) test B that interrogates SNV, indels, rearrangement and CNA including amplification and homozygous deletion in 114 genes, but hemizygous deletion only in limited genes. Result was discussed in molecular tumor board and actionable genes and candidate drug were determined. Primary objective was the number of actionable genomic alterations. Secondary objectives are the number of candidate drugs, SNVs, CAN, and rearrangement. When there was difference of results in two tests, other validation test, such as PCR-based copy number evaluation, was performed. The difference of two tests was statistically evaluated using student t-test. Results: Median age of patients was 56 (range 48 – 70), and 50% were male. Tumor types were neuroendocrine tumor (60%), ovarian cancer (30%) and pancreatic cancer (10%). In 10 patients, actionable genes were found as follows: 39 in test A and 9 in test B (P = 0.0056). Total 64 genomic alterations were found in test A compared 12 in test B. SNV was not statistically different among two tests (10 in test A, 6 in test B; P = 0.269). However, the number of CNA was different: 54 in test A and 6 in test B (P = 0.007). Among CNA, hemizygous alteration explained majority of the difference (30 in test A and 1 in test B, P = 0.059), followed by amplification (24 in test A and 5 in test B, P = 0.201). The number of drug candidates was 38 in test A and 11 in test B (P = 0.014). Conclusions: Detection of hemizygous deletion and larger panel size resulted in more actionable genes and drug candidates, which might impact clinical practice. Future study of clinical utility of hemizygous deletion and panel size is warranted.

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Guan, Michelle, R. Joseph Bender, Michael J. Pishvaian, David Charles Halverson, Richard Tuli, Samuel Jacob Klempner, Zev A. Wainberg, Aatur D. Singhi, Emanuel Petricoin, and Andrew Eugene Hendifar. "Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs)." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 214. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.214.

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214 Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.

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Aggarwal, Rahul, Jiaoti Huang, Joshi J. Alumkal, Li Zhang, Felix Y. Feng, George V. Thomas, Alana S. Weinstein, et al. "Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study." Journal of Clinical Oncology 36, no. 24 (August 20, 2018): 2492–503. http://dx.doi.org/10.1200/jco.2017.77.6880.

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Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)–targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell–like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

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Shen, Rong, Qiuan Yang, Zimin Liu, Yongjie Wang, Xinglong Fan, Lei Li, Bo Hu, et al. "The landscape of predictive biomarkers for ATR inhibition in Chinese solid-tumor patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3626. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3626.

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3626 Background: Ataxia Telangiectasia and Rad3-related (ATR) is one of the core regulators participating in DNA damage response as a sensor of replication stress. Besides, ATR also plays a role in cell cycle checkpoint activation and DNA replication regulation. Several ATR inhibitors (ATRi) have been demonstrated in anti-cancer clinical trials. Herein, we describe the distribution of selected biomarkers, which have been shown to predict a higher sensitivity to ATRi according to preclinical data, in Chinese cancer population. Methods: FFPE tumor tissues and matched blood samples from 10,194 Chinese patients with 25 different types of solid tumors were collected. NGS based 450 cancer genes panel assay were performed to detect genomic alterations, including SNV, short and long insertions/deletions, CNV and rearrangements/fusions. The testing was carried out by a CAP accredited and CLIA certified laboratory. Results: The prevalence of ARID1A mutations, ATM mutations, BRCA1/BRCA2 mutations, MYC amplification, and CCNE1 amplification accounted for 9.5%, 4.7%, 6.0%, 3.5% and 3.3% of this cohort respectively. The most common tumors with ARID1A mutations were endometrial carcinoma (EC, 34.4%), gastric carcinoma (GC, 19.4%), small bowel carcinoma (SBC, 19.3%), intrahepatic cholangiocarcinoma (19.3%), extrahepatic cholangiocarcinoma (17.7%) and urothelial carcinoma (UC, 16.7%). For ATM mutations, the prevalence was colorectal carcinoma (CRC, 8.9%), SBC (8.8%), pancreatic cancer (7.8%), UC (7.3%), gallbladder carcinoma (GBC, 7.1%) and GC (6.8%). For BRCA1/BRCA2 mutations, the prevalence was ovarian carcinoma (29.5%, Germline 23%), breast carcinoma (13.3%, Germline 7.1%), EC (11.5%, Germline 3.3%), UC (10.4%), melanoma (8.5%) and CRC (7.9%). For MYC amplification, the prevalence was breast carcinoma (10.2%), ovarian carcinoma (9.2%), esophageal carcinoma (7.2%), thymic tumor (6.1%), cancer of unknown primary (CUP, 5.8%) and gastrointestinal neuroendocrine tumor (GI-NET, 5.4%). For CCNE1 amplification, the prevalence was GC (11.9%), GBC (8.8%), bone sarcoma (7.7%), ovarian carcinoma (6.9%), CUP (4.2%) and GI-NET (4.1%). Conclusions: Our study reported the prevalence of gene mutations of ATRi sensitivity determinants in a large cohort of Chinese cancer patients. The results revealed the high prevalence and different distribution of these biomarkers across a wide spectrum of cancers. The genomic profile study also provided information for ATRi sensitivity assessment and the drug combinations with ATR inhibition.

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Ling, Jinjie, Lorenzo Tomassoni, Alvaro Curiel, Kenneth Olive, and Andrea Califano. "Abstract 2127: Master regulator analysis of the tumor microenvironment and the distinctive tumor sub-populations in pancreatic ductal adenocarcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2127. http://dx.doi.org/10.1158/1538-7445.am2022-2127.

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Abstract By 2030, pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-associated mortality in the United States. However, current strategies in targeting key driver mutations such as KRAS, CDKN2A, TP53, and SMAD4, have found limited translational success. As a result, the standard of care for PDAC patients continues to rely on cytotoxic chemotherapies. Master regulator (MR) proteins integrate upstream genomic alterations to generate a common downstream transcriptional signature characteristic of a tumor cell population. Importantly, aberrant MR protein activity is requisite to implementing and maintaining a pro-tumor state. Therefore, MR proteins serve as critical tumor dependencies and represent a promising class of therapeutic targets for cancer treatment. Here, we propose a novel, network-based approach to identify top MR proteins by utilizing a combination of ARACNe (Margolin et al, 2006) and VIPER (Alvarez et al, 2016) algorithms for the analysis of single-nuclei transcriptomic data. Specifically, we used VIPER to investigate the heterogeneity of the tumor microenvironment (TME) and to characterize the tumor sub-populations that co-exist in a patient PDAC specimen. Clustering analysis based on protein activity revealed six populations in the TME. The SingleR classifier subsequently annotated these clusters as myeloid and lymphoid immune, fibroblast, neuroendocrine, epithelial, and putative tumor cells. Next, we validated the putative tumor cells by performing InferCNV which detected widespread chromosomal copy number variations. We identified two distinct tumor subpopulations which were found to be enriched by the MR signatures of the Oncogenic Precursor (OP) and Lineage subtypes, previously demonstrated to represent more and less differentiated tumor cell populations, respectively (Laise et al, 2020). Interestingly, top MR proteins identified for the putative tumor cells using the single-nuclei transcriptomics closely corresponded with those identified by single-cell and previous bulk transcriptomics, providing orthogonal validation for the inferred protein activities. We characterized the diverse cell populations in the PDAC TME, delineated two distinct tumor cell subtypes, and demonstrated high concordance of inferred MR protein activity at the single-cell, single-nuclei, and bulk levels. These results demonstrate the feasibility of applying systems biology-based methods to identify MR proteins in an N = 1 context and represent a novel precision medicine approach in the treatment of PDAC patients. Future lines of inquiry center on identifying treatments against each tumor subpopulation via OncoTreat, an algorithm that leverages high-throughput drug perturbation data to predict effective therapies based on inferred ability to invert MR protein activity (Alvarez, 2018). Citation Format: Jinjie Ling, Lorenzo Tomassoni, Alvaro Curiel, Kenneth Olive, Andrea Califano. Master regulator analysis of the tumor microenvironment and the distinctive tumor sub-populations in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2127.

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Instituto Nacional de Câncer José de Alencar Gomes da Silva. "9º Simpósio Médico Internacional de VHL; III Encontro de Famílias com a Síndrome de VHL Data:." Revista Brasileira de Cancerologia 56, no. 3 (June 30, 2010): 395–406. http://dx.doi.org/10.32635/2176-9745.rbc.2010v56n3.1493.

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Resumos escolhidos para publicação. Nessa edição, os títulos foram: Extramitochondrial Fumarate Inhibits Multiple 2-OG Oxygenases in Fumarate Hydratase Deficient Cells; What is the Best Treatment for Renal Lesions in VHL?; Characterization of the VHL-ECM Pathway; Induction of Extreme Metabolic Depression by the Nucleolus; Mutation of SDHB and Inherited RCC Susceptibility; Metabolic Links to Renal Cancer; Radiosurgery for Cerebellar Hemangioblastomas; Neoplastic Diagnosis Timing Profile in von Hippel-Lindau´s Patients in a Personal Series; Regulation of the VHL Tumor Suppressor; Destructive Targeting via VHL Beyond HIF; Folliculin Functional Studies and Mouse Models of Birt-Hogg-Dube’ Syndrome; A Zebrafish Model for VHL; Relief of Intractable Nausea after Resection of Brainstem Hemangioblastoma in Patients with von Hippel-Lindau Disease: a Clinical Series; Somatic Alteration of the VHL Gene in Sporadic Renal-Cell Carcinomas as a Potential Biomarker; VHL Tumor Suppressor Protein Regulates Oncogenic Macroautophagy in Renal Clear Cell Carcinoma (RCC); Identification of Germline Mutations in the VHL Gene of Families with the von Hippel-Lindau Disease; Expression Profile in von Hippel-Lindau Disease Associated and Sporadic Clear-Cell Renal Cell Carcinomas; Proposed Changes to the VHL Handbook; Evaluation of the Somatic Alterations of the VHL Gene in Renal Cell Carcinoma Associated with von Hippel-Lindau Disease (VHL); Copy Number Variation Analysis of a Pancreatic Neuroendocrine Tumor (NET) from a Patient with von Hippel-Lindau (VHL); Molecular Dynamics Study of the Mutant pVHL Phe76del and its Interactions with Components of the pVHL Complex; Genomic Copy Number Variation Analysis in VHL-Associated Renal Cell Carcinomas Suggests Clonality; Management of Brainstem and Spinal cord Hemangioblastomas in Patients with von Hippel-Lindau Disease; The Benefits of Ultrasound in Resection of CNS Hemangioblastomas; Management of Central Nervous System Hemangioblastomas in von Hippel-Lindau Disease; Neuronal Differentiation of Stem cells by Transfer of a VHL Peptide and Regenerative Therapy; Endolymphatic Sac Tumors (ELST) in VHL Patients - Evaluation of Screening Methods in a National Study; Delineating Genotype-Phenotype Correlations Among Brazilian Families with von Hippel-Lindau Disease; Endothelial Fenestrations Associated with VHL Gene Alteration is a Potent Target of Anti-VEGF Therap; Role of Pregnancy on Hemangioblastomas in von Hippel-Lindau Disease: a Retrospective French Study; An Evaluation of the Danish National Clinical Guidelines for Von Hippel-Lindau (VHL); Vitreoretinal Surgery for Severe Retinal Capillary Hemangiomas; Oncololytic Targeting of Renal Cell Carcinoma via Encephalomyocarditis Virus; Emerging Therapeutic Options for VHL Patients: a Tale of three Studies; Altering the Stability of Mutant VHL: Potential Therapeutic Consequences; Tale of the Tail: Clinical and Functional Properties of Novel VHL Mutation (X214L) Consistent with Type 2A Phenotype and Low Risk of Renal Cell Carcinoma; Knife for Intracranial Hemangioblastomas in von Hippel-Lindau Patients. When and How?; VHL in Brazil: Genetics, Biobanking and VHL Family Care; Understanding VHL Disease: Molecular Characterization of a Spanish Series; Case Report: Radiosurgery for Endolymphatic Sac Tumor in a Patient with von Hippel-Lindau Disease; Primary Cilium: a Tumor Suppressor Organelle.

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Yang, Zhizhou, Jorge G. Zarate Rodriguez, Haley Beck, Kathleen Byrnes, Nikolaos A. Trikalinos, and Chet W. Hammill. "Acinar cell carcinoma with PRKAR1A and PTEN alterations and paraneoplastic panniculitis." BMJ Case Reports 15, no. 12 (December 2022): e251400. http://dx.doi.org/10.1136/bcr-2022-251400.

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Pancreatic acinar cell carcinoma is a rare type of pancreatic malignancy, which can be confused with pancreatic neuroendocrine neoplasm. Here, we describe a woman in her 80s who presented with abdominal pain and bilateral lower extremity panniculitis. She underwent surgery for a presumed diagnosis of neuroendocrine tumour with PTEN and PRKAR1A alterations; 19 months, later, a recurrence of her pancreatic malignancy was discovered. The patient underwent repeat resection and this time immunohistochemical staining confirmed the diagnosis of acinar cell carcinoma. Staining for acinar cell carcinoma should be prompted based on clinical suspicion in context of PTEN or PRKAR1A mutation when appropriate.

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Cros, Jerôme, Nathalie Théou-Anton, Valérie Gounant, Remy Nicolle, Cécile Reyes, Sarah Humez, Ségolène Hescot, et al. "Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology." Neuroendocrinology 111, no. 1-2 (February 3, 2020): 158–69. http://dx.doi.org/10.1159/000506292.

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Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). Results: Genomic patterns were heterogeneous ranging from “quiet” to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6–17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating “neuroendocrine carcinoma-like” genetic alterations through progression such as TP53/RB1 alterations. Conclusion: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.

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Singhi, Aatur D., Philip J. Stephens, Jeffrey S. Ross, Vincent A. Miller, Siraj Mahamed Ali, and Alexa Betzig Schrock. "Utility of comprehensive genomic profiling (CGP) to distinguish neoplasms pathologically diagnosed as PanNETs and PanNECs and identify potentially actionable genomic alterations (GA)." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 274. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.274.

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274 Background: The majority of pancreatic neuroendocrine neoplasms are classified as pancreatic neuroendocrine tumors (PanNETs) or carcinomas (PanNECs). These are distinct entities with respect to clinical presentation, prognosis and treatment; however, locally advanced/metastatic cases may exhibit overlapping histopathologic features and, thus are challenging to differentiate and may result in inappropriate management. Recent sequencing studies have identified key differences between PanNETs and PanNECs. PanNECs often harbor recurrent GA in RB1, and members of the RAS/MAPK and TGF-β pathways. In contrast, PanNETs frequently exhibit GA in chromatin remodeling genes (e.g., MEN1, DAXX and ATRX). The purpose of this study was to evaluate the utility of CGP in the pathologic assessment of locally advanced/metastatic pancreatic neuroendocrine neoplasms. Methods: Hybrid-capture based CGP was performed for up to 315 cancer-related genes and intronic regions of up to 28 genes rearranged in cancer on 318 locally advanced/metastatic pancreatic neuroendocrine neoplasms. Results were correlated with submitting histopathologic diagnoses. Results: Among 50 pathologically-classified PanNETs, 41 (82%) and 9 (18%) cases harbored GA consistent with a PanNET and PanNEC, respectively. In comparison, among 268 pathologically-classified PanNECs, 209 (78%) and 59 (22%) cases had GA compatible with a PanNET and PanNEC, respectively. Commonly altered genes in CGP-classified PanNETs include: MEN1 (37%), DAXX (21%), CDKN2A/B (20%), ATRX (11%), TSC2 (10%), TP53 (8%), PTEN (8%), ARID1A (7%) and SETD2 (5%). Defects in the BRCA pathway were seen in 10% of PanNETs. Conversely, CGP-classified PanNECs had GA in TP53 (54%), RB1 (49%), KRAS (46%), CDKN2A/B (21%), GNAS (10%), PTEN (9%), SMAD4 (7%), MYC (7%) and ARID1A (6%). Conclusions: Pathologic discrimination between PanNETs and PanNECs can be difficult, but incorporating CGP improves the classification of these neoplasms. Further, the identification of recurrent GA in members of the BRCA family highlights a potential therapeutic target for locally advanced/metastatic PanNETs.

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Yachida, Shinichi, Yasushi Totoki, Michaël Noë, Yoichiro Nakatani, Masafumi Horie, Kenta Kawasaki, Hiromi Nakamura, et al. "Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System." Cancer Discovery 12, no. 3 (March 1, 2022): 692–711. http://dx.doi.org/10.1158/2159-8290.cd-21-0669.

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Abstract The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer. Significance: GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic and epigenomic features. This article is highlighted in the In This Issue feature, p. 587

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Maharjan, Chandra K., Po Hien Ear, Catherine G. Tran, James R. Howe, Chandrikha Chandrasekharan, and Dawn E. Quelle. "Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets." Cancers 13, no. 20 (October 12, 2021): 5117. http://dx.doi.org/10.3390/cancers13205117.

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Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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Perera, Sheron, Robert Edward Denroche, Spring Holter, Deirdre Kelly, Amy Zhang, Yifan Wang, Anna Dodd, et al. "Genomic characterization of ATM alterations in advanced pancreatic ductal adenocarcinoma (PDAC)." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 396. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.396.

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396 Background: BRCA1/2 and PALB2 are genes critical to the faithful repair of double strand breaks through the homologous recombination repair (HRR) pathway. Alterations in these genes serve as predictive biomarkers to both platinum and PARP inhibitors. Ataxia-telangiectasia mutated ( ATM) is also indirectly involved in HRR; however, its role as a predictive biomarker to DNA damage response agents is debated. Herein we evaluated the genomic characteristics and clinical outcomes of patients with ATM alterations on the Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection (COMPASS) trial. Methods: Patients on this study undergo a biopsy for whole genome sequencing (WGS) and RNA sequencing prior to chemotherapy; those with germline variants in ATM were reviewed by a genetics counsellor and defined as pathogenic, likely pathogenic, variant of unknown significance (VUS) or benign/likely benign. Genomic characteristics were reviewed and published classifiers of homologous recombination deficiency (HRD) were applied to all cases and included the percentage of substitution base signature (SBS) 3, the HRDetect score, the computed algorithm of large scale transitions, telomeric allelic imbalances and loss of heterozygosity (LOH), otherwise known as the genomic instability score (GIS). Results: As of January 2020, 304 patients were enrolled and 245 patients had both WGS and clinical data available. 86 germline variants in ATM were present in 70 patients. The majority of these (80%) were classified as benign or likely benign. 10 VUS were detected and 4 patients (2%) had pathogenic/likely pathogenic variants (PV). Of these 4 patients, LOH or a second somatic hit was evident in 1 case. Upon review of the PVs and VUS, SBS were consistent with typical PDAC and tumour mutational burden was low. HRDetect scores were low ( < 0.1) for 13/14 cases with either a VUS or PV; one VUS without biallelic loss, had a high HRDetect score, with presence of SBS 3 and a high GIS. This particular case was also found to have a tandem duplicator phenotype. None of the 4 cases with PV had evidence of HRD. Furthermore all four were treated with platinum based regimens without evidence of response. Conclusions: In a large series of sequenced pancreatic cancers, the presence of pathogenic germline variants in ATM was rare, with none of the cases demonstrating evidence of HRD. This suggests that this population is unlikely to benefit from PARP inhibition.

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Lawrence, B., C. Blenkiron, K. Parker, S. Fitzgerald, P. Shields, P. Tsai, S. James, et al. "Pancreatic neuroendocrine tumour (pNET) profiles in the NETwork! programme: clinic–enabled genomics for genomic-enabled clinical decisions." Annals of Oncology 27 (October 2016): vi137. http://dx.doi.org/10.1093/annonc/mdw369.03.

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Gaspar, Tiago Bordeira, Sofia Macedo, Ana Sá, Mariana Alves Soares, Daniela Ferreira Rodrigues, Mafalda Sousa, Nuno Mendes, et al. "Characterisation of an Atrx Conditional Knockout Mouse Model: Atrx Loss Causes Endocrine Dysfunction Rather Than Pancreatic Neuroendocrine Tumour." Cancers 14, no. 16 (August 10, 2022): 3865. http://dx.doi.org/10.3390/cancers14163865.

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ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.

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Ishida, Hirotaka, and Alfred King-yin Lam. "Pancreatic neuroendocrine neoplasms: Updates on genomic changes in inherited tumour syndromes and sporadic tumours based on WHO classification." Critical Reviews in Oncology/Hematology 172 (April 2022): 103648. http://dx.doi.org/10.1016/j.critrevonc.2022.103648.

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Kafita, Doris, Panji Nkhoma, Mildred Zulu, and Musalula Sinkala. "Proteogenomic analysis of pancreatic cancer subtypes." PLOS ONE 16, no. 9 (September 10, 2021): e0257084. http://dx.doi.org/10.1371/journal.pone.0257084.

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Pancreatic cancer remains a significant public health problem with an ever-rising incidence of disease. Cancers of the pancreas are characterised by various molecular aberrations, including changes in the proteomics and genomics landscape of the tumour cells. Therefore, there is a need to identify the proteomic landscape of pancreatic cancer and the specific genomic and molecular alterations associated with disease subtypes. Here, we carry out an integrative bioinformatics analysis of The Cancer Genome Atlas dataset, including proteomics and whole-exome sequencing data collected from pancreatic cancer patients. We apply unsupervised clustering on the proteomics dataset to reveal the two distinct subtypes of pancreatic cancer. Using functional and pathway analysis based on the proteomics data, we demonstrate the different molecular processes and signalling aberrations of the pancreatic cancer subtypes. In addition, we explore the clinical characteristics of these subtypes to show differences in disease outcome. Using datasets of mutations and copy number alterations, we show that various signalling pathways previously associated with pancreatic cancer are altered among both subtypes of pancreatic tumours, including the Wnt pathway, Notch pathway and PI3K-mTOR pathways. Altogether, we reveal the proteogenomic landscape of pancreatic cancer subtypes and the altered molecular processes that can be leveraged to devise more effective treatments.

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Espiau-Romera, Pilar, Sarah Courtois, Beatriz Parejo-Alonso, and Patricia Sancho. "Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification." Journal of Clinical Medicine 9, no. 12 (December 21, 2020): 4128. http://dx.doi.org/10.3390/jcm9124128.

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Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is an extremely lethal disease due to late diagnosis, aggressiveness and lack of effective therapies. Considering its intrinsic heterogeneity, patient stratification models based on transcriptomic and genomic signatures, with partially overlapping subgroups, have been established. Besides molecular alterations, PDAC tumours show a strong desmoplastic response, resulting in profound metabolic reprogramming involving increased glucose and amino acid consumption, as well as lipid scavenging and biosynthesis. Interestingly, recent works have also revealed the existence of metabolic subtypes with differential prognosis within PDAC, which correlated to defined molecular subclasses in patients: lipogenic subtype correlated with a classical/progenitor signature, while glycolytic tumours associated with the highly aggressive basal/squamous profile. Bioinformatic analyses have demonstrated that the representative genes of each metabolic subtype are up-regulated in PDAC samples and predict patient survival. This suggests a relationship between the genetic signature, metabolic profile, and aggressiveness of the tumour. Considering all this, defining metabolic subtypes represents a clear opportunity for patient stratification considering tumour functional behaviour independently of their mutational background.

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Lamarca, Angela, Melissa Frizziero, Jorge Barriuso, Zainul Kapacee, Wasat Mansoor, Mairéad G. McNamara, Richard A. Hubner, and Juan W. Valle. "Molecular Profiling of Well-Differentiated Neuroendocrine Tumours: The Role of ctDNA in Real-World Practice." Cancers 14, no. 4 (February 17, 2022): 1017. http://dx.doi.org/10.3390/cancers14041017.

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Background: The role of tumour genomic profiling in the clinical management of well-differentiated neuroendocrine tumours (WdNETs) is unclear. Circulating tumour DNA (ctDNA) may be a useful surrogate for tumour tissue when the latter is insufficient for analysis. Methods: Patients diagnosed with WdNETs underwent ctDNA genomic profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly-differentiated neuroendocrine carcinoma) were used for comparison. The aim was to determine the rate of: test failure (primary end-point), “pathological alterations” (PAs) (secondary end-point) and patients for whom ctDNA analysis impacted management (secondary end-point). Results: Forty-five patients were included. A total of 15 patients with WdNETs (18 ctDNA samples) were eligible: 8 females (53.3%), median age 63.2 years (range 23.5–86.8). Primary: small bowel (8; 53.3%), pancreas (5; 33.3%), gastric (1; 6.7%) and unknown primary (1; 6.7%); grade (G)1 (n = 5; 33.3%), G2 (9; 60.0%) and G3 (1; 6.7%); median Ki-67: 5% (range 1–30). A total of 30 patients with non-WdNETs (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs. 17.65% in non-WdNETs; p-value 0.395). Of the 13 WdNET samples with successful ctDNA analyses, PAs were detected in 6 (46.15%) (vs. 82.14% in non-WdNETs; p-value 0.018). In WdNETs, the PA rate was independent of concomitant administration anti-cancer systemic therapies (2/7; 28.57% vs. 4/6; 66.67%; p-value 0.286) at the time of the ctDNA analysis: four, one and one samples had one, two and three PAs, respectively. These were: CDKN2A mutation (mut) (one sample), CHEK2mut (one), TP53mut (one), FGFR2 amplification (one), IDH2mut (one), CTNNB1mut (one), NF1mut (one) and PALB2mut (one). None were targetable (0%) or impacted clinical management (0%). There was a lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs. non-WdNETs (mean 26.99), even though differences did not reach statistical significance (p-value 0.0584). Conclusions: Although feasible, mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. The rates of PAs and mMAFs were higher in non-WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding the likelihood of the results impacting their treatment.

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Pea, Antonio, Jun Yu, Luigi Marchionni, Claudio Luchini, Michael Noe, Neda Rezaee, Claudio Bassi, et al. "Comparative genomic analysis on well-differentiated pancreatic neuroendocrine tumors with small size (< 3cm) reveals genetic alterations associated with distant metastases." Pancreatology 17, no. 3 (July 2017): S5—S6. http://dx.doi.org/10.1016/j.pan.2017.05.017.

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Mishra, Amrendra, Fatemeh Emamgholi, Zulrahman Erlangga, Björn Hartleben, Kristian Unger, Katharina Wolff, Ulrike Teichmann, et al. "Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing." Carcinogenesis 41, no. 3 (June 6, 2019): 334–44. http://dx.doi.org/10.1093/carcin/bgz108.

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Abstract Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.

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Andersson, Ellinor, Christina Swärd, Göran Stenman, Håkan Ahlman, and Ola Nilsson. "High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids." Endocrine-Related Cancer 16, no. 3 (September 2009): 953–66. http://dx.doi.org/10.1677/erc-09-0052.

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Ileal carcinoids are malignant neuroendocrine tumours of the small intestine. The aim of this study was to obtain a high-resolution genomic profile of ileal carcinoids in order to define genetic changes important for tumour initiation, progression and survival. Forty-three patients with ileal carcinoids were investigated by high-resolution array-based comparative genomic hybridization. The average number of copy number alterations (CNAs) per tumour was 7.1 (range 1–22), with losses being more common than gains (ratio 1.4). The most frequent CNA was loss of chromosome 18 (74%). Other frequent CNAs were gain of chromosome 4, 5, 14 and 20, and loss of 11q22.1–q22.2, 11q22.3–q23.1 and 11q23.3, and loss of 16q12.2–q22.1 and 16q23.2-qter. Two distinct patterns of CNAs were found; the majority of tumours was characterized by loss of chromosome 18 while a subgroup of tumours had intact chromosome 18, but gain of chromosome 14. Survival analysis, using a series of Poisson regressions including recurrent CNAs, demonstrated that gain of chromosome 14 was a strong predictor of poor survival. In conclusion, high-resolution profiling demonstrated two separate patterns of CNAs in ileal carcinoids. The majority of tumours showed loss of chromosome 18, which most likely represents a primary event in the development and pathogenesis of tumours. A different genetic pathway is operative in a subgroup of tumours; this is characterized by gain of chromosome 14 and is strongly associated with poor prognosis. Predictive fluorescence in situ hybridization analysis of chromosome 14 status in patients with ileal carcinoids is suggested.

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Nicolle, Remy, Jerome Raffenne, Valerie Paradis, Anne Couvelard, Aurelien de Reynies, Yuna Blum, and Jerome Cros. "Prognostic Biomarkers in Pancreatic Cancer: Avoiding Errata When Using the TCGA Dataset." Cancers 11, no. 1 (January 21, 2019): 126. http://dx.doi.org/10.3390/cancers11010126.

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Data from the Cancer Genome Atlas (TCGA) are now easily accessible through web-based platforms with tools to assess the prognostic value of molecular alterations. Pancreatic tumors have heterogeneous biology and aggressiveness ranging from the deadly adenocarcinoma (PDAC) to the better prognosis, neuroendocrine tumors. We assessed the availability of the pancreatic cancer TCGA data (TCGA_PAAD) from several repositories and investigated the nature of each sample and how non-PDAC samples impact prognostic biomarker studies. While the clinical and genomic data (n = 185) were fairly consistent across all repositories, RNAseq profiles varied from 176 to 185. As a result, 35 RNAseq profiles (18.9%) corresponded to a normal, inflamed pancreas or non-PDAC neoplasms. This information was difficult to obtain. By considering gene expression data as continuous values, the expression of the 5312 and 4221 genes were significantly associated with the progression-free and overall survival respectively. Considering the cohort was not curated, only 4 and 14, respectively, had prognostic value in the PDAC-only cohort. Similarly, mutations in key genes or well-described miRNA lost their prognostic significance in the PDAC-only cohort. Therefore, we propose a web-based application to assess biomarkers in the curated TCGA_PAAD dataset. In conclusion, TCGA_PAAD curation is critical to avoid important biological and clinical biases from non-PDAC samples.

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Capurso, Gabriele, Stefano Festa, Roberto Valente, Matteo Piciucchi, Francesco Panzuto, Robert T. Jensen, and Gianfranco Delle Fave. "Molecular pathology and genetics of pancreatic endocrine tumours." Journal of Molecular Endocrinology 49, no. 1 (May 14, 2012): R37—R50. http://dx.doi.org/10.1530/jme-12-0069.

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Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel–Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.

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Heymann, Jonas J., and Momin T. Siddiqui. "Ancillary Techniques in Cytologic Specimens Obtained from Solid Lesions of the Pancreas: A Review." Acta Cytologica 64, no. 1-2 (April 10, 2019): 103–23. http://dx.doi.org/10.1159/000497153.

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Advanced methods of molecular characterization have elucidated the genetic, epigenetic, and proteomic alterations associated with the broad spectrum of pancreatic disease, particularly neoplasia. Next-generation sequencing, in particular, has revealed the genomic diversity among pancreatic ductal adenocarcinoma, neuroendocrine and acinar tumors, solid pseudopapillary neoplasm, and other pancreatico-biliary neoplasms. Differentiating these entities from one another by morphologic analysis alone may be challenging, especially when examining the small quantities of diagnostic material inherent to cytologic specimens. In order to enhance the sensitivity and specificity of pancreatic cytomorphology, multiple diagnostic, prognostic, and predictive ancillary tests have been and continue to be developed. Although a great number of such tests have been developed for evaluation of specimens collected from cystic lesions and strictures, ancillary techniques also play a significant role in the evaluation of cytologic specimens obtained from solid lesions of the pancreas. Furthermore, while some tests have been developed to differentiate diagnostic entities from one another, others have been developed to simply identify dysplasia and malignancy. Ancillary studies are particularly important in the subset of cases for which cytomorphologic analysis provides a result that is equivocal or insufficient to guide clinical management. Selection of appropriate ancillary testing modalities requires familiarity with both their methodology and the molecular basis of the pancreatic diseases for which testing is being performed.

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Arnes, Luis, Zhaoqi Liu, Jiguang Wang, Carlo Maurer, Irina Sagalovskiy, Marta Sanchez-Martin, Nikhil Bommakanti, et al. "Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma." Gut 68, no. 3 (February 10, 2018): 499–511. http://dx.doi.org/10.1136/gutjnl-2017-314353.

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ObjectivePancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome.DesignWe developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA.ResultsWe generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673andFAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines.ConclusionsOur findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.

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Lui, Goldie Y. L., Carla Grandori, and Christopher J. Kemp. "CDK12: an emerging therapeutic target for cancer." Journal of Clinical Pathology 71, no. 11 (August 13, 2018): 957–62. http://dx.doi.org/10.1136/jclinpath-2018-205356.

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Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3’ end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.

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Hong, Xiafei, Sitan Qiao, Fuqiang Li, Wenze Wang, Rui Jiang, Huanwen Wu, Hao Chen, et al. "Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system." Gut 69, no. 5 (August 28, 2019): 877–87. http://dx.doi.org/10.1136/gutjnl-2018-317233.

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ObjectiveInsulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES) to identify genetic differences between insulinomas and NF-PanNETs.DesignThe mutational profiles and copy-number variation (CNV) patterns of 211 PanNETs, including 84 insulinomas and 127 NF-PanNETs, were obtained from WGS/WES data provided by Peking Union Medical College Hospital and the International Cancer Genome Consortium. Insulinoma RNA sequencing and immunohistochemistry data were assayed.ResultsPanNETs were categorised based on CNV patterns: amplification, copy neutral and deletion. Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. In contrast, NF-PanNETs had all three CNV patterns, and NF-PanNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes. NF-PanNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period.ConclusionThese WGS/WES data allowed a comprehensive assessment of genetic differences between insulinomas and NF-PanNETs, reclassifying these tumours into novel molecular subtypes. We also proposed a novel relapse risk stratification system using CNV patterns and DAXX/ATRX mutations.

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Korpershoek, Esther, Nanne K. Kloosterhof, Angelique Ziel-van der Made, Hanneke Korsten, Lindsey Oudijk, Jan Trapman, Winand N. M. Dinjens, and Ronald R. de Krijger. "Trp53 inactivation leads to earlier phaeochromocytoma formation in pten knockout mice." Endocrine-Related Cancer 19, no. 6 (August 28, 2012): 731–40. http://dx.doi.org/10.1530/erc-12-0088.

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Phaeochromocytomas (PCCs) are benign neuroendocrine tumours of the adrenal medulla. Approximately 10% of PCC patients develop metastases, but this frequency is much higher in specific subtypes of patients. The reliable diagnosis of malignant PCC can only be made after identification of a metastasis. To study the effect of Trp53 inactivation on PCC pathogenesis in Pten KO mice, we investigated the adrenals of a large cohort of mice with conditional monoallelic and biallelic inactivation of Trp53 and Pten. The adrenal weights were determined for all mice, and in a proportion of these mice, immunohistochemistry for tyrosine hydroxylase and dopamine β-hydroxylase was performed on the adrenals and corresponding lungs. Finally, comparative genomic hybridization (CGH) was performed. The histological and immunohistochemical results confirmed that the adrenal tumours were PCCs. Inactivation of one or both alleles of Trp53 resulted in earlier tumour occurrence in the PtenloxP/loxP mice as well as in the PtenloxP/+ mice. In addition, lung metastases were found in up to 67% of mice. The CGH results showed that the most frequent genomic alterations were loss of chromosome 19 (86%) and gain of chromosome 15 (71%). In this study, we have shown that Pten/Trp53 KO mice showed metastatic PCC at high frequency and primary tumours occurred at younger ages in mice with Trp53 inactivation. Therefore, the present model appears to be a suitable model that might allow the preclinical study of new therapeutics for these tumours.

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Catenacci, Daniel V. T., Emma Green, Michael Epstein, Greg Jones, Clive D. Morris, Emily O'Day, S. Lomnicki, Melissa Maranto, Theodore G. Karrison, and Hedy L. Kindler. "Molecular profiling of advanced pancreatic cancer (PC) patients from a phase I/II study using circulating tumor DNA." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4124. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4124.

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4124 Background: PC has a poor prognosis with a 5-year survival of 9%. Targeted therapies have yet to demonstrate improved outcomes in this disease. Circulating tumour DNA (ctDNA) may be used as a non-invasive method for the detection and quantification of genomic abnormalities. We performed a retrospective-prospective study to assess molecular alterations in the ctDNA of advanced PC patients. Methods: Plasma samples were banked from patients enrolled in the previously reported Phase Ib/II trial of gemcitabine with placebo or vismodegib (NCT01064622; Catenacci et al JCO 2015). Eligible patients had unresectable PC and no prior therapy for metastatic disease. Patient samples ( < 3ml) collected pre-treatment and at regular intervals and stored for ~6-8 years were analyzed using InVision (enhanced tagged-amplicon sequencing) for “hotspot” regions of 34 genes, including KRAS (exons 2 and 3), and select full gene coverage. Results: Of 113 patients enrolled in the trial, a cohort of 72 patients were included in this study. Baseline plasma ctDNA profiling detected any genomic event in 88% of patients (SNV/indels found at range of 0.07%-23% allele fraction (AF) with 20% detected at < 0.5% AF). Patients had between 1-5 mutations (median, 2): KRAS mutations were detected in 80% of patients tested, of which 86% had concurrent KRAS/TP53 mutation(s) and 16% with concurrent KRAS/TP53/CDK2NA. Of note, 2 cases presented with IDH1 point mutations (R132C, R132H). An ERBB2 amplification and a FGFR2 amplification were detected in 2 individuals. An update on the analyses will include serial ctDNA testing during treatment and correlation with outcomes. Conclusions: ctDNA analysis of this cohort of banked PC plasma samples described the landscape of genomic aberrations at baseline and over time, including rare but potentially important actionable events including ERBB2 and FGFR2 amplifications and IDH1 mutation. We demonstrate a sensitive method for re-analysing trial outcomes, despite limiting plasma volume and time lapse since samples were collected.

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McNamara, Mairéad G., Jean-Yves Scoazec, and Thomas Walter. "Extrapulmonary poorly differentiated NECs, including molecular and immune aspects." Endocrine-Related Cancer 27, no. 7 (July 2020): R219—R238. http://dx.doi.org/10.1530/erc-19-0483.

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Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.

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Aijazi, Muaz, Aatur Singhi, Michael A. Nalesnik, Roderick O'Sullivan, Somak Roy, Kenneth Lee, Nathan Bahary, et al. "374 A SYSTEMATIC EVALUATION OF CELL LINEAGE AMONG NONFUNCTIONAL PANCREATIC NEUROENDOCRINE TUMORS (PANNETS) AND THEIR RELATIONSHIP TO GENOMIC ALTERATIONS ASSOCIATED WITH METASTATIC DISEASE AND POOR PATIENT SURVIVAL." Gastroenterology 158, no. 6 (May 2020): S—69. http://dx.doi.org/10.1016/s0016-5085(20)30852-0.

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Huynh, C., E. Clement, D. DeGirolamo, A. Kleiman, R. Ralph-Edwards, L. Streith, J. Bogach, et al. "Canadian Surgery Forum 201901. The future of general surgery training: a Canadian resident nationwide Delphi consensus statement02. Traumatized: Can mindfulness lead to improved mental health outcomes after multisystem trauma?03. Operating room availability for general surgery in 2007 versus 2017 at a regional hospital in BC04. Perceptions and barriers to Gastrografin protocol implementation05. Resident opinions and educational experience of a mixed night-float system for general surgery resident call06. A scoping review of best management for hepato-pancreatobiliary trauma07. Simultaneous versus staged resection for synchronous colorectal liver metastases: a population-based cohort study08. Weight loss following hepatopancreatobiliary surgery. How much is too much?09. Uptake and patient outcomes of laparoscopic liver resection for colon cancer liver metastases: a population-based analysis10. Simultaneous resection of colorectal cancer with synchronous liver metastases: a survey-based analysis11. When is it safe to start VTE prophylaxis after blunt solid organ injury? A prospective study from a level I trauma centre12. Undertriaged trauma patients: Who are we missing?13. Trauma team activation at a level I trauma centre: time of day matters14. The diagnostic dilemma of shotgun injuries15. Evaluating the efficacy of self-study videos for the surgery clerkship rotation: an innovative project in undergraduate surgical education16. Systematic review and meta-analysis: preoperative anti-TNF therapy does not increase the risk of postoperative complications in patients with inflammatory bowel disease undergoing elective surgery17. Simulation platforms to assess laparoscopic suturing skills: a scoping review18. Cost analysis of simultaneous versus staged resection of colorectal cancer liver metastases: a population-based study19. Complementary and alternative medicine use among general surgery patients in Nova Scotia20. General surgery in Canada: current scope of practice and future needs21. Impact of dedicated operating time on access to surgical care in an acute care surgery model22. Adolescent appendicitis management and outcomes: comparison study between adult and pediatric institutions23. A systematic review of behavioural interventions to improve opioid prescribing after surgery24. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in trauma: a gap analysis of the Edmonton Zone Trauma Registry25. Learning by holographic anatomic models for surgical education26. The nature of learning from trauma team simulation27. Comparing reversing half-hitch alternating postsurgical knots and square knots for closure of enterotomy in a simulated deep body cavity: a randomized controlled trial28. Propagating the “SEAD”: exploring the value of an overnight call shift in the Surgical Exploration and Discovery Program29. Comparing 2 approaches to residency application file review30. A Canadian experience with posterior retroperitoneoscopic adrenalectomy31. A cost-efficient, realistic breast phantom for oncoplastic breast surgery training32. Impact of patient frailty on morbidity and mortality after common emergency general surgery operations33. Preventing opioid prescription after major surgery: a scoping review of the literature on opioid-free analgesia34. Correct usage of propensity score methodology in contemporary high-impact surgical literature35. Responsible blood compatibility testing for appendectomy: practice assessment at a single Canadian academic centre36. What patient factors are associated with participation in a provincial colorectal cancer screening program?37. Missed appendix tumours owing to nonoperative management for appendicitis38. Operative delay increases morbidity and mortality in emergency general surgery patients: a study of multiple EGS services within a single city39. Withdrawn40. Improved disease-free survival after prehabilitation for colorectal cancer surgery41. Development of a conceptual framework of recovery after abdominal surgery42. Comparison of Dor and Nissen fundoplication following laparoscopic paraesophageal hernia repair43. A systematic review and summary of clinical practice guidelines on the periprocedural management of patients on antithrombotic medications undergoing gastroenterological endoscopy44. Impact of socioeconomic status on postoperative complications following Whipple procedure for pancreatic ductal adenocarcinoma45. Clinical outcomes of high-risk breast lesions and breast cancer patients treated with total mastectomy and immediate reconstruction46. My On Call (MOC) Pager App: practising and assessing safe clinical decision-making47. Comprehensive complication index for major abdominal surgeries: an external validation using the American College of Surgeons’ National Surgical Quality Improvement Program (ACS NSQIP)48. The impact of surgeon experience on script concordance test scoring49. Decay of competence with extended research absences during postgraduate residency training: a scoping review50. Long-term outcomes of elderly patients managed nonoperatively for choledocholithiasis51. Predictors of mortality and cost among surgical patients admitted to hospital and requiring rapid response team activation52. Sex-based disparities in the hourly earnings of surgeons in Ontario’s fee-for-service system53. Outcomes of intestinal ischemia among patients undergoing cardiac surgery54. Factors influencing resident teaching evaluations: the relationship between resident interest in teaching, career plan, training level and their performance in teaching junior learners55. Validating a uniform system for measuring disease severity in acute colonic diverticulitis56. Active negative pressure peritoneal therapy and C-reactive protein (CRP) levels after abbreviated laparotomy for abdominal trauma or intraabdominal sepsis: the validity of serum and peritoneal CRP in measuring outcomes in critically ill patients57. Intraoperative use of indocyanine green fluorescence in emergency general surgery: a systematic review58. Is it safe? Nonoperaive management of blunt splenic injuries in geriatric trauma patients59. Bladder injury from laparoscopic appendicectomy: a multicentre experience over 5 years60. Perioperative cardiac investigations for chest pain after parathyroidectomy rarely yield a cardiac diagnosis61. Entero-hepatic axis injury following hemorrhagic shock: a role for uric acid62. Loss of functional independence after emergency abdominal surgery in older patients: a prospective cohort study63. Association between use of nonsteroidal antiinflammatory drugs, diuretics or angiotensin converting enzyme inhibitor/receptor blockers after major surgery and acute kidney injury: a nested, population-based case–control study64. Timing of CT for adhesive small bowel obstructions (SBO)65. The ABDO (Acute Biliary Disease Optimization) Study: improving the management of biliary diseases in emergency general surgery66. Rates and predictors of advanced biliary imaging and interventions in acute care surgery: a quality improvement study67. The use of early warning scores in patients undergoing emergency general surgery: a systematic review68. Does primary closure versus resection and anastomosis in patients with hollow viscus injury affect 30-day mortality?69. Impact of sarcopenia on morbidity and mortality after Whipple procedure for pancreatic ductal adenocarcinoma70. Mind the speaker gap: a cross-specialty analysis of the representation of women at surgical meetings in 5 different geographic regions71. Immediate breast reconstruction in locally advanced breast cancer: Is it safe?72. An administrative review of the incidence of adverse events involving electrocautery73. If you don’t document it, did it really happen? A review of the documentation of informed consent in laparoscopic cholecystectomy74. Can an online module help medical students gain confidence and proficiency in writing orders?75. The influence of undergraduate medical education anatomy exposure on choice of surgical specialty: a national survey76. Association between patient engagement and surgical outcomes: a pilot study77. Guidelines on the intraoperative transfusion of red blood cells: a systematic review78. Cancer is common in missed appendicitis: a retrospective cohort study79. Everyone is awesome: analyzing letters of reference in a general surgery residency selection process80. Evaluating the true additional costs of general surgery complications using a propensity score weighted model81. Deriving literature-based benchmarks for surgical complications from national databases in high-income countries: a systematic review on pancreatectomy outcomes82. The impact of distance on postoperative follow-up in pediatric general surgery patients: a retrospective review83. Water-soluble contrast in adhesive small bowel obstruction management: a Canadian centre’s experience84. Recognizing predatory journals in general surgery and their common violations85. Prophylactic negative pressure wound therapy for closed laparotomy incisions: a meta-analysis of randomized controlled trials86. Choosing Wisely Canada: 2019 general surgery recommendations87. Content-specific resident teaching can improve medical student learning outcomes on certifying examinations88. Transition to practice: preparedness for independent practice in general surgery graduates89. CAGS Exam 2.0: maximizing the potential for teaching and learning90. Resident attitudes toward the introduction of synoptic operative reporting for appendectomy and cholecystectomy91. Determining the individual, hospital and environmental cost of unnecessary laboratory investigations for patients admitted to general surgery services at an academic centre92. Gender-based compensation disparity among general surgeons in British Columbia93. Transgastric robotic resection for gastrointestinal stromal tumours of the stomach94. Recurrent gallstone ileus after laparoscopic-assisted enterolithotomy treated with totally laparoscopic enterolithotomy01. Predictors and outcomes among patients requiring salvage APR for the treatment of squamous cell carcinoma of the anus: a population-based study02. Short-course radiotherapy with perioperative systemic chemotherapy for patients with rectal cancer and synchronous resectable liver metastases: a single-centre Canadian experience03. Compliance with preoperative elements of the American Society of Colon and Rectal Surgeons rectal cancer surgery checklist improves pathologic and postoperative outcomes04. Clinical predictors of pathologic complete response following neoadjuvant chemoradiation therapy for rectal cancer: a systematic review and meta-analysis05. Rejected06. The impact of laparoscopic technique on the rate of perineal hernia after abdominoperineal resection of the rectum07. An assessment of the current perioperative practice, barriers and predictors for utilization of enhanced recovery after surgery protocols: a provincial survey08. Regional variation in the utilization of laparoscopy for the treatment of rectal cancer: the importance of fellowship training sites09. Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy: a systematic review and meta-analysis10. The relation between the gut microbiota and anastomotic leak in patients with colorectal cancer: a preliminary feasibility study11. Optimizing discharge decision-making in colorectal surgery: an audit of discharge practices in a newly implemented enhanced recovery pathway12. Trends in colectomy for colorectal neoplasms in ulcerative colitis (UC) patients over 2 decades: a National Inpatient Sample database analysis13. Spin in minimally invasive transanal total mesorectal excision articles (TaTME): an assessment of the current literature14. Venous thromboembolism (VTE) in colon cancer: a population-based cohort study of VTE rates following surgery and during adjuvant chemotherapy15. Robotic-assisted lateral lymph node dissection for rectal neuroendocrine tumor16. Loop ileostomy and colonic lavage as an alternative to colectomy for fulminant Clostridium difficile colitis17. Recurrent diverticulitis: Is it all in the family?18. Le traitement des fistules entérocutanées complexes : expérience du Centre hospitalier de l’Université de Montréal (CHUM)19. A North American single-blinded pilot randomized controlled trial for outpatient nonantibiotic management of acute uncomplicated diverticulitis (MUD TRIAL): feasibility and lessons learned20. Treatment failure after conservative management of acute diverticulitis: a nationwide readmission database analysis21. Impact of immunosuppression on mortality and major morbidity following sigmoid colectomy for diverticulitis: a propensity-score weighted analysis of the National Inpatient Sample22. Presentation and survival in colorectal cancer under 50 years of age: a systematic review and meta-analysis23. Genetics of postoperative recurrence of Crohn’s disease: a systematic review and meta-analysis24. Improving the identification and treatment of preoperative anemia in patients undergoing elective bowel resection25. Impact of postoperative complications on quality of life after colorectal surgery26. Colon cancer survival by subsite: a retrospective analysis of the National Cancer Database27. A second opinion for T1 colorectal cancer pathology reports results in frequent changes to clinical management28. Effects of the quadratus lumborum block regional anesthesia on postoperative pain after colorectal resection: a double-blind randomized clinical trial29. Safety of a short-stay postoperative unit for the early discharge of patients undergoing a laparosocpic right hemicolectomy30. What is the optimal bowel preparation to reduce surgical site infection in Crohn disease?31. TaTME surgery and the learning curve: our early experience32. Watch-and-wait experience in patients with rectal cancer: results in selected patients at a high-volume centre01. Automatic referral of suspicious findings detected on thoracic CT scan decreases delays in care without compromising referral quality02. Variation in receipt of therapy and survival with provider volume in noncurative esophagogastric cancer: a population-based analysis03. What makes patients high risk for lobectomy in the era of minimally invasive lobectomy?04. The value proposition of minimally invasive esophagectomy: a community hospital perspective05. Deviation from treatment plan in patients with potentially curable esophageal carcinoma06. Implementation of a standardized minimal opioid prescription for post-thoracic surgery patients is feasible and provides adequate pain control07. Sentinel node navigation surgery using indocyanine green in lung cancer: a systematic review and meta-analysis08. Surgical outcomes with trimodality neoadjuvant versus adjuvant therapy for esophageal cancer: results of the QUINTETT randomized trial09. Enhanced invasive mediastinal staging in an academic thoracic surgical unit by employing a shared accountability model for quality improvement10. Evaluation and harmonization of international database elements for adverse events monitoring following thoracic surgery: the pursuit of a common language11. Endobronchial ultrasound staging of operable non–small cell lung carcinoma: triple-negative lymph nodes may not require routine biopsy12. Wait times in the management of non-small cell lung cancer before, during and after regionalization of lung cancer care: a high-resolution analysis13. Wearable technology for preconditioning before thoracic surgery: a feasibility study14. Impact of carbohydrate-loading enhanced recovery after surgery protocol on adverse cardiopulmonary events in a thoracic surgery population15. Heat production during pulmonary artery sealing with energy vessel-sealing devices in a porcine model16. Who can afford to wait? The effect of wait times on survival in lung cancer patients: clinical predictors of poor outcomes17. Impact of the Integrated Comprehensive Care Program after thoracic surgery: a propensity score matched study18. Incidence, severity and risk of postoperative pulmonary complications in patients undergoing pulmonary resection for cancer19. Evaluation of the limits of use of a thoracoscopic lung palpation device to identify artificial tumour nodules in ex-vivo tissue20. Personalized surgical management of esophagogastric junction cancers21. Validity of a model to predict the risk of atrial fibrillation after thoracic surgery22. Severe symptoms persist for up to 1 year after diagnosis of stage I–III lung cancer: an analysis of province-wide patient-reported outcomes23. Do postoperative infectious adverse events influence cancer recurrence and survival after surgical resection of esophagogastric cancers? Experience from a Canadian university centre24. Utilization, safety and efficacy of hybrid esophagectomy on a population level25. Endoscopic submucosal dissection for upper gastrointestinal neoplasia: lessons learned from a high-volume North American centre26. Long-term quality of life after esophagectomy27. Early and late outcomes after surgery for pT4 NSCLC reclassified by AJCC 8th edition criteria28. Early results on the learning curve for subxiphoid video-assisted thoracoscopic lobectomy29. Should adjuvant therapy be offered for patients undergoing esophagectomy after neoadjuvant CROSS protocol for esophageal cancer? A multicentre cohort study30. Outcomes of patients discharged home with a chest tube following anatomic lung resection: a multicentre cohort study01. Management of cancer-associated intestinal obstruction in the final year of life02. Evaluating the prognostic significance of lymphovascular invasion in stage II and III colon cancer03. A matched case–control study on real-time electromagnetic navigation for breast-conserving surgery using NaviKnife04. Gaps in the management of depression symptom screening following cancer diagnosis: a population-based analysis of prospective symptom screening05. Patterns of symptom burden in neuroendocrine tumours: a population-based analysis of patient-reported outcomes06. Outcomes of salvage surgery for anal canal squamous cell carcinoma: a systematic review and meta-analysis07. Expression of the Plk4 inhibitor FAM46C predicts better survival following resection of gastric adenocarcinoma08. Current treatment strategies and patterns of recurrence in locally advanced colon cancer09. A 5-year retrospective review of outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in a provincial peritoneal malignancy program10. Withdrawn11. Geographic disparities in care and outcomes for noncurative pancreatic adenocarcinoma: a population-based study12. How often is implant-based breast reconstruction following postmastectomy radiation unsuccessful?13. Comparison of partial mastectomy specimen volume and tumour volume following neoadjuvant chemotherapy in breast cancer14. Two-year experience with hookwire localized clipped node and sentinel node as alternative to targeted axillary dissection in a regional centre15. Opioid use among cancer patients undergoing surgery and their associated risk of readmissions and emergency department visits in the 1-year postsurgical period16. Preliminary results of a pilot randomized controlled trial comparing axillary reverse mapping with standard axillary surgery in women with operable breast cancer17. Complementary and alternative medicine among general surgery patients in Nova Scotia18. Improving wait times and patient experience through implementation of a provincial expedited diagnostic pathway for BI-RADS 5 breast lesions19. Population-based regional recurrence patterns in Merkel cell carcinoma: a 15-year review20. Survival and health care cost benefits of high-volume care in the noncurative management of pancreatic adenocarcinoma: a population-based analysis21. Trends in the use of sentinel node biopsy after neoadjuvant chemotherapy in the United States22. Predictors of grossly incomplete resection in primary retroperitoneal sarcoma (RPS)23. Mastectomy versus breast conservation therapy: an examination of how individual, clinicopathologic and physician factors influence decision making24. Immunophenotyping postoperative myeloid-derived suppressor cells in cancer surgery patients25. Adherence to sentinel lymph node biopsy guidelines in the management of cutaneous melanoma in the province of British Columbia26. Breast cancer with supraclavicular and internal mammary node metastases: therapeutic options27. Textbook outcomes and survival in patients with gastric cancer: an analysis of the population registry of esophageal and stomach tumours of Ontario (PRESTO)28. Withdrawn29. Symptomatic bowel complications in patients with metastatic cancer: comparison of surgical versus medical outcomes and development of a prediction model for successful surgical palliation30. Rejected31. Gastric cancer biopsies show distinct biomarker profiles compared with normal gastric mucosa in Canadian patients32. Withdrawn01. Management of high patient-reported pain scores in noncurative pancreatic adenocarcinoma: a population-based analysis02. Outcomes of liver donors with a future liver remnant less than or equal to 30%: a matched-cohort study03. The applicability of intraoperative fluorescent imaging with indocyanine green in hepatic resection for malignancy: a systematic review and meta-analysis04. Impact of adjuvant chemotherapy completion on outcomes following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma05. Primary hepatic acinar cell carcinoma06. Laparoscopic distal pancreatectomy provides equivalent oncologic outcomes for pancreatic ductal adenocarcinoma07. Passive versus active intraabdominal drainage following pancreatic resection: Does a superior drainage system exist? A systematic review and meta-analysis08. Low yield of preoperative MRCP and ERCP in the management of low-intermediate suspicion choledocholithiasis09. Pancreatic cancer resection rates and survival in the United States and Canada10. Prognostic value of immune heterogeneity in colorectal cancer liver metastases11. Impact of intraoperative hypovolemic phlebotomy on blood loss and perioperative transfusion in patients undergoing hepatectomy for cancer12. Prediction of postoperative pancreatic fistula following pancreatectomy: a systematic review of clinical tools13. The impact of preoperative frailty in liver resection: an analysis of the American College of Surgeons’ National Surgical Quality Improvement Program (ACS NSQIP)14. Topical agents as adjuncts in pancreatic surgery for prevention of postoperative pancreatic fistula: a systematic review and meta-analysis15. Phlebotomy resulting in controlled hypovolemia to prevent blood loss in major hepatic resections (PRICE-1): a feasibility randomized controlled trial16. Pylorus-preserving versus classic pancreaticoduodenectomy: a single-centre retrospective review of total lymph node yield17. An audit and evaluation of appropriateness of intraoperative allogenic red blood cell transfusion in liver surgery: application of 3 decision rules18. A comparison of lymph node ratio with AJCC lymph node status for survival after Whipple resection for pancreatic adenocarcinoma19. Duodenopancréatectomie céphalique (intervention de Whipple) par voie laparoscopique pure20. Use of the Molecular Adsorbent Recirculating System (MARS) in acute liver failure: a multicentre experience21. Barriers to adjuvant chemotherapy after resection for pancreatic cancer22. Comparison of primary and metastatic pancreatic cancer by clinical and genomic features23. Factors associated with invasion and postoperative overall survival in resected IPMN01. Incisional hernia repair surgery improves patient-reported outcomes02. Prospective study of single-stage repair of contaminated hernias with the novel use of calcium sulfate antibiotic beads in conjunction with biologic porcine submucosa tissue matrix03. e-TEP transversus abdominus release04. Umbilical hernias05. Review of 1061 femoral hernias done at the Shouldice Hospital over a period of 6 years01. Metabolic outcomes after bariatric surgery for a provincial Indigenous population02. Outcomes of sleeve gastrectomy performed in a regional hospital03. A longitudinal analysis of wait times in a publicly funded, regionalized bariatric care system04. Concurrent laparoscopic ventral hernia repair with bariatric surgery: a propensity-matched analysis05. Outcomes from explantation of laparoscopic adjustable gastric band: experience from a Canadian bariatric centre of excellence06. Development of consensus-derived quality indicators for laparoscopic sleeve gastrectomy07. Conversion of sleeve gastrectomy to laparoscopic Roux-en-Y gastric bypass in intestinal nonrotation08. The utility of routine preoperative upper gastrointestinal series for laparoscopic sleeve gastrectomy09. Body image concerns, depression, suicidality and psychopharmacological changes in postoperative bariatric surgery patients: a mixed-methods study10. Technical factors associated with early sleeve stenosis after sleeve gastrectomy: an analysis of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database11. Analysis of complication and readmission rates after laparoscopic sleeve gastrectomy at a single bariatric surgery centre: a retrospective NSQIP study12. Management of common bile duct stones in patients after Roux-en-Y gastric bypass: a systematic review13. Improvement and resolution of urinary incontinence after bariatric surgery: a systematic review and meta-analysis14. Bridging interventions for weight loss prior to bariatric surgery in patients with superobesity: a systematic review and meta-analysis15. Secondary and tertiary learning curves in bariatric surgery16. Achalasia following laparoscopic sleeve gastrectomy: a case report17. Multidisciplinary approach to halving length of stay after bariatric surgery18. Prospective analysis of staple line haemostatic materials in stapled bariatric surgery19. Barriers and facilitators to managing patients with class II and III obesity in primary care: a qualitative study20. The Edmonton Obesity Staging System predicts risk of postoperative complications and mortality following bariatric surgery21. The impact of attention-deficit/hyperactivity disorder on bariatric surgery outcomes: systematic review and meta-analysis22. The effect of bariatric surgery on migraines: a systematic review and meta-analysis23. A population-based matched cohort study of mortality after bariatric surgery24. Safety and outcomes of bariatric surgery performed at an ambulatory site associated with a tertiary care hospital in Canada25. Race and sex predict adverse outcomes following bariatric surgery: a propensity-matched MBSAQIP analysis26. A survey of primary care physician referral to bariatric surgery: access, perceptions and barriers." Canadian Journal of Surgery 62, no. 4 Suppl 2 (August 2019): S89—S169. http://dx.doi.org/10.1503/cjs.011719.

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Raoul, Jean-Luc, Marie-Françoise Heymann, Frédéric Dumont, Alain Morel, Hélène Senellart, and François Bertucci. "Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components." Frontiers in Oncology 11 (March 31, 2021). http://dx.doi.org/10.3389/fonc.2021.646992.

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Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?

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Pareja, Fresia, Mahsa Vahdatinia, Caterina Marchio, Simon S. K. Lee, Arnaud Da Cruz Paula, Fatemeh Derakhshan, Edaise M. da Silva, et al. "Neuroendocrine tumours of the breast: a genomic comparison with mucinous breast cancers and neuroendocrine tumours of other anatomic sites." Journal of Clinical Pathology, November 4, 2020, jclinpath—2020–207052. http://dx.doi.org/10.1136/jclinpath-2020-207052.

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AimsBreast neuroendocrine tumours (NETs) constitute a rare histologic subtype of oestrogen receptor (ER)-positive breast cancer, and their definition according to the WHO classification was revised in 2019. Breast NETs display histologic and transcriptomic similarities with mucinous breast carcinomas (MuBCs). Here, we sought to compare the repertoire of genetic alterations in breast NETs with MuBCs and NETs from other anatomic origins.MethodsOn histologic review applying the new WHO criteria, 18 breast tumours with neuroendocrine differentiation were reclassified as breast NETs (n=10) or other breast cancers with neuroendocrine differentiation (n=8). We reanalysed targeted sequencing or whole-exome sequencing data of breast NETs (n=10), MuBCs type A (n=12) and type B (n=11).ResultsBreast NETs and MuBCs were found to be genetically similar, harbouring a lower frequency of PIK3CA mutations, 1q gains and 16q losses than ER-positive/HER2-negative breast cancers. 3/10 breast NETs harboured the hallmark features of ER-positive disease (ie, PIK3CA mutations and concurrent 1q gains/16q losses). Breast NETs showed an enrichment of oncogenic/likely oncogenic mutations affecting transcription factors compared with common forms of ER-positive breast cancer and with pancreatic and pulmonary NETs.ConclusionsBreast NETs are heterogeneous and are characterised by an enrichment of mutations in transcription factors and likely constitute a spectrum of entities histologically and genomically related to MuBCs. While most breast NETs are distinct from ER-positive/HER2-negative IDC-NSTs, a subset of breast NETs appears to be genetically similar to common forms of ER-positive breast cancer, suggesting that some breast cancers may acquire neuroendocrine differentiation later in tumour evolution.

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Cives, Mauro, Stefano Partelli, Raffaele Palmirotta, Domenica Lovero, Barbara Mandriani, Davide Quaresmini, Eleonora Pelle’, et al. "DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors." Scientific Reports 9, no. 1 (December 2019). http://dx.doi.org/10.1038/s41598-019-55156-0.

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AbstractManagement of localized well-differentiated pancreatic neuroendocrine tumors (panNETs) is controversial and primarily dependent on tumor size. Upfront surgery is usually recommended for tumors larger than 2 cm in diameter since they frequently show metastatic potential, whereas smaller panNETs are generally characterized by an indolent clinical course, with a rate of relapse or metastasis below 15%. To explore whether increased tumor size is paralleled by genomic variations, we compared the rate and the mutational patterns of putative driver genes that are recurrently altered in these tumors by investigating differential cohorts of panNET surgical specimens smaller (n = 27) or larger than 2 cm (n = 29). We found that the cumulative number of mutations detected in panNETs >2 cm was significantly higher (p = 0.03) relative to smaller tumors, while mutations of DAXX were significantly more frequent in the cohort of larger tumors (p = 0.05). Moreover, mutations of DAXX were associated with features of malignancy including increased grade, nodal involvement and lymphovascular invasion, and independently predicted both relapse after surgery (p = 0.05) and reduced DFS in multivariable analysis (p = 0.02). Our data suggest that alterations of the DAXX/ATRX molecular machinery increase the malignant potential of panNETs, and that identification of mutations of DAXX/ATRX in small, nonfunctioning tumors can predict the malignant progression observed in a minority of them.

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Sausen, Mark, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Michael T. Barrett, Valsamo Anagnostou, et al. "Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients." Nature Communications 6, no. 1 (July 7, 2015). http://dx.doi.org/10.1038/ncomms8686.

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