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Articles de revues sur le sujet "Pancreatic neuroendocrine tumour, genomic alterations"
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Mafficini, Andrea, et Aldo Scarpa. « Genomic landscape of pancreatic neuroendocrine tumours : the International Cancer Genome Consortium ». Journal of Endocrinology 236, no 3 (mars 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 et Ola Nilsson. « The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines ». Endocrine-Related Cancer 25, no 3 (mars 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 et Andrew Eugene Hendifar. « Multi-omic molecular profiling of pancreatic neuroendocrine tumors. » Journal of Clinical Oncology 35, no 15_suppl (20 mai 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 et Pashtoon Murtaza Kasi. « Circulating tumor DNA analysis of neuroendocrine tumors. » Journal of Clinical Oncology 37, no 15_suppl (20 mai 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 (20 mai 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 et Philip Agop Philip. « Molecular profiling of pancreatic neuroendocrine neoplasms (panNENs) : A single-institution experience. » Journal of Clinical Oncology 39, no 15_suppl (20 mai 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 et Rama R. Gullapalli. « Site-Specific Genomic Alterations in a Well-Differentiated Pancreatic Neuroendocrine Tumor With High-Grade Progression ». Pancreas 47, no 4 (avril 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 (avril 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 (novembre 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 et 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 (1 février 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.