Journal articles on the topic 'Pancancer'
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1
Wong, Chi Chun, and Jun Yu. "Mapping the pancancer metastasis tumor microbiome." Cell 187, no. 9 (April 2024): 2126–28. http://dx.doi.org/10.1016/j.cell.2024.03.040.
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Kappmeier, Claudia, Sherina Edward, Corinna Hochstein, Ellen Inga Bruske, Francesca Di Pasquale, and Ronny Kellner. "Abstract 1470: Advancing cancer research: A novel PanCancer digital PCR tool for simultaneous detection of multiple hallmark mutations in BRAF and EGFR." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1470. http://dx.doi.org/10.1158/1538-7445.am2024-1470.
Abstract:
Abstract The paradigm shift towards precision medicine in oncology emphasizes the importance of identifying specific genetic mutations driving cancer. Some hallmark mutations in cancer-associated genes, such as BRAF and EGFR, are important in analyzing many cancer types. With the emergence of digital PCR (dPCR) technology, high-sensitivity and quantitative mutation analysis can be performed, lending valuable support to cancer research. In this work, we introduce a new and innovative dPCR method, the dPCR PanCancer assays (RUO), designed for concurrently detecting multiple hallmark mutations in BRAF and EGFR. This work includes two novel PanCancer assays for BRAF and EGFR, each tailored to target a spectrum of mutations associated with these genes, facilitating a comprehensive mutation analysis. The dPCR assay for BRAF targets multiple V600 hallmark mutations, and the dPCR assay for EGFR targets various important deletions on exon 19. This also includes a reference gene as a control for PCR efficiency in the duplex reaction. Here, we present our initial data from various sample types, including blood, plasma and FFPE samples. Through a meticulously optimized dPCR setup, we achieved exceptional sensitivity and specificity, enabling the detection of multiple mutations in a single channel at allelic frequencies below 1%. Both dPCR PanCancer Kits (RUO) have potential use in research for pre-screening samples (e.g., prior to next-generation sequencing) or monitoring cancer cells. They simultaneously assess the mutations, reducing time and costs and saving sample material. Additionally, our technology is adaptable to other cancer-associated genes, where similar assays can potentially be developed. Overall, we have demonstrated that our dPCR PanCancer Kits (RUO) provide a robust, fast and efficient technology to identify critical mutations, ultimately enhancing our understanding of BRAF and EGFR-driven cancers. The dPCR PanCancer Kit is for research use only. Not for the diagnosis, prevention, or treatment of a disease. Citation Format: Claudia Kappmeier, Sherina Edward, Corinna Hochstein, Ellen Inga Bruske, Francesca Di Pasquale, Ronny Kellner. Advancing cancer research: A novel PanCancer digital PCR tool for simultaneous detection of multiple hallmark mutations in BRAF and EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1470.
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Li, Fei, Jing Chen, Xiaoyan Zhang, Dongxiao Yang, Liang Xia, Dazhong Wang, Kai Jin, et al. "Characterization of MET exon 14 skipping in pancancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e20530-e20530. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e20530.
Abstract:
e20530 Background: MET exon 14 skipping ( METex14) is characterized oncogenic that possesses susceptibility to targeted inhibitors. We retrospectively investigated a Chinese Pan-cancer cohort to characterize METex14 alterations and co-mutation. Methods: We screened tumor tissues or body fluids of a pan-cancer patients by DNA-based next-generation sequencing assay (Genetron Health) from 2017 to 2020. And distribution of co-mutation with METex14 was analyzed. Results: 233 samples from 187 patients (190 tissues and 43 circulating tumor DNA) were identified with METex14. Average age of these METex14 patients was 67.84 ± 12.19 years old, indicating they were characterized by advanced age. The cancer distribution involved METex14 was 95.72% of lung cancer (179 cases), 3.21% of brain tumors (4 glioma blastoma, 1 anaplastic astrocytoma and 1 ependymoma), 0.535% of gastrointestinal stromal tumor (1 case) and 0.535% of sarcoma (1 case). Referring to different transcripts (NM_001127500.1/2 or NM_000245.2), a total of 68 distinct sequence variants of METex14 were identified spanning functional regions: 31 forms in splice donor site (SD, 148 cases, including 1 case of D1010H), 5 in splice acceptor site (SA, 5 cases), 13 in poly-pyrimidine tract (PPT, 15 cases), 19 cover PPT and SA (19 cases). In non-lung cancers, 5 of 8 cases were detected of METex14 variation in SD site. Among the driver coexisting cases of lung cancer, METex14 samples mainly coexisted with MET amplification, EGFR driver mutations and functional fusions. Co-mutation cases with MET amplification (13) and SEMA3D-MET fusion (1) may benefit from MET inhibitors, which may be the same as the samples of METex14 alone. 13 of METex14 cases occurred with MDM2 and 9 of CDK4 amplification, respectively. There were 2 of METex14 cases coexisted with EGFR 19del or L858R, which may benefit from combination or sequential therapies of MET inhibitor and EGFR TKIs. In addition, 2 of METex14 cases were detected with functional fusions (1 ALK-EML4, 1 KIFI5B-RET), resulting in potential benefit from combination of corresponding targeted agents. Among non-lung cancer cases, 2 of 8 case had coexistence of METex14 and MET amplification, 6 of 8 patients had coexistence of METex14 and TP53, similar phenomenon was also observed in lung cancer samples. Conclusions: Here we reported diverse METex14 alterations in a Chinese pan-cancer cohort that contribute to oncogenic transformation. METex14 mutations of pan-cancer mainly occurred in SD site. TP53 was its main co-mutant gene among pan-cancers, and MET amplification was also observed.
4
Cheerla, Anika, and Olivier Gevaert. "Deep learning with multimodal representation for pancancer prognosis prediction." Bioinformatics 35, no. 14 (July 2019): i446—i454. http://dx.doi.org/10.1093/bioinformatics/btz342.
Abstract:
Abstract Motivation Estimating the future course of patients with cancer lesions is invaluable to physicians; however, current clinical methods fail to effectively use the vast amount of multimodal data that is available for cancer patients. To tackle this problem, we constructed a multimodal neural network-based model to predict the survival of patients for 20 different cancer types using clinical data, mRNA expression data, microRNA expression data and histopathology whole slide images (WSIs). We developed an unsupervised encoder to compress these four data modalities into a single feature vector for each patient, handling missing data through a resilient, multimodal dropout method. Encoding methods were tailored to each data type—using deep highway networks to extract features from clinical and genomic data, and convolutional neural networks to extract features from WSIs. Results We used pancancer data to train these feature encodings and predict single cancer and pancancer overall survival, achieving a C-index of 0.78 overall. This work shows that it is possible to build a pancancer model for prognosis that also predicts prognosis in single cancer sites. Furthermore, our model handles multiple data modalities, efficiently analyzes WSIs and represents patient multimodal data flexibly into an unsupervised, informative representation. We thus present a powerful automated tool to accurately determine prognosis, a key step towards personalized treatment for cancer patients. Availability and implementation https://github.com/gevaertlab/MultimodalPrognosis
5
Liu, Kui, Jing Ma, Jiao Ao, Lili Mu, Yixian Wang, Yue Qian, Jin Xue, and Wei Zhang. "The Oncogenic Role and Immune Infiltration for CARM1 Identified by Pancancer Analysis." Journal of Oncology 2021 (October 27, 2021): 1–15. http://dx.doi.org/10.1155/2021/2986444.
Abstract:
Chromatin-modifying enzymes, especially protein arginine methyltransferases (PRMTs), have been identified as candidate targets for cancer. Cellular or animal-based evidence has suggested an association between coactivator-linked arginine methyltransferase 1 (CARM1) and cancer progression. However, the relationship between CARM1 and patient prognosis and immune infiltration in pancancer patients is unknown. On the basis of the GEO and TCGA databases, we first investigated the possible oncogenic functions of CARM1 in thirty-three tumor types. CARM1 expression was elevated in many types of tumors. In addition, there was a significant association between CARM1 expression and the survival rate of tumor patients. Uterine corpus endometrial carcinoma (UCES) samples had the highest CARM1 mutation frequency of all cancer types. In head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC), CARM1 expression was associated with the level of CD8+ T cell infiltration, and cancer-associated fibroblast infiltration was also observed in other tumors including kidney renal papillary cell carcinoma (KIRC) and prostate adenocarcinoma (PRAD). CARM1 was involved in immune modulation and played an important role in the tumor microenvironment (TME). Furthermore, activities associated with RNA transport and its metabolism were included in the possible mechanisms of CARM1. Herein, our first pancancer research explores the oncogenic role of CARM1 in various tumors. CARM1 is associated with immune infiltrates and can be employed as a predictive biomarker in pancancer.
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Jiang, Aimin, Ye Zhou, Wenliang Gong, Xin Pan, Xinxin Gan, Zhenjie Wu, Bing Liu, Le Qu, and Linhui Wang. "CCNA2 as an Immunological Biomarker Encompassing Tumor Microenvironment and Therapeutic Response in Multiple Cancer Types." Oxidative Medicine and Cellular Longevity 2022 (March 31, 2022): 1–35. http://dx.doi.org/10.1155/2022/5910575.
Abstract:
Background. Cancer is a major threat to human health worldwide. Although recent innovations and advances in early detection and effective therapies such as targeted drugs and immune checkpoint inhibitors have saved more lives of cancer patients and improved their quality of life, our knowledge about cancer remains largely unknown. CCNA2 belongs to the cell cyclin family and has been demonstrated to be a tumorigenic gene in multiple solid tumor types. The aim of the present study was to make a comprehensive analysis on the role of CCNA2 at a pancancer level. Methods. Multidatabases were collected to evaluate the different expression, prognostic value, DNA methylation, tumor mutation burden, microsatellite instability, mismatch repair, tumor immune microenvironment, and drug sensitivity of CCNA2 across pancancer. IHC was utilized to validate the expression and prognostic value of CCNA2 in ccRCC patients from SMMU cohort. Results. CCNA2 was differentially expressed in most cancer types vs. normal tissues. CCNA2 may significantly influence the prognosis of multiple cancer types, especially clear cell renal cell carcinoma (ccRCC). CCNA2 was also frequently mutated in most cancer types. Notably, CCNA2 was significantly correlated with immune cell infiltration and immune checkpoint inhibitory genes. In addition, CCNA2 was also strongly related to drug resistance. Conclusion. CCNA2 may prove to be a new biomarker for prognostic prediction, tumor immunity assessment, and drug susceptibility evaluation in pancancer level, especially in ccRCC.
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Karpova, Alla, Nadezhda V. Terekhanova, Siqi Chen, Reyka G. Jayasinghe, Andrew Houston, Wagma Caravan, Ryan C. Fields, and Li Ding. "Abstract 2627: PanCancer epigenetic regulators of lymphocyte activation states." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2627. http://dx.doi.org/10.1158/1538-7445.am2024-2627.
Abstract:
Abstract Several immune cell types have been successfully targeted for immunomodulatory therapy; however, the efficacies of such therapies are hindered by incompatible immune cell activation states. CD8+ T-cell exhaustion is one of the most studied T-cell states in the context of cancer and was shown to limit checkpoint blockade efficacy. Although CD8+ T-cell exhaustion studies in mice showed this state is tightly regulated by chromatin accessibility of cis-regulatory elements (CREs) and transcription factor activation, the exploration of these mechanisms, their prevalence, and their specificity in human cancers remains limited. In addition, chromatin accessibility signatures of other lymphocyte (CD4+ and NK) states frequently found in solid tumors have not been carefully characterized in a pan-cancer setting. Here we introduce the first single-nuclei atlas of pan-cancer and disease-specific cis- and trans-regulatory elements in tumor infiltrating lymphocytes. We profiled ~140K T-cell and NK cell nuclei with snATAC-seq and snRNA-seq from 227 tumor and normal samples from eleven cancer types. We distinguished two major subpopulations among exhausted CD8+ T-cells: GZMK expressing (CD8+ GZMK+ Tex) and ITGAE+ tissue-resident (CD8+ Trm ex). CD8+ GZMK+ Tex was enriched in clear cell renal cell carcinoma, while CD8+ Trm ex was found in all other cancers. Both exhausted groups featured high motif accessibility and expression of NR4A1, NFATC2, and NFKB2 transcription factors (previously reported to regulate exhaustion), but differed in EOMES motif accessibility and gene expression. We have identified other lymphocyte subpopulations showing exhaustion signatures, including CD4+ follicular helpers (CD4+ Tfh), CD4+ regulatory cells (CD4+ Tregs), and weakly cytotoxic tissue-resident NK cells (trNK weak). All these subpopulations showed increased expression and motif accessibility of the NR4A1 transcription factor, highlighting its role in regulating dysfunctional states not only in CD8+ T-cells, but also in CD4+ and NK cells. Additionally, CD4+ Tfh and Tregs showed enhanced activity of NFKB1, NFKB2, and POU2F2, and trNK weak cells had increased activity of NR4A2 and NR2F2. To put our results into clinical perspective, we have collected cohorts of renal cancer, melanoma and triple-negative breast tumors treated with immunotherapy in clinical trial settings, and showed elevated GZMK expression in exhausted T-cells in responders compared to non-responders. Citation Format: Alla Karpova, Nadezhda V. Terekhanova, Siqi Chen, Reyka G. Jayasinghe, Andrew Houston, Wagma Caravan, Ryan C. Fields, Li Ding. PanCancer epigenetic regulators of lymphocyte activation states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2627.
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Ji, Haizhou, Mi Ren, Tongyu Liu, and Yang Sun. "Prognostic and Immunological Significance of CXCR2 in Ovarian Cancer: A Promising Target for Survival Outcome and Immunotherapeutic Response Assessment." Disease Markers 2021 (November 19, 2021): 1–21. http://dx.doi.org/10.1155/2021/5350232.
Abstract:
Objective. Uncovering genetic and immunologic tumor features is critical to gain insights into the mechanisms of immunotherapeutic response. Herein, this study observed the functions of CXCR2 in prognosis and immunology of ovarian cancer. Methods. Expression, prognostic significance, and genetic mutations of CXCR2 were analyzed in diverse cancer types based on TCGA and GTEx datasets. Associations of CXCR2 expression with immune checkpoints, neoantigens, tumor mutational burden (TMB), and microsatellite instability (MSI) were evaluated across pancancer. CXCR2-relevant genes were identified, and their biological functions were investigated in ovarian cancer. Through three algorithms (TIMER, quanTIseq, and xCell), we assessed the relationships of CXCR2 with immune cell infiltration in ovarian cancer. GSEA was adopted for inferring KEGG and hallmark pathways involved in CXCR2. Results. CXCR2 presented abnormal expression in tumors than paired normal tissues across pancancer. Higher expression of CXCR2 was found in ovarian cancer. Moreover, its expression was in relation to overall survival and progression including ovarian cancer. Prominent associations of CXCR2 with immune checkpoints, neoantigens, TMB, and MSI were observed in human cancers. Somatic mutations of CXCR2 frequently occurred across pancancer. Amplification was the main mutational type of CXCR2 in ovarian cancer. CXCR2-relevant genes were markedly enriched in immunity activation and carcinogenic pathways in ovarian cancer. Moreover, it participated in modulating immune cell infiltration in the tumor microenvironment of ovarian cancer such as macrophage and immune response was prominently modulated by CXCR2. Conclusion. Collectively, CXCR2 acts as a promising prognostic and immunological biomarker as well as a novel immunotherapeutic target of ovarian cancer.
9
Cooper, Lee AD, Elizabeth G. Demicco, Joel H. Saltz, Reid T. Powell, Arvind Rao, and Alexander J. Lazar. "PanCancer insights from The Cancer Genome Atlas: the pathologist's perspective." Journal of Pathology 244, no. 5 (February 22, 2018): 512–24. http://dx.doi.org/10.1002/path.5028.
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Norton, John T., Callie B. Pollock, Chen Wang, Julian C. Schink, J. Julie Kim, and Sui Huang. "Perinucleolar compartment prevalence is a phenotypic pancancer marker of malignancy." Cancer 113, no. 4 (August 15, 2008): 861–69. http://dx.doi.org/10.1002/cncr.23632.
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Chen, Hao, Fan Xu, Anqi Qin, Shuai Guo, Ge Zhang, Bo Yu, and Quanhui Zheng. "A pancancer analysis of histone deacetylase 3 in human tumors." Translational Cancer Research 13, no. 1 (January 2024): 65–80. http://dx.doi.org/10.21037/tcr-23-1228.
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Yu, Xiaoqing, Song Li, Ling Cen, and Xuefeng Wang. "Abstract 3557: A pancancer gamma delta T cell repertoire atlas." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3557. http://dx.doi.org/10.1158/1538-7445.am2024-3557.
Abstract:
Abstract While representing only a small portion of T cell population, Gamma delta (γδ) T cells have unique contributions to both innate and adaptive immunity. Compared to αβ T, γδ T cells have a more diverse TCR repertoire, allowing them to recognize a broader range of tumor antigens. Recent breakthrough discoveries indicate that the antitumor efficacy of γδ T cells can be potentiated or rescued through targeted therapeutic approaches. Despite their functional and translational significance, a comprehensive understanding of the γδ T cell repertoire within tumor tissues has yet to be fully achieved.In this work, we generated a pan-cancer γδ T cell repertoire Atlas through reanalyzing RNA-seq data from more than 11,000 tumors in TCGA utilizing TRUST4, an advanced computational method for reconstruction of TCR repertoires. This allowed us to offer the most accurate and comprehensive examination of the γδ TCR landscape spanning 33 cancer types, marking it the largest collection of γδ clones on human cancer to date. We processed 660 billion RNAseq reads, identified ~3 million CDR3 reads, applied a series of stringent filtering criteria to remove biologically implausible, ambiguous sequences, and out-of-frame TCRs, which resulted in 22,205 unique γδ TCR clones from 6,751 tumors. TCR gene enrichment scores were calculated to represent overall expression of γδ in each tumor. The γδ enrichment is highly variable between and within cancer types. As expected, tumors traditionally classified as immune-cold (UVM and GBM) show the lowest scores. Cancers intrinsically related to lymphatic system (LAML, THYM and DLBC), exhibit the highest scores. Beyond THYM, the top five solid-tumor cancers carrying the highest enrichment are PRAD, KIRC, TGCT, LUAD and KICH. We further profiled the clone counts, spectrum of clone sizes, CDR3 length, V-J pair usage, and clonality in 33 cancers. Overall, a dominant presence of large clone segment is not observed in most cancers. The most prevalent V-J pairs are TRGV10/9/2-TRGJ1 for γ, and TRDV1-TRDJ1 for δ chain. Cancers including LAML, KIRC, LUAD, SKCM, CESC, LUSC, STAD, display a relatively higher proportion of intermediate to larger clones. THYM exists the highest γδ diversity, with the lowest clonality and most diverse V-J pairs. In addition, we evaluated the prognostics value of γδ genes by multivariate Cox regression, adjusting for age, sex, stage, and tumor purity, and identified 38 γδ genes associated with patient survival with p<0.05 in 25 cancer types. Finally, within HNSC, we observed higher γδ gene enrichment (p=1.6e-9) and clone diversity (p=0.014) in HPV+ vs. HPV- tumors. The γδ gene enrichment is also found associated with patients’ survival (p=0.002) in HPV+, but not in HPV- HNSC. Similarly, COAD tumors with high Microsatellite Instability (MSI) shows higher γδ gene enrichment and clone diversity compared to MSI low COAD. Collectively, our findings serve as a foundational resource for γδ T cell research in oncology. . Citation Format: Xiaoqing Yu, Song Li, Ling Cen, Xuefeng Wang. A pancancer gamma delta T cell repertoire atlas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3557.
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Wu, Yunhui, Jingying Zhang, Can Hou, Hongyu Wang, Min Zhu, and Xin Yao. "A Pancancer Study of PIEZO1 as a Prognosis and Immune Biomarker of Human Tumors." Journal of Oncology 2022 (June 14, 2022): 1–15. http://dx.doi.org/10.1155/2022/6725570.
Abstract:
PIEZO1, a mechanosensitive ion channel protein, has been identified in the correlation between several cancers. However, the systematic pancancer study of PIEZO1 still lacks. We examined PIEZO1 across thirty-three types of cancers to explore its role in prognosis and immunological function for the first time. Based on the open databases TCGA, GTEx and CPTAC, PIEZO1 has been demonstrated to be differentially expressed in most cancers compared to adjacent normal tissues. The distinct correlation between PIEZO1 and prognosis of tumor patients was explored by GEPIA2. Genetic alteration of PIEZO1 in the TCGA tumors showed that mutation is the alteration which is linked to OS, DSS, DFS and PFS in some tumors. Alterations of protein phosphorylation levels were detected in some cancers based on the CPTAC dataset. PIEZO1 expression was linked with immune cell infiltration, such as endothelial cell and cancer-associated fibroblast. Finally, KEGG and GO enrichment analyses were applied to investigate the molecular mechanism of PIEZO1. Our first pancancer analysis illustrated the roles of PIEZO1 in different types of tumors.
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Peng, Ge, Saya Tsukamoto, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, and François Niyonsaba. "A Pancancer Analysis of the Oncogenic Role of S100 Calcium Binding Protein A7 (S100A7) in Human Tumors." Biology 11, no. 2 (February 11, 2022): 284. http://dx.doi.org/10.3390/biology11020284.
Abstract:
Background: Although emerging studies support the relationship between S100 calcium binding protein A7 (S100A7) and various cancers, no pancancer analysis of S100A7 is available thus far. Methods: We investigated the potential oncogenic roles of S100A7 across 33 tumors based on datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Moreover, a survival prognosis analysis was performed with the gene expression profiling interactive analysis (GEPIA) web server and Kaplan–Meier plotter, followed by the genetic alteration analysis of S100A7 and enrichment analysis of S100A7-related genes. Results: S100A7 was highly expressed in most types of cancers, and remarkable associations were found between S100A7 expression and the prognosis of cancer patients. S100A7 expression was associated with the expression of DNA methyltransferase and mismatch repair genes in head and neck squamous cell carcinoma, the infiltration of CD8+ T cells and cancer-associated fibroblasts in different tumors. Moreover, glycosaminoglycan degradation and lysosome-associated functions were involved in the functional mechanisms of S100A7. Conclusions: The current pancancer study shows a relatively integrative understanding of the carcinogenic involvement of S100A7 in numerous types of cancers.
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Aharonov, Ranit, Gal Dinstag, Eldad Shulman, Efrat Elis, Doreen Ben-Zvi, Omer Tirosh, Danh-Tai Hoang, et al. "ENLIGHT: Pancancer response prediction to targeted and immunotherapies via tumor transcriptomics." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e13556-e13556. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e13556.
Abstract:
e13556 Background: Precision oncology is gradually advancing into mainstream clinical practice. Despite the significant recent growth in the number of approved biomarkers for immune and targeted therapies, demonstrating significant survival benefits, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We developed ENLIGHT - a transcriptomics-based computational platform that identifies and utilizes clinically relevant genetic interactions (GIs) to predict a patient’s response to cancer treatments. ENLIGHT markedly extends and improves upon SELECT, a previous GI-based framework for obtaining transcriptomics-based response biomarkers. In this study, we focus on three key translational aspects: (i) the number of drugs for which predictions can be obtained (ii) defining a biomarker-based test for Personalized Medicine (PM) that would identify favorable treatments for an individual; and (iii) Improving clinical trial design by excluding a sub-population of patients likely not to respond to the treatment. A key translational feature of the approach is that it does not require training on treatment response data. Thus, in addition to its ability to predict patients' response to approved and well-studied therapies, it can predict the response to new, unexplored treatments. Results: We first tested Enlight in the PM scenario, analyzing 21 patient cohorts from diverse indications, treated with a variety of targeted and immunotherapies. The ENLIGHT treatment matching score is associated with better response with an aggregate Odds Ratio (OR) of 2.59 (95% confidence interval [1.85, 3.55], p= 3.41 e-8). Applied to the WINTHER trial data, encompassing multiple indications and individualized treatments, ENLIGHT recommendations achieved a highly remarkable OR of 11.15 ([2.3, 54.5], p = 8 e-04), demonstrating ENLIGHT’s strong predictive power across a broad spectrum of treatments and cancer types. Second, using ENLIGHT to exclude patients from clinical trials increases the trial response rate, achieving more than 90% of the response rate attainable under an optimal exclusion strategy. Conclusions: ENLIGHT is a powerful transcriptomics-based precision oncology pipeline developed by Pangea Biomed that broadly predicts response to both extant and novel targeted and immune therapies in translationally oriented, clinical terms, going beyond case-specific biomarkers.
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Aharonov, Ranit, Gal Dinstag, Eldad Shulman, Efrat Elis, Doreen Ben-Zvi, Omer Tirosh, Danh-Tai Hoang, et al. "ENLIGHT: Pancancer response prediction to targeted and immunotherapies via tumor transcriptomics." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e13556-e13556. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e13556.
Abstract:
e13556 Background: Precision oncology is gradually advancing into mainstream clinical practice. Despite the significant recent growth in the number of approved biomarkers for immune and targeted therapies, demonstrating significant survival benefits, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We developed ENLIGHT - a transcriptomics-based computational platform that identifies and utilizes clinically relevant genetic interactions (GIs) to predict a patient’s response to cancer treatments. ENLIGHT markedly extends and improves upon SELECT, a previous GI-based framework for obtaining transcriptomics-based response biomarkers. In this study, we focus on three key translational aspects: (i) the number of drugs for which predictions can be obtained (ii) defining a biomarker-based test for Personalized Medicine (PM) that would identify favorable treatments for an individual; and (iii) Improving clinical trial design by excluding a sub-population of patients likely not to respond to the treatment. A key translational feature of the approach is that it does not require training on treatment response data. Thus, in addition to its ability to predict patients' response to approved and well-studied therapies, it can predict the response to new, unexplored treatments. Results: We first tested Enlight in the PM scenario, analyzing 21 patient cohorts from diverse indications, treated with a variety of targeted and immunotherapies. The ENLIGHT treatment matching score is associated with better response with an aggregate Odds Ratio (OR) of 2.59 (95% confidence interval [1.85, 3.55], p= 3.41 e-8). Applied to the WINTHER trial data, encompassing multiple indications and individualized treatments, ENLIGHT recommendations achieved a highly remarkable OR of 11.15 ([2.3, 54.5], p = 8 e-04), demonstrating ENLIGHT’s strong predictive power across a broad spectrum of treatments and cancer types. Second, using ENLIGHT to exclude patients from clinical trials increases the trial response rate, achieving more than 90% of the response rate attainable under an optimal exclusion strategy. Conclusions: ENLIGHT is a powerful transcriptomics-based precision oncology pipeline developed by Pangea Biomed that broadly predicts response to both extant and novel targeted and immune therapies in translationally oriented, clinical terms, going beyond case-specific biomarkers.
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Swami, Nishwant, Edward Christopher Dee, Brandon A. Mahal, Fumiko Chino, and Narjust Duma. "Financial toxicity in Hispanic cancer survivors: A nationally representative pancancer analysis." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 6528. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.6528.
Abstract:
6528 Background: A cancer diagnosis can pose a significant financial burden to patients and their families, both during and after treatment. Financial toxicity has long-term consequences, with cancer being the most commonly cited reason for medical cost-associated bankruptcy in the United States. We used nationally representative survey data to assess financial toxicity in cancer survivors, with a focus on Hispanic patients given known disparities in socioeconomic and cancer outcomes. Methods: 2013-2018 data from the National Health Interview Survey (NHIS) was used to select individuals aged 18 years old and older who reported any previous diagnosis of cancer. Financial toxicity was defined as unmet healthcare need, health care unaffordability, and/or general financial stress. Individuals were disaggregated by race/ethnicity, and patients who self-identified as Hispanic were further classified by country of origin. Survey-adjusted percentages characterize the cohort. Multivariable logistic regression generated adjusted odds ratios (aORs) with 95% CI for each category of financial toxicity, with non-Hispanic White (NHW) used as reference. Results: Hispanic patients in aggregate had the highest prevalence of all 3 categories of financial toxicity when compared to other racial/ethnicity groups (35% unmet healthcare need, 61% healthcare unaffordability, 61% financial stress). Mexican (aOR: 2.53 95%CI: 1.82–3.52), Cuban/Cuban-American (aOR: 1.97 95%CI: 1.17–3.34), and patients of Central/South American heritage (aOR: 2.61 95%CI: 1.67–4.10) were more likely to have healthcare unaffordability. Unmet healthcare needs were higher in Mexican patients (aOR: 1.43 95%CI: 1.03-1.99) and patients of Cuban descent (aOR: 1.96 95%CI: 1.07-3.58). Financial stress was highest among patients of Central/South American heritage (aOR: 4.20 95%CI: 2.50-7.05) and Mexican patients (aOR: 1.84 95%CI: 1.27-2.66). Mediator analyses further revealed that disparities persisted even after adjusting for socioeconomic status in Mexican patients (healthcare unaffordability - aOR: 1.65 95%CI: 1.14-2.40) and patients of Central/South American heritage (healthcare unaffordability – aOR: 1.99 95%CI: 1.23-3.21; general financial stress – aOR: 2.97 95%CI: 1.71 – 5.17). Conclusions: Our study highlights significant disparities in the financial impact of cancer treatments on Hispanic patients. Disaggregation by Hispanic country of origin illustrates differences within the Hispanic and Hispanic-American population and reveals specific groups that may be at particular risk of financial harm. Targeted interventions to improve health care access and affordability are needed to increase equity and improve outcomes.
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Cui, Jing, Yongjie Tian, Tianhang Liu, Xueyan Lin, Lanyu Li, Zhonghui Li, and Liang Shen. "Pancancer Analysis of Revealed TDO2 as a Biomarker of Prognosis and Immunotherapy." Disease Markers 2022 (September 9, 2022): 1–18. http://dx.doi.org/10.1155/2022/5447017.
Abstract:
Background. Tryptophan 2,3-dioxygenase (TDO) encoded by TDO2, a rate-limiting enzyme in the kynurenine pathway, catabolizes tryptophan to kynurenine, evades immune surveillance, and promotes tumor growth. Although accumulating evidence suggests a crucial role of TDO2 during tumor formation and development, systematic evaluation of TDO2 across human cancers has rarely been reported. Methods. To shed more light on the role of TDO2 in human cancer, we explored the expression profiles of TDO2 and identified its prognostic value in pancancer analysis through TCGA, CCLE, and GTEx databases. We further utilized TCGA data to evaluate the association between TDO2 and tumor immunological features, such as mismatch repair (MMR), tumor immune infiltration, immune checkpoint-related genes, tumor mutational burden (TMB), microsatellite instability (MSI), and DNA methyltransferase (DNMT). Results. TDO2 exhibited different expression levels in various cancer cell lines. Frequently, TDO2 was detected to be highly expressed in the majority of cancers. In addition, high TDO2 expression was correlated with an unfavorable prognosis for patients in KIRP, LGG, TGCT, and UVM. Moreover, high TDO2 expression level positively correlated with higher immune infiltration, especially dendritic cells. Additionally, there is a close relationship between TDO2 and immune checkpoint-related gene markers, such as LAIR1, CD276, NRP1, CD80, and CD86. Finally, correlation analysis has demonstrated a high-correlation between TDO2 and TMB, MSI, MMR, and DNMT of multiple cancer types. Conclusion. Therefore, our results suggest that TDO2 can function as a potential prognostic biomarker due to its role in tumor immunity regulation.
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Wu, Changwu, Yingjuan Duan, Siming Gong, Sonja Kallendrusch, Nikolas Schopow, and Georg Osterhoff. "Integrative and Comprehensive Pancancer Analysis of Regulator of Chromatin Condensation 1 (RCC1)." International Journal of Molecular Sciences 22, no. 14 (July 9, 2021): 7374. http://dx.doi.org/10.3390/ijms22147374.
Abstract:
Regulator of Chromatin Condensation 1 (RCC1) is the only known guanine nucleotide exchange factor that acts on the Ras-like G protein Ran and plays a key role in cell cycle regulation. Although there is growing evidence to support the relationship between RCC1 and cancer, detailed pancancer analyses have not yet been performed. In this genome database study, based on The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases, the potential role of RCC1 in 33 tumors’ entities was explored. The results show that RCC1 is highly expressed in most human malignant neoplasms in contrast to healthy tissues. RCC1 expression is closely related to the prognosis of a broad variety of tumor patients. Enrichment analysis showed that some tumor-related pathways such as “cell cycle” and “RNA transport” were involved in the functional mechanism of RCC1. In particular, the conducted analysis reveals the relation of RCC1 to multiple immune checkpoint genes and suggests that the regulation of RCC1 is closely related to tumor infiltration of cancer-associated fibroblasts and CD8+ T cells. Coherent data demonstrate the association of RCC1 with the tumor mutation burden and microsatellite instability in various tumors. These findings provide new insights into the role of RCC1 in oncogenesis and tumor immunology in various tumors and indicate its potential as marker for therapy prognosis and targeted treatment strategies.
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Yang, Jing, Xiaojing Liu, Yueqin Shao, Hong Zhou, Lijun Pang, and Wei Zhu. "Diagnostic, Prognostic, and Immunological Roles of FABP4 in Pancancer: A Bioinformatics Analysis." Computational and Mathematical Methods in Medicine 2022 (December 8, 2022): 1–19. http://dx.doi.org/10.1155/2022/3764914.
Abstract:
Background. Fatty acid binding protein 4 (FABP4) is mainly involved in the regulation of systemic metabolism through various lipid signaling pathways. Metabolic reprogramming is one of the important factors in the development and progression of cancer. It has been recently reported that FABP4 is closely related to the development of cancer and may be involved in tumor invasion and metastasis. Methods. In this study, we explored the expression pattern of FABP4 in pancancer through TCGA and CPTAC. Using TCGA, Kaplan-Meier Plotter, and STRING databases, to explore its diagnostic and prognostic value, and function through GO/KEGG and GSEA. Then, using the TIMER2.0 database, we investigated the correlation between FABP4 expression and immune infiltration in cancers, especially stomach adenocarcinomas (STAD) and colorectal adenocarcinoma (COADREAD). Results. Compared with normal tissues, the expression of FABP4 in more than 10 tumor tissues was lower ( p < 0.05 ). Through the receiver operating characteristic (ROC) curve, the diagnostic value was found higher in colorectal cancer, breast cancer, thyroid cancer, and lung cancer, with the area under the curve AUC > 0.9 . Through the K-M curve, FABP4 was found to correlate to the prognosis of various cancers. The results of gastric cancer and colorectal cancer are consistent. The low-expression group has a better prognosis than the high-expression group, and the expression of FABP4 in the early T and N stages of gastrointestinal tumors is lower. FABP4 highly expressed gene set is mostly enriched in extracellular matrix degradation and cell adhesion functions. Gastrointestinal tumors with high expression of FABP4 may have more immunosuppressive effects on macrophages and have a worse prognosis. Conclusion. FABP4 can be used as a diagnostic and prognostic biomarker in pancancer, and its high expression in gastrointestinal tumors suggests poor prognosis. This may be correlated to the immune infiltration of macrophages and epithelial-mesenchymal transition.
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Fox, Eleonore, Guillaume Appe, Abdelkader Behdenna, Lea Meunier, Akpeli Nordor, Solene Weill, and Camille Marijon. "Abstract 1915: A scalable pancancer antigen target discovery platform for precision oncology." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1915. http://dx.doi.org/10.1158/1538-7445.am2024-1915.
Abstract:
Abstract With the emergence of precision oncology as a new paradigm in cancer care, there is an urgent need to develop tools capable of mining the massive amounts of rich omic data generated every year. To support target discovery programs at scale, we developed a pan-cancer bioinformatics platform combining patient data with extensive biological and pharmaceutical knowledge for the identification and prioritization of novel antigen targets. Our pipeline was first validated with the discovery of new antigen targets amenable to CAR-T therapy for relapsed/refractory multiple myeloma. Here, we are exploring AML, a type of leukemia with several unmet needs. First, we identified and integrated 36 relevant microarray datasets from the GEO database using a proprietary data identification and integration pipeline. The clinical data was curated using our proprietary oncology ontology, machine learning models, and domain expert quality control processes. The molecular data was normalized and the datasets aggregated into a virtual patient cohort of unprecedented size and quality, comprising 2,995 AML patients and 220 healthy controls. To both find a clinically relevant patient sub-population and reduce the cohort heterogeneity, AML patients were stratified based on their transcriptomic profile using a consensus clustering analysis, which we interpreted thanks to the curated clinical data. Among multiple others, we identified a highly stable cluster enriched in AML-M3 patients, a very distinct and aggressive subtype of AML caused by a t(15;17) translocation. A differential gene expression analysis was performed comparing this cluster with the control group and 574 genes were found to be overexpressed. We then applied proteomic filters to exclusively focus on cell surface-bound protein targets demonstrating an acceptable level of anticipated cytotoxicity. Finally, the 23 short-listed antigen targets were prioritized with additional multi-omic patient and cell line data to optimize their safety and efficacy profiles as well as expression robustness. Interestingly, well-known targets, such as CD96 and ABCC1, were found in the top targets. Developing scalable pipelines will be instrumental in the advent of precision oncology. Combining unbiased data-driven tools with cancer biology-driven approaches, our state-of-the-art pipeline can be used for any cancer type and antigen-targeting modality, including CAR-T and antibody-based therapies. The present study illustrates the potential of our platform when applied to AML, one of the most heterogeneous groups of neoplastic disorders. Leveraging our large and unique AML patient cohort, we were not only able to detect a relevant subgroup of patients, but also identified novel antigen target candidates for this specific population, which were then prioritized based on domain expertise. A broader study addressing other cancer indications, including solid tumors, is underway. Citation Format: Eleonore Fox, Guillaume Appe, Abdelkader Behdenna, Lea Meunier, Akpeli Nordor, Solene Weill, Camille Marijon. A scalable pancancer antigen target discovery platform for precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1915.
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Ye, Tao, Lan-lan Li, Xue-mei Peng, and Qin Li. "CYP1B1-AS1 Is a Novel Biomarker in Glioblastoma by Comprehensive Analysis." Disease Markers 2021 (December 29, 2021): 1–8. http://dx.doi.org/10.1155/2021/8565943.
Abstract:
Objective. Growing evidence shows that enhancer RNAs (eRNAs) are pivotal for tumor progression. In this research, our team aimed to identify the survival-related eRNAs and further explore their potential function in glioblastoma (GBM). Methods. RNA-sequencing data in 31 tumor types were acquired from TCGA datasets. The survival-related eRNAs were identified by the use of Kaplan-Meier survival analyses and Spearman’s correlation analyses. KEGG pathway enrichment analysis was completed to investigate the underlying signal paths of the critical eRNA. Pancancer assays were applied to explore the association between CYP1B1-AS1 and CYP1B1. Results. We identified 74 survival-related eRNAs and focused on CYP1B1-AS1 which displayed the greatest cor value. CYP1B1 was identified as a regulatory target of CYP1B1-AS1. KEGG analyses suggested that CYP1B1-AS1 might play an essential role through CK-CKR mutual effect, complement and coagulation cascades, TNF signal path, and JAK-STAT signal path. The pancancer verification outcomes revealed that CYP1B1-AS1 was related to survival in 4 cancers, i.e., LIHC, KIRP, KICH, and KIRC. Association was discovered between CYP1B1-AS1 and the targeted gene, CYP1B1, in 29 cancer types. Conclusion. The outcomes herein provided the first evidence that overexpression of CYP1B1-AS1 might be a potential molecular biomarker for predicting the prognosis of patients with GBM.
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Nguyen, Phuong Thao, Yudai Shimojukkoku, Yuka Kajiya, Yasunobu Oku, Ayami Tomishima, Kaori Shima, and Tomonori Sasahira. "Gene alterations in the nuclear transport receptor superfamily: A study of head and neck cancer." PLOS ONE 19, no. 5 (May 31, 2024): e0300446. http://dx.doi.org/10.1371/journal.pone.0300446.
Abstract:
In cancer cells, the nuclear transport system is often disrupted, leading to abnormal localization of nuclear proteins and altered gene expression. This disruption can arise from various mechanisms such as mutations in genes that regulate nuclear transport, altered expression of transport proteins, and changes in nuclear envelope structure. Oncogenic protein build-up in the nucleus due to the disturbance in nuclear transport can also boost tumor growth and cell proliferation. In this study, we performed bioinformatic analyses of 23 key nuclear transport receptors using genomic and transcriptomic data from pancancer and head and neck squamous cell carcinoma (HNSCC) datasets from The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia and found that the total alteration frequency of 23 nuclear transport receptors in 2691 samples of the PCAWG Consortium was 42.1% and a high levels of genetic alterations was significantly associated with poor overall survival. Amplification was the most common type of genetic alterations, and results in the overexpression of nuclear transport receptors in HNSCC compared to normal tissues. Furthermore, our study revealed that seven out of eight cell cycle genes (CDK1, CDK2, CDK4, CDK6, CCNA1, CCNB1, and CCNE2) were significantly and positively correlated with nuclear transport receptor genes in TCGA pancancer and CCLE datasets. Additionally, functional enrichment analysis showed that nuclear transport receptor genes were mainly enriched in the adhesion junction, cell cycle, ERBB, MAPK, MTOR and WNT signaling pathways.
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Lin, Xin, Min Xiao, Zhitao Chen, Chenchen Ding, Ting Zhang, and Qiyong Li. "Pancancer Analyses Reveal Genomics and Clinical Characteristics of the SETDB1 in Human Tumors." Journal of Oncology 2022 (May 23, 2022): 1–40. http://dx.doi.org/10.1155/2022/6115878.
Abstract:
Background. Malignant tumor is one of the most common diseases that seriously affect human health. The prior literature has reported the biological function and potential therapeutic targets of SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) as an oncogene. However, SETDB1 has rarely been analyzed from a pan-cancer perspective. Methods. Bioinformatics analysis tools and databases, including GeneCards, National Center for Biotechnology Information (NCBI), UniProt, Illustrator for Biological Sequences (IBS), Human Protein Atlas (HPA), GEPIA, TIMER2, Sangerbox 3.0, UALCAN, Kaplan-Meier (K-M) plotter, cBioPortal, Catalogue Of Somatic Mutations In Cancer (COSMIC), PhosphoSitePlus, TISIDB, STRING, and GeneMANIA, were utilized to clarify the biological functions and clinical significance of SETDB1 from a pan-cancer perspective. Results. In this study, the pan-cancer analysis demonstrated that SETDB1 showed significantly differential expression in most tumor tissues and paracancerous tissues, and SETDB1 expression was associated with clinicopathological features and clinical prognosis. We also found that SETDB1 mutations occurred in most tumors and were related to tumorigenesis. In addition, DNA methylation of SETDB1 primarily occurred at the cg10444928 site and was associated with prognosis in several human tumors. The predicted phosphorylation site of SETDB1 was Ser1006. We found that SETDB1 was significantly related to the specific tumor-infiltrating immune cell populations and expression of clinically targetable immune checkpoints and may be a promising immunotherapy target. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses also indicated that SETDB1 may function as crucial regulator in carcinogenesis of human cancers. Conclusions. SETDB1 is an important oncogene involved in tumorigenesis and tumor progression through different biological mechanisms. Furthermore, SETDB1 may be a potential therapeutic target for cancer treatment.
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Zhou, Yiyi, Shuangshuang Xu, Qinying Sun, and Yuchao Dong. "An Analysis of BMP1 Associated with m6A Modification and Immune Infiltration in Pancancer." Disease Markers 2022 (October 11, 2022): 1–28. http://dx.doi.org/10.1155/2022/7899961.
Abstract:
Background. This research explores the underlying link between diagnosis and therapy between bone morphogenetic protein 1 (BMP1) and various cancers. Methods. Three immunotherapeutic cohorts, by the composition of IMvigor210, GSE35640, and GSE78220 were obtained from previously published articles and the Gene Expression Omnibus database. The different expressions of BMP1 in various clinical parameters were conducted, and prognostic analysis was executed utilizing Cox proportional hazard regression and Gene Expression Profiling Interactive Analysis. Moreover, the correlation between BMP1 and tumor microenvironment was analyzed using ESTIMATE and CIBERSORT algorithms. Tumor mutational burden and microsatellite instability were also included. The correlation between m6A modification and the gene expression level was analyzed using Tumor IMmune Estimation Resource, the University of Alabama at Birmingham Cancer data analysis portal. Gene Set Cancer Analysis analyzed the correlation of BMP1 expression level with copy number variations and methylation. Furthermore, the correlation between BMP1 and therapeutic response after antineoplastic drug use was illustrated for further discussion. Results. BMP1 expression had significant differences in 14 cancers. It presented an intimate relationship with immune-relevant biomarkers. A variation analysis indicated that BMP1 had a significant association with immunotherapeutic response. The expression level of BMP1 was closely associated with insulin-like growth factor binding protein 3, an m6A modification relative gene. Except for a few cancer types, methylation negatively correlated with BMP1, and copy number variations positively correlated with BMP1. Notably, low BMP1 expression was connected with immunotherapeutic response in the cohorts, and its expression was related to increased sectional sensitivity of drugs. Conclusion. BMP1 may serve as a potential biomarker for prognostic prediction and immunologic infiltration in diversified cancers, providing a new thought approach for oncotherapy.
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Ou, Qiyun, Yunfang Yu, Haitao Zhong, Anlin Li, Yongjian Chen, HaiYu Zhou, Shaopeng Zheng, Luyu Huang, and Herui Yao. "Association of immune-related adverse events with immune checkpoint inhibitor efficacy in pancancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14087-e14087. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14087.
Abstract:
e14087 Background: Immune-related adverse events (irAEs) have been shown to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced cancer, but the reported effect sizes have varied greatly in previous trials. We did a meta-analysis to assess immune checkpoint inhibitors efficacy and further explored the correlation of irAEs with efficacy in cancer. Methods: We systematically searched database inception to January, 2019 for randomized trials of immune checkpoint inhibitor in patients with advanced cancer that had available data for overall survival (OS) and progression-free survival (PFS), and irAEs. We calculated the pooled hazard ratios (HRs) and 95% confidence intervals [CIs] using a random-effects model, and assessed the association between the irAEs and PFS or OS using coefficient of determination ( R²). The PROSPERO registry number is CRD42017075610. Results: Thirty eight trials with 19,521 patients were included. Compared with conventional therapy, anti-PD-1 or PD-L1 combined with conventional therapy significantly enhanced survival (HR = 0.62, 95% CI 0.53 to 0.72 for PFS; HR = 0.71, 95% CI 0.58 to 0.87 for OS), and anti-PD1 or PD-L1 combined with anti-CTLA4 (HR = 0.75, 95% CI 0.63 to 0.90 for PFS). Anti-CTLA4 plus conventional therapy prolonged PFS (HR = 0.80, 95% CI 0.72 to 0.89) and OS (HR = 0.80, 95% CI 0.66 to 0.96) than conventional therapy alone. Anti-PD1 or PD-L1 outperformed anti-CTLA4 on OS (HR = 0.68, 95% CI 0.57 to 0.81). Significant correlation between treatment efficacy and irAEs was only identified in pneumonitis ( R2 0.59, P = 0.026 for PFS) and diarrhea ( R2 0.22, P = 0.006 for OS). Conclusions: We recommended the concurrent use of immune checkpoint inhibitor and conventional therapy or dual immunotherapy as the most appropriate regimens for advanced cancer. Furthermore, development of pneumonitis and diarrhea were associated with survival outcome of immune checkpoint inhibitors in patients with advanced cancer.
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Liu, Ranran, Tianyu Li, Guohong Zhang, Yejuan Jia, Jingxuan Liu, Lijia Pan, Yunfeng Li, and Chunsheng Jia. "Pancancer Analysis Revealed the Value of RAC2 in Immunotherapy and Cancer Stem Cell." Stem Cells International 2023 (May 12, 2023): 1–17. http://dx.doi.org/10.1155/2023/8485726.
Abstract:
Objective. To investigate the oncogenic effect and clinical significance of RAC2 in pancarcinoma from the perspective of tumor immunity and cancer stem cell. Methods. After in-depth mining of TCGA, GEO, UCSC, and other databases, basic information of the RAC2 gene and its expression in tumor tissues as well as the relationship between RAC2 and tumor were analyzed based on survival, mutation, immune microenvironment, tumor stemness, and enrichment analysis on related pathways. Results. RAC2 mRNA expression was increased in most tumor tissues and was associated with their prognosis. Compared to normal tissues, the RAC2 mutation rate was higher in patients with skin melanoma, uterine sarcoma, and endometrial cancer. RAC2 had a strong relation with immune cell infiltration, immunomodulators, immunotherapy markers, cancer stem cell of THYM, and immune-related pathways. Conclusions. This study explored the potential importance of RAC2 in the prognosis, immunotherapy, and cancer stem cell of 33 cancers, laying the foundation for mechanistic experiments and its future application in clinical practice. However, the results using bioinformatics methods could be affected by the differences in patients across databases. Thus, the present results were preliminary and required further experimental validation.
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Niederhausern, Andrew, Nadia S. Bahadur, Gary Wallace, Gilan E. Saadawi, and John Philip. "Abstract 4966: Machine learning and large language model approach to pancancer data elements." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4966. http://dx.doi.org/10.1158/1538-7445.am2024-4966.
Abstract:
Abstract Introductory Statement: The goal is to use machine learning (ML) and large language model (LLM) to augment the manual curation of cancer data elements. Introduction: Memorial Sloan Kettering Cancer Center (MSKCC) has ~100,000 cancer patients and counting with genomic testing. Clinicians use genomic data for research but lack clinical data to analyze together. We use a vendor, VASTA Global to hire curators to manually curate cancer patient’s core clinical data elements (CCDE) within unstructured/paragraph text in electronic medical record (EMR) notes. CCDE encompasses 122 data elements that include a patient’s full cancer history that can take up to 1 working day to curate. We collaborated with the Realyze Intelligence Healthcare Solutions vendor to use their AI pipeline to generate the manual curated dataset. Realyze generated the CCDE data elements such as histology, pathology site, MMR, TNM staging, ECOG, and KPS for a pilot lung cancer cohort of 150 patients. We manually validated the generated data for 74 out of 150 patients. Methods:The Realyze platform uses a combination of LLMs, ML algorithms and standard terminologies to create a cancer patient model. These models are flexible enough to address the unique needs and challenges of a pan-cancer oncology model. By using standardized FHIR export, results were delivered to a data lake solution and written into a REDCap database to enable human review. Summary:We manually assessed 74 patients. The NLP gave concordant values for MMR, KPS and TNM staging for 100% of the instances. For MMR these were all null values with false negative (FN) of 100% accuracy. Pathology site had 92.15% accuracy while histology has 97.5% accuracy. Conclusion:Will work on refining pathology site and histology’s ICDO3 list to increase the percentage of accuracy. Once Realyze refines their model for these data elements we will re-run it on a larger cohort of cancer patients and calculate the accuracy. Accuracy Results Clinical data elements 74 patients assessed: Accuracy % ECOG 98.6 KPS 100 T (path) 100 T (clinical) 100 N (path) 100 N (clinical) 100 M (path) 100 M(clinical) 100 MMR 100 Histology (path) 97.5 Path site 92.15 Citation Format: Andrew Niederhausern, Nadia S. Bahadur, Gary Wallace, Gilan E. Saadawi, John Philip. Machine learning and large language model approach to pancancer data elements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4966.
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Gong, Xiaoming, Tao Chen, Cheyu Lin, Haiqin Ping, Xin Tong, Kai Zhang, Zhaojun Chen, Caiyun Cai, Zhiyan Lu, and Hengning Ke. "Bioinformatics Analysis of the Prognostic Significance of VPS16 in Hepatocellular Carcinoma and Its Role in Drug Screening." BioMed Research International 2023 (April 17, 2023): 1–13. http://dx.doi.org/10.1155/2023/2501596.
Abstract:
Background. Vacuolar protein sorting 16 (VPS16) overexpression was recently considered related to cancer growth and drug resistance; however, little is known about whether VPS16 plays a vital role in liver hepatocellular carcinoma (LIHC). Methods. The TIMER2 online database was used to analyze the expression of VPS16 in pancancer, and the Xena Browser was used to explore the correlation between VPS16 expression level and survival time. R language was used to test the survival data of 374 LIHC cases in the TCGA database. DESeq2 was used for differentially expressed gene (DEG) analysis. The HPA database was used to verify the expression level of VPS16 in LIHC. The clusterProfiler package was used to analyze functions and related signaling pathways via GO/KEGG enrichment analysis. Drug sensitivity analysis and molecular docking technology were used to screen the most sensitive drugs targeting VPS16 molecules. Results. Pancancer analysis showed that VPS16 was highly expressed in various tumors, especially in LIHC. With the increase in the T stage and grade of LIHC, the expression level of VPS16 was also increased. The expression of VPS16 was negatively correlated with the overall survival of LIHC patients. The stage can be used as an independent prognostic factor. A total of 63 sensitive drugs were found, and 19 drugs were displaying strong molecular binding energy with VPS16. Conclusion. VPS16 may be a potential biomarker for the diagnosis and prognosis of LIHC. Drugs targeting VPS16 may be used in the treatment of LIHC in the future.
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Wu, Zixuan, Yanhui Jiang, Xuyan Huang, Minjie Cai, Kai Yuan, Peidong Huang, and Zuhong Wang. "In the Tumor Microenvironment, ETS1 Is an Oncogenic Immune Protein: An Integrative Pancancer Analysis." Evidence-Based Complementary and Alternative Medicine 2022 (April 15, 2022): 1–12. http://dx.doi.org/10.1155/2022/7730433.
Abstract:
Background. Previous research suggested that ETS1 (ETS proto-oncogene 1, transcription factor) could be useful for cancer immunotherapy. The processes underlying its therapeutic potential, on the other hand, have yet to be thoroughly investigated. The purpose of this study was to look into the relationship between ETS1 expression and immunity. Methods. TCGA and GEO provide raw data on 33 different cancers as well as GSE67501, GSE78220, and IMvigor210. In addition, we looked at ETS1's genetic changes, expression patterns, and survival studies. The linkages between ETS1 and TME, as well as its association with immunological processes/elements and the major histocompatibility complex, were explored to effectively understand the role of ETS1 in cancer immunotherapy. Three distinct immunotherapeutic cohorts were employed to examine the relationship between ETS1 and immunotherapeutic response. Results. ETS1 expression was shown to be high in tumor tissue. ETS1 overexpression is linked to a worse clinical outcome in individuals with overall survival. Immune cell infiltration, immunological modulators, and immunotherapeutic signs are all linked to ETS1. Overexpression of ETS1 is linked to immune-related pathways. However, no statistically significant link was found between ETS1 and immunotherapeutic response. Conclusions. ETS1 may be a reliable biomarker for tumor prognosis and a viable prospective therapeutic target for human cancer immunotherapy (e.g., KIRP, MESO, BLCA, KIRC, and THYM).
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Yang, Ziyue, Yuanyuan Zhu, Zhenfen Li, Zhangya Pu, Ying Lin, Ying Deng, Ning Li, and Fang Peng. "Pancancer Analysis of the Prognostic and Immunotherapeutic Value of Progestin and AdipoQ Receptor 4." Computational and Mathematical Methods in Medicine 2022 (December 17, 2022): 1–24. http://dx.doi.org/10.1155/2022/2528164.
Abstract:
AdipoQ receptor 4 (PAQR4) belongs to the family of progestin and AdipoQ receptors. PAQR4 plays an oncogenic role in lung and breast cancer. However, systematic pancancer analyses of PAQR4 have not been performed. The purpose was to investigate the prognostic and immunological significance of PAQR4 across 31 tumor types. Data were obtained from the following sources: TCGA, GEO, UALCAN, TIMER, GEPIA2, KM plotter, and TISIDB databases. The results proved that PAQR4 expression was significantly elevatory in most cancer types. We then explored the utility of PAQR4 as a prognostic indicator across all cancers. Using Cox proportional risk regression models, it has been demonstrated that PAQR4 is an independent risk factor in. High PAQR4 expression was not associated with other prognostic indicators, including overall survival, disease-free interval, disease-specific survival, and progression-free period. Subsequently, we explored the immunological value of PAQR4 and found that PAQR4 expression significantly correlated with tumor mutational burden, microsatellite instability, neoantigen, and immune checkpoint genes in tumors. It also significantly negatively correlated with most tumors’ ESTIMATE scores, indicating that PAQR4 can influence the cellular composition of the tumor microenvironment. Our findings suggest the immunotherapeutic potential of PAQR4 in tumors. Finally, we explored the role of PAQR4 in tumor drug resistance and found that PAQR4 expression affected the sensitivity to multiple chemotherapeutic agents. A significant role for PAQR4 in tumor immunity is evident in these studies, as well as its potential role in cancer diagnosis, prognosis, and treatment precision.
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Liu, Qiaojun, Renjian Xie, and Yumei Li. "Pancancer Analysis of the Oncogenic and Prognostic Role of NOL7: A Potential Target for Carcinogenesis and Survival." International Journal of Molecular Sciences 23, no. 17 (August 25, 2022): 9611. http://dx.doi.org/10.3390/ijms23179611.
Abstract:
Despite growing evidence suggesting the critical function of NOL7 in cancer initiation and development, a systematic pancancer analysis of NOL7 is lacking. Herein, we present a comprehensive study of NOL7 which aimed to explore its potential role and detailed mechanisms across 33 human tumors based on The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CATPAC) databases. As a result, both gene and protein levels of NOL7 were found to be increased in various tumor tissues, including breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and head and neck squamous cell carcinoma (HNSC) as compared with corresponding normal tissues. Meanwhile, dysregulated NOL7 expression was found to be closely related to pathological stage and prognosis in several cancers, including LIHC, ovarian serous cystadenocarcinoma (OV), and bladder urothelial carcinoma (BLCA). The DNA methylation level of NOL7 was found to be decreased in most cancers and to be negatively associated with NOL7 expression. Furthermore, NOL7 expression was determined to be significantly associated with levels of infiltrating cells and immune checkpoint genes, including HMGB1. Analysis of NOL7-related genes revealed that RNA metabolism pathways, including “ribosome biogenesis”, “spliceosome”, and “RNA transport”, were mainly involved in the functional mechanism of NOL7 in human cancers. In summary, this pancancer study characterized the relationship between NOL7 expression and clinicopathologic features in multiple cancer types and further showed its potential regulatory network in human cancers. It represents a systemic analysis for further functional and therapeutic studies of NOL7 and highlights its predictive value with respect to the carcinogenesis and prognosis of various cancers, especially LIHC.
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El-Deiry, Wafik S., Taylor Arnoff, Ilyas Sahin, Hossein Borghaei, Vivek Subbiah, Hina Khan, Benedito A. Carneiro, et al. "A pancancer analysis of impact of MDM2/MDM4 on immune checkpoint blockade (ICB)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2630. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2630.
Abstract:
2630 Background: MDM2/MDM4 are implicated in hyperprogression after immune checkpoint blockade (ICB). Our preclinical studies showed reduced T-cell killing of MDM2-amplified tumor cells that was overcome by an MDM2 antagonist or gene knockdown, and we observed additional tumor killing by T-cells with MDM2 inhibition plus anti-PD1. We hypothesized that MDM2/4 gene amplification/overexpression correlates with resistance to ICB and investigated the association of MDM2/4 alterations to overall survival (OS) following ICB across multiple solid tumors. Methods: Solid tumors tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (NGS) were analyzed. MDM2/4 amplification (amp) was tested by NGS and determined as either amp4 (cutoff of >=4.0 copies) or amp6 (>=6.0) or amp8 (>=8.0). Real-world OS was obtained from insurance claims data and calculated from treatment start or tissue collection to last contact. Kaplan-Meier estimates were calculated for molecularly defined groups. X2/Fisher-Exact were used and significance determined as P-value adjusted for multiple comparisons (q<0.05). Results: In a large cohort of TP53-wild type solid tumors, 2785 had MDM2 amp4 (262 were ICB-treated), 2108 had MDM2 amp6 (ICB: 192), 1721 had MDM2 amp8 (ICB: 149); 1040 tumors had MDM4 amp4 (ICB: 59), 293 had MDM4 amp6 (ICB: 8) and 217 had amp8 (ICB: 4). NSCLC, GBM, breast, bladder cancer and liposarcoma had the highest MDM2 amp and breast cancer, GBM, uterine, NSCLC and ovarian cancers had the highest MDM4 amp. When all tumors were considered, MDM2 amp4, 6 and 8 significantly associated with shortened OS (amp4: HR 1.31; amp6: HR 1.31; amp8: 1.29, all p<0.0001); similar results were seen with MDM4 (amp4: HR 1.14, p=0.004; amp6: HR 1.51, p<0.00001 and amp8: HR 1.6, p<0.00001). Of note, MDM4 amp4 but not MDM2 amp4 was associated with significantly worse post-ICB survival (HR: 1.55, p=0.009).When comparing molecular differences between MDM2 amp4 and MDM4 amp4, significantly higher PDL1 expression was associated with MDM2 amp (Ab clone 28.8: 58% vs. 28%; clone 22c3: 48% vs.25%, q<0.05); while higher mutation rates of ARID1A, PIK3CA, PTEN, KRAS and CTNNB1 were associated with MDM4 amp (all q<0.05). When investigating NSCLC, MDM4 amp4 was associated with decreased post-ICB survival in NSCLC (HR: 2.59, p=0.001) but not MDM2; when comparing the molecular alterations, MDM2 amp was associated with significantly higher PDL1 (22c3) (54% vs. 27%), EGFR mutation (36% vs. 14%) but less prevalent KRAS (15% vs. 50%), STK11 (11% vs. 41%), KEAP1 (2.5% vs. 27%) and BRAF (2% vs. 16%) mutations. The association with poor prognosis of MDM2 amp4/6 (HR: 1.2 and 1.3, p<0.05) and MDM4 amp4/6 (HR: 1.3 and 1.6, p<0.05) was seen in breast cancer, but not in NSCLC, GBM, bladder or uterine cancers. Conclusions: MDM2 and MDM4 amplification are negative prognostic factors in TP53-WT breast cancer while MDM4 amp is associated with reduced survival in ICB-treated NSCLC.
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Douglass, Eugene F., Robert J. Allaway, Bence Szalai, Wenyu Wang, Tingzhong Tian, Adrià Fernández-Torras, Ron Realubit, et al. "A community challenge for a pancancer drug mechanism of action inference from perturbational profile data." Cell Reports Medicine 3, no. 1 (January 2022): 100492. http://dx.doi.org/10.1016/j.xcrm.2021.100492.
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Gao, Chao, Xiangqin Fan, Yanyan Liu, Yanyan Han, Shiqi Liu, Huanrong Li, Qiaoling Zhang, Yingmei Wang, and Fengxia Xue. "Comprehensive Analysis Reveals the Potential Roles of CDKN3 in Pancancer and Verification in Endometrial Cancer." International Journal of General Medicine Volume 16 (December 2023): 5817–39. http://dx.doi.org/10.2147/ijgm.s438479.
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Lu, Jianyun, Jasmin Sponagel, Jill Jones, Hannah Gass, Elena Nunez, Cheryl Frankfater, Sierra Williams-McLeod, et al. "TMET-13. SEX DIFFERENCES IN GLUCOSE METABOLISM AND MITOCHONDRIAL FUNCTION IN GLIOBLASTOMA IMPLICATE HYPOXIA-INDUCIBLE FACTOR 1 ALPHA (HIF1A) ACTIVITY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii264. http://dx.doi.org/10.1093/neuonc/noac209.1018.
Abstract:
Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients have better survival. Investigating the molecular mechanisms underlying this disparity is imperative for understanding its development and progression as well as developing novel treatment paradigms. Carbohydrate (namely glucose) metabolism is a critical GBM nutrient source for biosynthesis, energetics, and reducing equivalents. Previously, our group discovered that elevated glycolytic activity uniquely predicted the outcomes of male, but not female, lower grade glioma patients. Our goal was to characterize sex differences in GBM carbohydrate metabolism and their effects on cellular phenotype. First, we discovered that male transformed murine astrocytes were more susceptible to glucose deprivation than females. We confirmed this phenotype with irreversible inhibition of hexokinase with 2-deoxyglucose as well as a GLUT1-selective inhibitor. Time-resolved stable isotope tracing of cell metabolism with carbon-13 glucose in transformed astrocytes further supported these findings; male cells had significantly higher rates of glucose uptake and metabolism than female cells. These results were validated with stable isotope metabolomics datasets from human cancer cell lines. Using additional assays of cellular metabolism, we discovered that male transformed astrocytes had a higher glycolytic rate, higher pyruvate kinase activity, higher mitochondrial respiration, and higher mitochondrial mass compared to females. This was validated by a TCGA pancancer analysis that revealed significantly higher expression of nuclear genes involved in mitochondrial regulation in males than in females. This prompted us to identify possible regulators of this metabolic phenotype. We discovered that HIF1A had robust hypoxia-inducible expression that was significantly higher in male transformed astrocytes. Moreover, HIF1A expression as well as its target transcripts were significantly higher in TCGA pancancer tumor datasets. Together, our data underscore the potential for developing sex-specific metabolic targeting approaches for patients with GBM.
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Deng, Chao, Hang Guo, Dongliang Yan, Tao Liang, Xuxiao Ye, and Zuowei Li. "Pancancer Analysis of Neurovascular-Related NRP Family Genes as Potential Prognostic Biomarkers of Bladder Urothelial Carcinoma." BioMed Research International 2021 (April 15, 2021): 1–31. http://dx.doi.org/10.1155/2021/5546612.
Abstract:
Background. Neurovascular-related genes have been implicated in the development of cancer. Studies have shown that a high expression of neuropilins (NRPs) promotes tumourigenesis and tumour malignancy. Method. A multidimensional bioinformatics analysis was performed to examine the relationship between NRP genes and prognostic and pathological features, tumour mutational burden (TMB), microsatellite instability (MSI), and immunological features based on public databases and find the potential prognostic value of NRPs in pancancer. Results. Survival analysis revealed that a low NRP1 expression in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), low-grade glioma (LGG), and stomach adenocarcinoma (STAD) was associated with poor prognosis. A high NRP2 expression in bladder urothelial carcinoma (BLCA), kidney renal papillary cell carcinoma (KIRP), and mesothelioma (MESO) was associated with poor prognosis. Moreover, NRP1 and NRP2 were associated with TMB and MSI. Subsequent analyses showed that NRP1 and NRP2 were correlated with immune infiltration and immune checkpoints. Genome-wide association analysis revealed that the NRP1 expression was strongly associated with kidney renal clear cell carcinoma (KIRC), whereas the NRP2 expression was closely associated with BLCA. Ultimately, NRP2 was found to be involved in the development of BLCA. Conclusions. Neurovascular-related NRP family genes are significantly correlated with cancer prognosis, TME, and immune infiltration, particularly in BLCA.
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Miyashita, Hirotaka, Nicholas J. Bevins, Kartheeswaran Thangathurai, Suzanna Lee, Sarabjot Pabla, Mary Nesline, Sean Glenn, et al. "Comprehensive transcriptomic analysis of immune checkpoint markers in a pancancer cohort: Implications for response and resistance." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2555. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2555.
Abstract:
2555 Background: Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, not all patients with cancer benefit from ICB. One possible explanation for poor responders/resistance is the variable expression level of the target molecules (e.g., PD-1 and PD-L1) in the tumor microenvironment. There are recent or ongoing trials targeting variable pathways for immune evasion (e.g., LAG3 or IDO1). It is therefore of interest to know the expression levels related to variable immune checkpoints so that clinical trials can focus on the patients who can benefit from the cognate treatment. Methods: Overall, 514 patients with various solid tumors seen at the University of San Diego, Moores Center for Personalized Cancer Therapy were analyzed. The expression levels of checkpoint markers (ADORA2A, BTLA, CD276, CTLA4, IDO1, IDO2, LAG3, NOS2, PD-1, PD-L1, PD-L2, PVR, TIGIT, TIM3, VISTA, and VTCN) in the tumor samples were measured through RNA sequencing and normalized to internal housekeeping gene profiles, and ranked from 0 to 100 percentile based on a reference population. The expressions of each checkpoint marker were correlated with cancer types, microsatellite instability (MSI), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) status on immunohistochemistry. Results: In this cohort, 60% were female, median age of 60, and included 30 different tumor types, with colorectal cancer being the most common (27%). The rank values of all checkpoint markers were distributed broadly from 0 to 99 or 100. CD276 and NOS2 had the highest (68th percentile) and lowest (13.5 percentile) median rank values, respectively. When rank values were categorized to “Low” (0-24), “Intermediate” (25-74), and “High” (75-100), 41.6% of patients showed high expression of CD276 while only 13% showed high expression of PD-L1. Each patient had a distinctive protfolio of the categorical expression levels of 16 checkpoint markers. Several checkpoint markers, especially NOS2, showed a significant correlation with cancer type. (median rank values in colorectal, stomach, pancreatic, and breast cancer were 79, 76, 5 and 0 respectively, p < 0.001) Five markers (IDO1, LAG3, PD-1, PD-L1, and TIGIT) showed significant correlation with MSI, while seven markers (CTLA4, IDO1, LAG3, PD-1, PD-L1, PD-L2, and TIGIT) were significantly associated with positive PD-L1 status. However, no significant association was seen based on TMB or tissue-specific grouping of patients. Conclusions: The expression of immune checkpoint markers varies from patient to patient, though transcript expression of several markers correlates with cancer type, MSI, and PD-L1 status. Clinical trials with patient selection based on the expression level of checkpoint markers matched to the corresponding ICB drug are warranted.
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Niavarani, Ahmadreza, Asieh Shahrabi Farahani, Maryam Sharafkhah, and Minoo Rassoulzadegan. "Pancancer analysis identifies prognostic high-APOBEC1 expression level implicated in cancer in-frame insertions and deletions." Carcinogenesis 39, no. 3 (January 13, 2018): 327–35. http://dx.doi.org/10.1093/carcin/bgy005.
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Arigbede, Olumide, Sarah G. Buxbaum, Sara Falzarano, and Suhn Rhie. "Abstract A078: Exploration, analysis and visualization of TCGA pancancer data in the cBioPortal: Prostate adenocarcinoma genomics." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): A078. http://dx.doi.org/10.1158/1538-7755.disp22-a078.
Abstract:
Abstract Background Prostate cancer cases are more likely among Black men than their counterparts – and only a few epigenetic studies of prostate cancer have been performed. We hypothesized that differential gene methylation may contribute to racial disparity of prostate adenocarcinoma. MethodsFrom the Prostate Adenocarcinoma in the TCGA PanCancer data, we selected 154 samples from 7 Blacks and 147 Whites. We analyzed the dataset by race/ethnicity, gene methylation and genomic alterations. We test our hypothesis by analyzing genetic alterations and methylation; genes with highest frequencies by race/ethnic group and significant methylation were recorded, respectively. Log ratio of mean methylation in Blacks to mean in whites were performed across the data. Multivariable data analysis, to test for association between race and genes, was performed using the Log Ratio statistic. Kaplan-Meier survival analysis was also performed on the sample data. Results A total of 494 prostate cancer patients were identified from the cBioPortal; a sample cohort of 154 patients comprising 7 Blacks and 147 Whites were used to for this analysis. The median age of the selected men was 63 years (range: 42-78). Using log ratio statistic, the data demonstrated significant (q < 0.05) by race/ethnicity. The association between race/ethnicity and methylation for the 60 genes (14 of which were Black and 46 were white) investigated in prostate cancer data also varied differentially. In Blacks, for example, UBL5 (m: 0.62 vs 0.53, q <0.05), ART4 (m: 0.95 vs 0.90, q <0.05), …, KATNB1 (m: 0.90 vs 0.82, q <0.05) were differentially methylated (Table 1) compared to Whites. Similarly, among Whites, ZNF57 (m: 0.30 vs 0.03, q <0.005), LRIG1 (m: 0.23 vs 0.07, q <0.005), …, EN2 (m: 0.08 vs 0.04, q <0.005) were also differentially methylated in comparison with Blacks. In the genomic alteration analysis: Blacks have more genes with frequent (>30%) alterations than Whites.10 genes had high percentage of gene alterations among Blacks (particularly CSMD1 and KHDRBS3) overlapping with 2 in whites (ERG and TMPRSS2). In this data, age groups 44-56 and 56-61 are the most frequent. On the survival analysis, NUDT12 (LR: 0.05, q <0.005), RPL26 (LR: 0.02 q <0.005), and others were associated with survival. Discussion Comparing the race/ethnicity groups using the methylation and the genetic alterations data, we were able to confirm that genetic alteration and DNA methylation are significantly differentiated, respectively. There exists significant association between race category, age category and genes, causing variation in methylation and genomic alterations. Conclusion In the prostate cancer data, race/ethnicity has an impact on genomic methylation. This factor also has an impact on genetic alterations. Prostate cancer epigenetic studies must take race/ethnicity into consideration. Our genomic samples were sufficient to show a difference in the epigenetic landscape between Blacks and whites. Citation Format: Olumide Arigbede, Sarah G. Buxbaum, Sara Falzarano, Suhn Rhie. Exploration, analysis and visualization of TCGA pancancer data in the cBioPortal: Prostate adenocarcinoma genomics [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A078.
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Champion, Magali, Kevin Brennan, Tom Croonenborghs, Andrew J. Gentles, Nathalie Pochet, and Olivier Gevaert. "Module Analysis Captures Pancancer Genetically and Epigenetically Deregulated Cancer Driver Genes for Smoking and Antiviral Response." EBioMedicine 27 (January 2018): 156–66. http://dx.doi.org/10.1016/j.ebiom.2017.11.028.
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Reckamp, Karen L., Jasmine A. McQuerry, Isa Mambetsariev, Rebecca Pharaon, Susan E. Yost, Jeremy Fricke, Tamara Mirzapoiazova, et al. "Co-stimulatory and co-inhibitory immune markers in solid tumors with MET alterations." Future Science OA 7, no. 2 (February 2021): FSO662. http://dx.doi.org/10.2144/fsoa-2020-0159.
Abstract:
The implication of MET alterations in solid tumors and the immune microenvironment remains elusive. Formalin-fixed, paraffin-embedded samples of 21 patients with solid tumors harboring MET alterations were used for immunohistochemical staining. Extracted RNA was analyzed with the NanoString nCounter human PanCancer immune profiling panel (NanoString Technologies, Inc., WA, USA). Patients were diagnosed with lung (n = 10), breast (n = 5), genitourinary (n = 3) or colorectal cancer (n = 3). Eleven had a MET missense mutation, four had an exon 14 splice site mutation and six had MET amplification. CD6, CCL19, CD40LG, XCR1, MAGEA1, ATM and CCL19 genes were significantly differentially expressed in MET-altered cancers. MET alterations may have a role in various solid tumors as potential therapeutic targets and combination therapy candidates with immune checkpoint inhibitors.
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Wu, Zixuan, Dongli Jiang, Xuyan Huang, Minjie Cai, Kai Yuan, and Peidong Huang. "S100A8 as a Promising Biomarker and Oncogenic Immune Protein in the Tumor Microenvironment: An Integrative Pancancer Analysis." Journal of Oncology 2022 (March 18, 2022): 1–15. http://dx.doi.org/10.1155/2022/6947652.
Abstract:
Background. S100 Calcium Binding Protein A8 (S100A8) is beneficial for cancer immunotherapy. However, the processes underlying its therapeutic potential have not been completely studied. Methods. The Cancer Genome Atlas provides raw data on 33 different cancer types. GEO made available GSE67501, GSE78220, and IMvigor210. We investigated S100A8’s genetic changes, expression patterns, and survival studies. The linkages between S100A8 and TME, as well as its association with immunological processes/elements and the major histocompatibility complex, were explored to effectively understand the role of S100A8 in cancer immunotherapy. Three distinct immunotherapeutic cohorts were employed to examine the relationship between S100A8 and immunotherapeutic response. Results. S100A8 expression was high in tumor tissue. The overexpression of S100A8 is associated with poor clinical outcome in patients with overall survival. S100A8 is associated with immune cell infiltration, immunological modulators, and immunotherapeutic indicators. S100A8 overexpression is connected to immune-related pathways. However, no statistically significant connection between S100A8 and immunotherapeutic response was identified. Conclusions. S100A8 may be a reliable biomarker for tumor prognosis and a viable prospective therapeutic target for human cancer immunotherapy (e.g., GBM, KIRC, LGG, and LIHC).
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Wu, Yumeng, Xuming Wu, Yuanyuan Li, Wenjing Zhao, Yanping Yue, Biao Wu, Jibin Liu, Xudong Chen, and Aiguo Shen. "Comprehensive Analysis of Glutamate-Rich WD Repeat-Containing Protein 1 and Its Potential Clinical Significance for Pancancer." BioMed Research International 2021 (September 27, 2021): 1–16. http://dx.doi.org/10.1155/2021/8201377.
Abstract:
Background and Objective. Glutamate-rich WD repeat-containing protein 1 (GRWD1), as a novel CDT1-binding protein, plays a critical role in the initial stage of DNA replication. To date, few studies have shown that GRWD1 is a driving factor for lung cancer, bladder cancer, and colorectal cancer. However, no systematic pancancer analysis has been carried out. This study was aimed at exploring its expression signature, prognostic value, immune infiltration pattern, and biological functions using bioinformatics tools. Methods. The expression level of GRWD1 in human cancer tissues was analyzed using the Tumor Immune Evaluation Resource (ver. 2.0, TIMER2), Gene Expression Profiling Interactive Analysis (ver. 2, GEPIA2), and UALCAN databases. The Kaplan-Meier plotter was utilized to analyze the survival data. Spearman’s correlation analysis was used to find out the correlation between the expression level of GRWD1 and predictive biomarkers, such as tumor mutation burden (TMB) and microsatellite instability (MSI). Furthermore, the MEXPRESS website was used to study the potential relationship between DNA methylation level of GRWD1 and pathological staging. We utilized the “immune” module provided on the TIMER2 website to explore the relationship between the expression level of GRWD1 and immune infiltration in all types of cancer in TCGA. Pearson’s correlation analysis was used to investigate the correlation between the expression level of GRWD1 and the expression levels of immune checkpoint-related genes. For protein expression analysis, we used the CPTAC module provided by the UALCAN portal to compare the total protein and phosphorylated protein level of GRWD1 in adjacent normal and tumor tissues. Results. GRWD1 was overexpressed in tissues of most types of cancer, in which the expression levels of GRWD1 in the kidney chromophobe (KICH), kidney renal papillary cell carcinoma (KIRP), and kidney renal clear cell carcinoma (KIRC) tissues showed an opposite trend, and the expression level of GRWD1 was correlated to only the KIRC tumor stage. The results of survival analysis showed that the expression level of GRWD1 was significantly associated with overall survival in six types of cancer and disease-free survival (DFS) in three types of cancer. Importantly, the increased expression level of GRWD1 was strongly correlated with prognosis of KIRC patients. There was a positive relationship between the expression level of GRWD1 and immune cell infiltration in several types of cancer, and the expression level of GRWD1 was also positively correlated with TMB, MSI, and DNA methylation in some types of cancer. The results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that “ubiquitin mediated proteolysis,” “spliceosome,” and “nucleotide excision repair” were involved in the effect of GRWD1 expression on tumor pathogenesis. Conclusion. This pancancer analysis provided a comprehensive overview of the carcinogenic effects of GRWD1 on a variety of human cancers. The results of bioinformatics analysis indicated GRWD1 as a promising biomarker for detection, prognosis, and therapeutic assessment of diverse types of cancer, and GRWD1 could act as a tumor suppressor in KIRC.
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Li, Xuanyi, Ben Ho Park, Justin M. Balko, and Douglas Buckner Johnson. "Pathway enrichment analysis in tumors with high mutation burdens and interferon-γ signature expression: A pancancer analysis." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 3138. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.3138.
Abstract:
3138 Background: Tumor mutation burden (TMB) correlates with immunotherapy response, but outcomes still vary in high TMB cancers, and many high TMB tumors lack T cell infiltration. Here, we assessed gene expression signatures of high TMB, including both inflamed and non-inflamed tumors (defined by interferon-γ [IFN-γ] gene signatures). Methods: Gene set enrichment analysis (GSEA) was assessed from RNA-sequencing data in tumors in TCGA. TMB and IFN-γ signature score were assessed by previously published methods. We performed GSEA on high vs low TMB tumors, and further stratified by high vs low IFN-γ signature expression within high TMB tumors. We validated results in Tempus RNA-sequencing data from 264 patients at Vanderbilt. Results: 4020 TCGA cases in non-small cell lung, melanoma, bladder, head and neck, kidney, and colorectal cancer were included. Major signatures upregulated in the high TMB group included cell cycle signaling, nuclear protein/mRNA export, cholesterol biosynthetics, and ubiquitin signaling. High TMB/high IFN-γ signature tumors were enriched in immune-related pathways (neutrophil and monocyte chemotaxis, T cell activation and proliferation, and interleukin-1 secretion), and non-immune pathways including cAMP metabolic process and phosphatidylinositol signaling. High TMB/low IFN-γ signature tumors had enriched pathways in nonsense mediated decay, electron transport chain/oxidative phosphorylation, and mitochondrial translational disassembly. 264 tumors from Vanderbilt were used for validation; pathways including cholesterol biosynthetics also correlated with immunotherapy response. Conclusions: High TMB tumors were enriched in pathways such as ubiquitin signaling, which could regulate immune cell function in antitumor immunity. Within high TMB cancers, tumors with higher IFN-γ signatures have enriched immune-related, and metabolic pathways, which could suggest novel therapeutic targets to make high TMB/ low IFN-γ tumors more immunogenic.
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Xu, Yining, Xinran Cui, Liyuan Zhang, Tianyi Zhao, and Yadong Wang. "Metastasis-related gene identification by compound constrained NMF and a semisupervised cluster approach using pancancer multiomics features." Computers in Biology and Medicine 151 (December 2022): 106263. http://dx.doi.org/10.1016/j.compbiomed.2022.106263.
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Deng, Hui, Hanming Yao, Shurui Zhou, Chong He, Yuzhou Huang, Yunlong Li, Hanwei Chen, and Jianchang Shu. "Pancancer analysis uncovers an immunological role and prognostic value of the m6A reader IGF2BP2 in pancreatic cancer." Molecular and Cellular Probes 73 (February 2024): 101948. http://dx.doi.org/10.1016/j.mcp.2023.101948.
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Huang, Juntao, Ziqian Xu, Dahua Chen, Chongchang Zhou, and Yi Shen. "Pancancer analysis reveals the role of disulfidptosis in predicting prognosis, immune infiltration and immunotherapy response in tumors." Medicine 102, no. 52 (December 29, 2023): e36830. http://dx.doi.org/10.1097/md.0000000000036830.
Abstract:
Disulfidptosis has been reported as a novel cell death process, suggesting a therapeutic strategy for cancer treatment. Herein, we constructed a multiomics data analysis to reveal the effects of disulfidptosis in tumors. Data for 33 kinds of tumors were downloaded from UCSC Xene, and disulfidptosis-related genes (DRGs) were selected from a previous study. After finishing processing data by the R packages, the expression and coexpression of DRGs in different tumors were assessed as well as copy number variations. The interaction network was drawn by STRING, and the activity of disulfidptosis was compared to the single-sample gene set enrichment analysis algorithm. Subsequently, the differences in DRGs for prognosis and clinicopathological features were evaluated, and the tumor immune microenvironment was assessed by the TIMER and TISCH databases. Tumor mutation burden, stem cell features and microsatellite instability were applied to predict drug resistance, and the expression of checkpoints was identified for the prediction of immunotherapy. Moreover, the TCIA, CellMiner and Enrichr databases were also utilized for selecting potential agents. Ten DRGs were differentially expressed in tumors, and the plots of coexpression and interaction revealed their correlation. Survival analysis suggested SLC7A11 as the most prognosis-related DRG with the most significant results. Additionally, the comparison also reflected the differences in DRGs in the status of pathologic lymph node metastasis for 5 types of tumors. The tumor immune microenvironment showed commonality among tumors based on immune infiltration and single-cell sequencing, and the analysis of tumor mutation burden, stemness and microsatellite instability showed a mostly positive correlation with DRGs. Moreover, referring to the prediction about clinical treatment, most DRGs can enhance sensitivity to chemotherapeutic agents but decrease the response to immune inhibitors with increasing expression. In this study, a primarily synthetic landscape of disulfidptosis in tumors was established and provided guidance for further exploration and investigation.
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International, BioMed Research. "Retracted: Pancancer Analysis of Neurovascular-Related NRP Family Genes as Potential Prognostic Biomarkers of Bladder Urothelial Carcinoma." BioMed Research International 2024 (March 20, 2024): 1. http://dx.doi.org/10.1155/2024/9802197.
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Leivonen, Suvi-Katri, Judit Jørgensen, Thomas Stauffer Larsen, Annika Pasanen, Marja-Liisa Karjalainen-Lindsberg, Helle M. Toldbod, Francesco d'Amore, and Sirpa Leppa. "Molecular Profiling of Aggressive Non-Hodgkin Lymphoma - Results from a Phase 1/2 Preben Study." Blood 134, Supplement_1 (November 13, 2019): 5314. http://dx.doi.org/10.1182/blood-2019-129113.
Abstract:
Background: Aggressive non-Hodgkin lymphoma (NHL) relapsing after standard first line chemotherapy represents an unmet clinical need. Currently, a phase 1/2 study with the combination of pixantrone, etoposide, bendamustine, and in CD20 positive tumors, rituximab, in patients with relapsed aggressive NHL of B- or T- cell phenotype (the PREBEN study) is ongoing. Here our aim was to molecularly characterize samples from the PREBEN trial and find clinical correlates for predicting treatment response. Methods: The profiling cohort consisted of 21 patients with pre-treatment RNA samples and clinical data. Nanostring PanCancer Pathways and PanCancer Immune profiling panels (altogether 1348 genes) were utilized for the gene expression analyses. The findings from gene expression analyses were correlated with clinical parameters. Results: Fourteen patients had diffuse large B-cell lymphoma (DLBCL), whereas seven had peripheral T-cell lymphoma (PTCL). In general, the expression of DNA replication genes distinguished DLBCL from PTCL. Additionally, gene expression analyses identified genes having differential expression based on the response to the treatment. Supervised hierarchical clustering of the ten most differentially expressed genes could separate the responding (n=4) and non-responding (n=10) DLBCL patients into two distinct subgroups (Fig. 1A). Similarly, the responding (n=3) and non-responding (n=4) PTCL patients could be separated into distinct subgroups by supervised clustering with the ten most differentially expressed genes (Fig. 1B). Conclusion: Molecular profiles of aggressive NHL are heterogeneous and may be utilized for predicting the treatment response. More detailed molecular analyses are currently ongoing. Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. d'Amore:Servier: Research Funding. Leppa:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: combination of bendamustine and pixantrone for relapsed NHL