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Cherniack, Andrew

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Cherniack

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Andrew

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Cherniack, Andrew

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2013 - 20184

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Author's Publications: search.filters.isAuthorOfPublication.5c5a6622-5ff6-44bf-b8d1-680fb12fe75f

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Now showing 1 - 4 of 4
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    Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas
    (2018) Way, Gregory P.; Sanchez-Vega, Francisco; La, Konnor; Armenia, Joshua; Chatila, Walid K.; Luna, Augustin; Sander, Chris; Cherniack, Andrew; Mina, Marco; Ciriello, Giovanni; Schultz, Nikolaus; Sanchez, Yolanda; Greene, Casey S.
    SUMMARY Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these “hidden responders” may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders.
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    Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
    (2018) Knijnenburg, Theo A.; Wang, Linghua; Zimmermann, Michael T.; Chambwe, Nyasha; Gao, Galen F.; Cherniack, Andrew; Fan, Huihui; Shen, Hui; Way, Gregory P.; Greene, Casey S.; Liu, Yuexin; Akbani, Rehan; Feng, Bin; Donehower, Lawrence A.; Miller, Chase; Shen, Yang; Karimi, Mostafa; Chen, Haoran; Kim, Pora; Jia, Peilin; Shinbrot, Eve; Zhang, Shaojun; Liu, Jianfang; Hu, Hai; Bailey, Matthew H.; Yau, Christina; Wolf, Denise; Zhao, Zhongming; Weinstein, John N.; Li, Lei; Ding, Li; Mills, Gordon B.; Laird, Peter W.; Wheeler, David A.; Shmulevich, Ilya; Monnat, Raymond J; Xiao, Yonghong; Wang, Chen
    SUMMARY DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.
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    Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles
    (2017) Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie-Claude; Newton, Yulia; Shih, Juliann; Robertson, A. Gordon; Hinoue, Toshinori; Hoadley, Katherine A.; Gibb, Ewan A.; Roszik, Jason; Covington, Kyle R.; Wu, Chia-Chin; Shinbrot, Eve; Stransky, Nicolas; Hegde, Apurva; Yang, Ju Dong; Reznik, Ed; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I.; Hess, Julian M.; Auman, J. Todd; Rhie, Suhn K.; Bowlby, Reanne; Borad, Mitesh J.; Zhu, Andrew; Stuart, Josh M.; Sander, Chris; Akbani, Rehan; Cherniack, Andrew; Deshpande, Vikram; Mounajjed, Taofic; Foo, Wai Chin; Torbenson, Michael S.; Kleiner, David E.; Laird, Peter W.; Wheeler, David A.; McRee, Autumn J.; Bathe, Oliver F.; Andersen, Jesper B.; Bardeesy, Nabeel; Roberts, Lewis R.; Kwong, Lawrence N.
    Summary Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
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    Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
    (American Association for Cancer Research (AACR), 2013) Akbay, Esra A.; Koyama, S.; Carretero, J.; Altabef, A.; Tchaicha, J. H.; Christensen, Camilla; Mikse, O. R.; Cherniack, Andrew; Beauchamp, Ellen; Pugh, Trevor J.; Wilkerson, M. D.; Fecci, Peter; Butaney, M.; Reibel, J. B.; Soucheray, M.; Cohoon, T. J.; Janne, Pasi; Meyerson, Matthew; Hayes, D. N.; Shapiro, Geoffrey; Shimamura, Takeshi; Sholl, Lynette; Rodig, Scott; Freeman, Gordon; Hammerman, Peter S.; Dranoff, Glenn; Wong, Kwok-Kin
    The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.