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1.  Unraveling the molecular pathways of DNA-methylation inhibitors: human endogenous retroviruses induce the innate immune response in tumors  
Oncoimmunology  2015;5(5):e1122160.
ABSTRACT
Loss of DNA methylation can activate endogenous retroviral expression and dsRNA in cancer cells. This leads to induction of toll-like receptor signaling stimulating an antiviral interferon response. Recent findings provide a therapeutic rationale for combining DNA methylation inhibitors with blockage of immune checkpoint proteins to fight cancer.
doi:10.1080/2162402X.2015.1122160
PMCID: PMC4910697  PMID: 27467919
DNA methylation;  dsRNA; endogeneous retrovirus (ERV); epigenetic therapy;  IFN-signalling;  immune checkpoints; innate immunity; TLR
2.  Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma 
PLoS ONE  2016;11(9):e0162929.
Background
O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA.
Methods
Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations.
Results
MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups.
Conclusions
Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs.
doi:10.1371/journal.pone.0162929
PMCID: PMC5028050  PMID: 27643594
3.  Genome-wide positioning of bivalent mononucleosomes 
BMC Medical Genomics  2016;9:60.
Background
Bivalent chromatin refers to overlapping regions containing activating histone H3 Lys4 trimethylation (H3K4me3) and inactivating H3K27me3 marks. Existence of such bivalent marks on the same nucleosome has only recently been suggested. Previous genome-wide efforts to characterize bivalent chromatin have focused primarily on individual marks to define overlapping zones of bivalency rather than mapping positions of truly bivalent mononucleosomes.
Results
Here, we developed an efficacious sequential ChIP technique for examining global positioning of individual bivalent nucleosomes. Using next generation sequencing approaches we show that although individual H3K4me3 and H3K27me3 marks overlap in broad zones, bivalent nucleosomes are focally enriched in the vicinity of the transcription start site (TSS). These seem to occupy the H2A.Z nucleosome positions previously described as salt-labile nucleosomes, and are correlated with low gene expression. Although the enrichment profiles of bivalent nucleosomes show a clear dependency on CpG island content, they demonstrate a stark anti-correlation with methylation status.
Conclusions
We show that regional overlap of H3K4me3 and H3K27me3 chromatin tend to be upstream to the TSS, while bivalent nucleosomes with both marks are mainly promoter proximal near the TSS of CpG island-containing genes with poised/low expression. We discuss the implications of the focal enrichment of bivalent nucleosomes around the TSS on the poised chromatin state of promoters in stem cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-016-0221-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-016-0221-6
PMCID: PMC5025636  PMID: 27634286
Bivalent mononucleosomes; Bivalency; DNA methylation; Chromatin; H3K4me3; H3K27me3
4.  Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses 
Cell  2015;162(5):974-986.
Summary
We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.
doi:10.1016/j.cell.2015.07.011
PMCID: PMC4556003  PMID: 26317466
5.  Comprehensive Molecular Characterization of Papillary Renal Cell Carcinoma 
Linehan, W. Marston | Spellman, Paul T. | Ricketts, Christopher J. | Creighton, Chad J. | Fei, Suzanne S. | Davis, Caleb | Wheeler, David A. | Murray, Bradley A. | Schmidt, Laura | Vocke, Cathy D. | Peto, Myron | Al Mamun, Abu Amar M. | Shinbrot, Eve | Sethi, Anurag | Brooks, Samira | Rathmell, W. Kimryn | Brooks, Angela N. | Hoadley, Katherine A. | Robertson, A. Gordon | Brooks, Denise | Bowlby, Reanne | Sadeghi, Sara | Shen, Hui | Weisenberger, Daniel J. | Bootwalla, Moiz | Baylin, Stephen B. | Laird, Peter W. | Cherniack, Andrew D. | Saksena, Gordon | Haake, Scott | Li, Jun | Liang, Han | Lu, Yiling | Mills, Gordon B. | Akbani, Rehan | Leiserson, Mark D.M. | Raphael, Benjamin J. | Anur, Pavana | Bottaro, Donald | Albiges, Laurence | Barnabas, Nandita | Choueiri, Toni K. | Czerniak, Bogdan | Godwin, Andrew K. | Hakimi, A. Ari | Ho, Thai | Hsieh, James | Ittmann, Michael | Kim, William Y. | Krishnan, Bhavani | Merino, Maria J. | Mills Shaw, Kenna R. | Reuter, Victor E. | Reznik, Ed | Shelley, Carl Simon | Shuch, Brian | Signoretti, Sabina | Srinivasan, Ramaprasad | Tamboli, Pheroze | Thomas, George | Tickoo, Satish | Burnett, Kenneth | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Mallery, David | Morris, Scott | Paulauskis, Joseph D. | Penny, Robert J. | Shelton, Candace | Shelton, W. Troy | Sherman, Mark | Thompson, Eric | Yena, Peggy | Avedon, Melissa T. | Bowen, Jay | Gastier-Foster, Julie M. | Gerken, Mark | Leraas, Kristen M. | Lichtenberg, Tara M. | Ramirez, Nilsa C. | Santos, Tracie | Wise, Lisa | Zmuda, Erik | Demchok, John A. | Felau, Ina | Hutter, Carolyn M. | Sheth, Margi | Sofia, Heidi J. | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean C. | Zhang, Jiashan (Julia) | Ayala, Brenda | Baboud, Julien | Chudamani, Sudha | Liu, Jia | Lolla, Laxmi | Naresh, Rashi | Pihl, Todd | Sun, Qiang | Wan, Yunhu | Wu, Ye | Ally, Adrian | Balasundaram, Miruna | Balu, Saianand | Beroukhim, Rameen | Bodenheimer, Tom | Buhay, Christian | Butterfield, Yaron S.N. | Carlsen, Rebecca | Carter, Scott L. | Chao, Hsu | Chuah, Eric | Clarke, Amanda | Covington, Kyle R. | Dahdouli, Mahmoud | Dewal, Ninad | Dhalla, Noreen | Doddapaneni, HarshaVardhan | Drummond, Jennifer | Gabriel, Stacey B. | Gibbs, Richard A. | Guin, Ranabir | Hale, Walker | Hawes, Alicia | Hayes, D. Neil | Holt, Robert A. | Hoyle, Alan P. | Jefferys, Stuart R. | Jones, Steven J.M. | Jones, Corbin D. | Kalra, Divya | Kovar, Christie | Lewis, Lora | Li, Jie | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Meng, Shaowu | Meyerson, Matthew | Mieczkowski, Piotr A. | Moore, Richard A. | Morton, Donna | Mose, Lisle E. | Mungall, Andrew J. | Muzny, Donna | Parker, Joel S. | Perou, Charles M. | Roach, Jeffrey | Schein, Jacqueline E. | Schumacher, Steven E. | Shi, Yan | Simons, Janae V. | Sipahimalani, Payal | Skelly, Tara | Soloway, Matthew G. | Sougnez, Carrie | Tam, Angela | Tan, Donghui | Thiessen, Nina | Veluvolu, Umadevi | Wang, Min | Wilkerson, Matthew D. | Wong, Tina | Wu, Junyuan | Xi, Liu | Zhou, Jane | Bedford, Jason | Chen, Fengju | Fu, Yao | Gerstein, Mark | Haussler, David | Kasaian, Katayoon | Lai, Phillip | Ling, Shiyun | Radenbaugh, Amie | Van Den Berg, David | Weinstein, John N. | Zhu, Jingchun | Albert, Monique | Alexopoulou, Iakovina | Andersen, Jeremiah J | Auman, J. Todd | Bartlett, John | Bastacky, Sheldon | Bergsten, Julie | Blute, Michael L. | Boice, Lori | Bollag, Roni J. | Boyd, Jeff | Castle, Erik | Chen, Ying-Bei | Cheville, John C. | Curley, Erin | Davies, Benjamin | DeVolk, April | Dhir, Rajiv | Dike, Laura | Eckman, John | Engel, Jay | Harr, Jodi | Hrebinko, Ronald | Huang, Mei | Huelsenbeck-Dill, Lori | Iacocca, Mary | Jacobs, Bruce | Lobis, Michael | Maranchie, Jodi K. | McMeekin, Scott | Myers, Jerome | Nelson, Joel | Parfitt, Jeremy | Parwani, Anil | Petrelli, Nicholas | Rabeno, Brenda | Roy, Somak | Salner, Andrew L. | Slaton, Joel | Stanton, Melissa | Thompson, R. Houston | Thorne, Leigh | Tucker, Kelinda | Weinberger, Paul M. | Winemiller, Cythnia | Zach, Leigh Anne | Zuna, Rosemary
The New England journal of medicine  2015;374(2):135-145.
Background
Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist.
Methods
We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas.
Results
Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene.
Conclusions
Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.
doi:10.1056/NEJMoa1505917
PMCID: PMC4775252  PMID: 26536169
6.  Epigenetic Therapeutics: A New Weapon in the War Against Cancer 
Annual review of medicine  2016;67:73-89.
The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.
doi:10.1146/annurev-med-111314-035900
PMCID: PMC4937439  PMID: 26768237
epigenetics; DNA methyltransferase inhibitor; histone deacetylase inhibitor therapy
7.  IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers 
Annals of surgery  2016;263(2):337-344.
Objectives
To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts.
Background
The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown.
Methods
IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics.
Results
Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low- and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04–4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10–5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence.
Conclusions
Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence.
doi:10.1097/SLA.0000000000001204
PMCID: PMC4648704  PMID: 25822686
colorectal cancer; IGFBP-3; methylation; recurrence
8.  Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer 
Epigenetics  2015;10(7):622-632.
Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, which are structural components of the cytoskeleton in mature neurons. Recent studies reported the deregulation of these proteins in several malignancies, suggesting that neurofilaments may have a role in other cell types as well. Using a comprehensive approach, we studied the epigenetic inactivation of neurofilament genes in breast cancer and the functional significance of this event. We report that DNA methylation-associated silencing of NEFH, NEFL, and NEFM in breast cancer is frequent, cancer-specific, and correlates with clinical features of disease progression. DNA methylation-mediated inactivation of these genes occurs also in multiple other cancer histologies including pancreas, gastric, and colon. Restoration of NEFH function, the major subunit of the neurofilament complex, reduces proliferation and growth of breast cancer cells and arrests them in Go/G1 phase of the cell cycle along with a reduction in migration and invasion. These findings suggest that DNA methylation-mediated silencing of the neurofilament genes NEFH, NEFM, and NEFL are frequent events that may contribute to the progression of breast cancer and possibly other malignancies.
doi:10.1080/15592294.2015.1050173
PMCID: PMC4622480  PMID: 25985363
breast cancer; DNA methylation; NEFH; NEFL; NEFM; TCGA
9.  Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer 
Purpose
Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer.
Experimental Design
We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of 8 promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis including methylation and expression. We used a nanoparticle-enabled MOB (Methylation On Beads) technology to detect early stage pancreatic cancers by analyzing DNA methylation in patient serum.
Results
We identified 2 novel genes, BNC1 (92%) and ADAMTS1, (68%) that showed a high frequency of methylation in pancreas cancers (n=143), up to 100% in PanIN-3 and 97% in Stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n=42) from pancreas cancer patients, with a sensitivity for BNC1 of 79% (95%CI:66-91%) and for ADAMTS1 of 48% (95%CI:33-63%), while specificity was 89% for BNC1 (95%CI:76-100%) and 92% for ADAMTS1 (95%CI:82-100%). Overall sensitivity using both markers is 81% (95%CI:69-93%) and specificity is 85% (95%CI:71-99%).
Conclusions
Promoter DNA methylation of BNC1 and ADAMTS1 are potential biomarkers to detect early stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.
doi:10.1158/1078-0432.CCR-12-3224
PMCID: PMC4310572  PMID: 24088737
DNA Methylation; Early detection biomarker; Pancreatic cancer; Cancer screening
10.  Harnessing the potential of epigenetic therapy to target solid tumors 
Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer.
doi:10.1172/JCI69736
PMCID: PMC3871229  PMID: 24382390
11.  Integrated Genomic Characterization of Papillary Thyroid Carcinoma 
Agrawal, Nishant | Akbani, Rehan | Aksoy, B. Arman | Ally, Adrian | Arachchi, Harindra | Asa, Sylvia L. | Auman, J. Todd | Balasundaram, Miruna | Balu, Saianand | Baylin, Stephen B. | Behera, Madhusmita | Bernard, Brady | Beroukhim, Rameen | Bishop, Justin A. | Black, Aaron D. | Bodenheimer, Tom | Boice, Lori | Bootwalla, Moiz S. | Bowen, Jay | Bowlby, Reanne | Bristow, Christopher A. | Brookens, Robin | Brooks, Denise | Bryant, Robert | Buda, Elizabeth | Butterfield, Yaron S.N. | Carling, Tobias | Carlsen, Rebecca | Carter, Scott L. | Carty, Sally E. | Chan, Timothy A. | Chen, Amy Y. | Cherniack, Andrew D. | Cheung, Dorothy | Chin, Lynda | Cho, Juok | Chu, Andy | Chuah, Eric | Cibulskis, Kristian | Ciriello, Giovanni | Clarke, Amanda | Clayman, Gary L. | Cope, Leslie | Copland, John | Covington, Kyle | Danilova, Ludmila | Davidsen, Tanja | Demchok, John A. | DiCara, Daniel | Dhalla, Noreen | Dhir, Rajiv | Dookran, Sheliann S. | Dresdner, Gideon | Eldridge, Jonathan | Eley, Greg | El-Naggar, Adel K. | Eng, Stephanie | Fagin, James A. | Fennell, Timothy | Ferris, Robert L. | Fisher, Sheila | Frazer, Scott | Frick, Jessica | Gabriel, Stacey B. | Ganly, Ian | Gao, Jianjiong | Garraway, Levi A. | Gastier-Foster, Julie M. | Getz, Gad | Gehlenborg, Nils | Ghossein, Ronald | Gibbs, Richard A. | Giordano, Thomas J. | Gomez-Hernandez, Karen | Grimsby, Jonna | Gross, Benjamin | Guin, Ranabir | Hadjipanayis, Angela | Harper, Hollie A. | Hayes, D. Neil | Heiman, David I. | Herman, James G. | Hoadley, Katherine A. | Hofree, Matan | Holt, Robert A. | Hoyle, Alan P. | Huang, Franklin W. | Huang, Mei | Hutter, Carolyn M. | Ideker, Trey | Iype, Lisa | Jacobsen, Anders | Jefferys, Stuart R. | Jones, Corbin D. | Jones, Steven J.M. | Kasaian, Katayoon | Kebebew, Electron | Khuri, Fadlo R. | Kim, Jaegil | Kramer, Roger | Kreisberg, Richard | Kucherlapati, Raju | Kwiatkowski, David J. | Ladanyi, Marc | Lai, Phillip H. | Laird, Peter W. | Lander, Eric | Lawrence, Michael S. | Lee, Darlene | Lee, Eunjung | Lee, Semin | Lee, William | Leraas, Kristen M. | Lichtenberg, Tara M. | Lichtenstein, Lee | Lin, Pei | Ling, Shiyun | Liu, Jinze | Liu, Wenbin | Liu, Yingchun | LiVolsi, Virginia A. | Lu, Yiling | Ma, Yussanne | Mahadeshwar, Harshad S. | Marra, Marco A. | Mayo, Michael | McFadden, David G. | Meng, Shaowu | Meyerson, Matthew | Mieczkowski, Piotr A. | Miller, Michael | Mills, Gordon | Moore, Richard A. | Mose, Lisle E. | Mungall, Andrew J. | Murray, Bradley A. | Nikiforov, Yuri E. | Noble, Michael S. | Ojesina, Akinyemi I. | Owonikoko, Taofeek K. | Ozenberger, Bradley A. | Pantazi, Angeliki | Parfenov, Michael | Park, Peter J. | Parker, Joel S. | Paull, Evan O. | Pedamallu, Chandra Sekhar | Perou, Charles M. | Prins, Jan F. | Protopopov, Alexei | Ramalingam, Suresh S. | Ramirez, Nilsa C. | Ramirez, Ricardo | Raphael, Benjamin J. | Rathmell, W. Kimryn | Ren, Xiaojia | Reynolds, Sheila M. | Rheinbay, Esther | Ringel, Matthew D. | Rivera, Michael | Roach, Jeffrey | Robertson, A. Gordon | Rosenberg, Mara W. | Rosenthall, Matthew | Sadeghi, Sara | Saksena, Gordon | Sander, Chris | Santoso, Netty | Schein, Jacqueline E. | Schultz, Nikolaus | Schumacher, Steven E. | Seethala, Raja R. | Seidman, Jonathan | Senbabaoglu, Yasin | Seth, Sahil | Sharpe, Samantha | Mills Shaw, Kenna R. | Shen, John P. | Shen, Ronglai | Sherman, Steven | Sheth, Margi | Shi, Yan | Shmulevich, Ilya | Sica, Gabriel L. | Simons, Janae V. | Sipahimalani, Payal | Smallridge, Robert C. | Sofia, Heidi J. | Soloway, Matthew G. | Song, Xingzhi | Sougnez, Carrie | Stewart, Chip | Stojanov, Petar | Stuart, Joshua M. | Tabak, Barbara | Tam, Angela | Tan, Donghui | Tang, Jiabin | Tarnuzzer, Roy | Taylor, Barry S. | Thiessen, Nina | Thorne, Leigh | Thorsson, Vésteinn | Tuttle, R. Michael | Umbricht, Christopher B. | Van Den Berg, David J. | Vandin, Fabio | Veluvolu, Umadevi | Verhaak, Roel G.W. | Vinco, Michelle | Voet, Doug | Walter, Vonn | Wang, Zhining | Waring, Scot | Weinberger, Paul M. | Weinstein, John N. | Weisenberger, Daniel J. | Wheeler, David | Wilkerson, Matthew D. | Wilson, Jocelyn | Williams, Michelle | Winer, Daniel A. | Wise, Lisa | Wu, Junyuan | Xi, Liu | Xu, Andrew W. | Yang, Liming | Yang, Lixing | Zack, Travis I. | Zeiger, Martha A. | Zeng, Dong | Zenklusen, Jean Claude | Zhao, Ni | Zhang, Hailei | Zhang, Jianhua | Zhang, Jiashan (Julia) | Zhang, Wei | Zmuda, Erik | Zou., Lihua
Cell  2014;159(3):676-690.
Summary
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
doi:10.1016/j.cell.2014.09.050
PMCID: PMC4243044  PMID: 25417114
12.  Cancer-like epigenetic derangements of human pluripotent stem cells and their impact on applications in regeneration and repair 
A growing body of work has raised concern that many human pluripotent stem cell (hPSC) lines possess tumorigenic potential following differentiation to clinically relevant lineages. In this review, we highlight recent work characterizing the spectrum of cancer-like epigenetic derangements in human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC) that are associated with reprogramming errors or prolonged culture that may contribute to such tumorigenicity. These aberrations include cancer-like promoter DNA hypermethylation and histone marks associated with pluripotency, as well as aberrant X-chromosome regulation. We also feature recent work that suggests optimized high-fidelity reprogramming derivation methods can minimize cancer-associated epigenetic aberrations in hPSC, and thus ultimately improve the ultimate clinical utility of hiPSC in regenerative medicine.
doi:10.1016/j.gde.2014.09.008
PMCID: PMC4262610  PMID: 25461449
13.  A Recombinant Reporter System for Monitoring Reactivation of an Endogenously DNA Hypermethylated Gene 
Cancer research  2014;74(14):3834-3843.
Reversing abnormal gene silencing in cancer cells due to DNA hypermethylation of promoter CpG islands may offer new cancer prevention or therapeutic approaches. Moreover, such approaches may be broadly applicable to enhance the efficacy of radiotherapy, chemotherapy or immunotherapy. Here we demonstrate the powerful utility of a novel gene reporter system to permit studies of the dynamics, mechanisms, and translational relevance of candidate therapies of this type in human colon cancer cells. The reporter system is based on in situ modification of the endogenous locus of the tumor suppressor gene SFRP1, a pivotal regulator of the Wnt pathway that is silenced by DNA hypermethylation in many colon cancers. The modified SFRP1-GFP reporter allele employed remained basally silent, like the unaltered allele, and it was activated only by drug treatments that de-repress gene silencing by reversing DNA hypermethylation. We employed the established DNA methyltransferase inhihibitor (DNMTi) 5-aza-deoxycitidine (DAC) to show how this system can be used to address key questions in the clinical development of epigenetic cancer therapies. First, we defined conditions for which clinically relevant dosing could induce sustained induction of RNA and protein. Second, we found that, in-vivo, a more prolonged drug exposure than anticipated was essential to de-repress gene silencing in significant cell numbers and this has implications for generating effective anticancer responses in patients with hematopoietic or solid tumors. Finally, we discovered how histone deacetylase inhibitors (HDACi) alone, when administered to cells actively replicating DNA, can robustly re-express the silenced gene with no change in promoter methylation status. Taken together, our findings offer a new tool and insights for devising optimal clinical experiments to evaluate DNMTi and HDACi, alone or in combination, and with other cancer treatments, as agents for the epigenetic management and prevention of cancer.
doi:10.1158/0008-5472.CAN-13-2287
PMCID: PMC4103012  PMID: 24876104
14.  Cancer epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance 
Molecular cell  2014;54(5):716-727.
Summary
The existence of sub-populations of cells in cancers with increased tumor initiating capacities and self-renewal potential, often termed ‘cancer stem cells’, is a much discussed and key area of cancer biology. Such cellular heterogeneity is very important due to its impact on therapy and especially states of treatment resistance. A major question is whether there is plasticity for evolution of these cell states during tumorigenesis which can involve movement between cell populations in a reversible fashion. In this review, we discuss the possible role of epigenetic abnormalities, as well as genetic alterations in such dynamics, and in the creation of cellular heterogeneity in cancers of all types.
doi:10.1016/j.molcel.2014.05.015
PMCID: PMC4103691  PMID: 24905005
15.  Alterations of immune response of non-small cell lung cancer with Azacytidine 
Oncotarget  2013;4(11):2067-2079.
Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA – Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints – in particular the PD-1/PD-L1 pathway – may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.
PMCID: PMC3875770  PMID: 24162015
Non-Small Cell Lung Cancer(NSCLC); Azacytidine; HDAC inhibitor
16.  CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas 
Epigenetics  2014;9(5):738-746.
CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.
doi:10.4161/epi.28082
PMCID: PMC4063833  PMID: 24518818
sporadic duodenal adenomas; ampullary adenomas; CpG island methylator phenotype; DNA methylation; gastrointestinal tumors
17.  Functional Identification of Cancer-Specific Methylation of CDO1, HOXA9, and TAC1 for the Diagnosis of Lung Cancer 
Purpose
Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer.
Experimental Design
Following previously validated methods for the discovery of cancer-specific hypermethylation changes we treated 8 NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publically available database and two independent cohorts of primary samples.
Results
We identified >300 candidate genes. Using The Cancer Genome Atlas (TCGA) and employing extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This 3-gene panel is 100% specific, showing no methylation in 75 TCGA normal and 7 primary normal samples and is 83–99% sensitive for NSCLC depending on the cohort.
Conclusion
This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this 3-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC.
doi:10.1158/1078-0432.CCR-13-2109
PMCID: PMC4019442  PMID: 24486589
18.  The Cancer Epigenome 
Epigenetic abnormalities in lung and other cancers continue to be defined at a rapid pace. We are coming to appreciate that cancers have an “epigenetic landscape” wherein genes vulnerable to abnormalities, such as promoter DNA hypermethylation and associated gene silencing, tend to reside in defined nuclear positions and chromosome domains and relationships to chromatin regulation, which facilitates states of stem cell renewal. These same genes and domains are also vulnerable to epigenetic abnormalities induced by factors to which cells are exposed during cancer risk states, such as chronic inflammation. We can use all of this basic information for translational purposes in terms of deriving biomarkers for cancer risk states and detection and therapeutic strategies.
doi:10.1513/pats.201201-001MS
PMCID: PMC3359110  PMID: 22550245
epigenetic; cancer; DNA hypermethylation
19.  Transient Low Doses of DNA Demethylating Agents Exert Durable Anti-tumor Effects on Hematological and Epithelial Tumor Cells 
Cancer Cell  2012;21(3):430-446.
SUMMARY
Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produce an anti-tumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genome-wide promoter DNA methylation, gene re-expression, and anti-tumor changes in key cellular regulatory pathways. Low dose decitabine and azacitidine may have broad applicability for cancer management.
doi:10.1016/j.ccr.2011.12.029
PMCID: PMC3312044  PMID: 22439938
20.  Cancer as a Manifestation of Aberrant Chromatin Structure 
In this article we review many important epigenetic changes in early carcinogenesis and discuss the possibility of these alterations being targeted for therapeutic intervention in the future. Both regional DNA methylation and global chromatin packaging are interrelated partners that function in concert to control gene transcription. We first summarize briefly DNA methylation and its role in gene expression. Then, we focus on how the DNA is packaged into chromatin and the tight relationship between chromatin and DNA methylation. A more complete understanding of these key, regulatory events is vital in approaching a more rational drug therapy to various malignancies.
doi:10.1097/PPO.0b013e31803c5415
PMCID: PMC3586529  PMID: 17464240
cancer; chromatin modification; DNA methylation; epigenetics
21.  Spectrin Repeat Containing Nuclear Envelope 1 and Forkhead Box Protein E1 Are Promising Markers for the Detection of Colorectal Cancer in Blood 
Identifying biomarkers in body fluids may improve the noninvasive detection of colorectal cancer. Previously, we identified N-Myc downstream-regulated gene 4 (NDRG4) and GATA binding protein 5 (GATA5) methylation as promising biomarkers for colorectal cancer in stool DNA. Here, we examined the utility of NDRG4, GATA5, and two additional markers [Forkhead box protein E1 (FOXE1) and spectrin repeat containing nuclear envelope 1 (SYNE1)] promoter methylation as biomarkers in plasma DNA. Quantitative methylation-specific PCR was performed on plasma DNA from 220 patients with colorectal cancer and 684 noncancer controls, divided in a training set and a test set. Receiver operating characteristic analysis was performed to measure the area under the curve of GATA5, NDRG4, SYNE1, and FOXE1 methylation. Functional assays were performed in SYNE1 and FOXE1 stably transfected cell lines. The sensitivity of NDRG4, GATA5, FOXE1, and SYNE1 methylation in all stages of colorectal cancer (154 cases, 444 controls) was 27% [95% confidence interval (CI), 20%–34%), 18% (95% CI, 12%–24%), 46% (95% CI, 38%– 54%), and 47% (95% CI, 39%–55%), with a specificity of 95% (95% CI, 93%–97%), 99% (95% CI, 98%–100%), 93% (95% CI, 91%–95%), and 96% (95% CI, 94%–98%), respectively. Combining SYNE1 and FOXE1, increased the sensitivity to 56% (95% CI, 48%–64%), while the specificity decreased to 90% (95% CI, 87%–93%) in the training set and to 58% sensitivity (95% CI, 46%–70%) and 91% specificity (95% CI, 80%–100%) in a test set (66 cases, 240 controls). SYNE1 overexpression showed no major differences in cell proliferation, migration, and invasion compared with controls. Overexpression of FOXE1 significantly decreased the number of colonies in SW480 and HCT116 cell lines. Overall, our data suggest that SYNE1 and FOXE1 are promising markers for colorectal cancer detection.
doi:10.1158/1940-6207.CAPR-14-0198
PMCID: PMC4316751  PMID: 25538088
22.  Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer 
Oncotarget  2014;6(1):56-70.
Recent clinical data in lung cancer suggests that epigenetically targeted therapy may selectively enhance chemotherapeutic sensitivity. There have been few if any studies rigorously evaluating this hypothesized priming effect. Here we describe a series of investigations testing whether epigenetic priming with azacitidine and entinostat increases sensitivity of NSCLC to cytotoxic agents.
We noted no differences in chemosensitivity following treatment with epigenetic therapy in in vitro assays of viability and colony growth. Using cell line and patient-derived xenograft (PDX) models, we also observed no change in responsiveness to cisplatin in vivo. In select models, we noted differential responses to irinotecan treatment in vivo. In vitro epigenetic therapy prior to tumor implantation abrogated response of H460 xenografts to irinotecan. Conversely, in vitro epigenetic therapy appeared to sensitize A549 xenografts (tumor growth inhibition 51%, vs. 22% in mock-pretreated control). In vivo epigenetic therapy enhanced the response of adenocarcinoma PDX to irinotecan.
Taken together, these data do not support broadly applicable epigenetic priming in NSCLC. Priming effects may be context-specific, dependent on both tumor and host factors. Further preclinical study is necessary to determine whether, and in which contexts, priming with epigenetic therapy has potential to enhance chemotherapeutic efficacy in NSCLC patients.
PMCID: PMC4381578  PMID: 25474141
epigenetic; azacitidine; entinostat; priming; chemosensitivity; non-small cell lung cancer (NSCLC)
23.  Genomic and epigenomic integration identifies a prognostic signature in colon cancer 
Purpose
The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis.
Experimental Design
Merging genome-wide genomic and epigenomic alterations, we identify key genes and pathways altered in colorectal cancers (CRC). DNA Methylation analysis was tested for predicting survival in CRC patients using Cox proportional hazard model.
Results
We identified 29 low frequency mutated genes that are also inactivated by epigenetic mechanisms in CRC. Pathway analysis showed the extracellular matrix (ECM) remodeling pathway is silenced in CRC. 6 ECM pathway genes were tested for their prognostic potential in large CRC cohorts (n=777). DNA Methylation of IGFBP3 and EVL predicted for poor survival (IGFBP3: HR=2.58, 95%CI:1.37-4.87, p=0.004; EVL: HR=2.48, 95%CI:1.07-5.74, p=0.034) and simultaneous methylation of multiple genes predicted significantly worse survival (HR=8.61, 95%CI:2.16-34.36, p<0.001 for methylation of IGFBP3, EVL, CD109 and FLNC). DNA Methylation of IGFBP3 and EVL was validated as a prognostic marker in an independent contemporary matched cohort (IGFBP3 HR=2.06, 95% CI:1.04-4.09, p=0.038; EVL HR=2.23, 95%CI:1.00-5.0, p=0.05) and EVL DNA methylation remained significant in a secondary historical validation cohort (HR=1.41, 95%CI:1.05-1.89, p=0.022). Moreover, DNA methylation of selected ECM genes helps to stratify the high-risk Stage 2 colon cancers patients who would benefit from adjuvant chemotherapy (HR: 5.85, 95%CI:2.03-16.83, p=0.001 for simultaneous methylation of IGFBP3, EVL and CD109).
Conclusions
CRC that have silenced in ECM pathway components show worse survival suggesting that our finding provides novel prognostic biomarkers for CRC and reflects the high importance of integrative analyses linking genetic and epigenetic abnormalities with pathway disruption in cancer.
doi:10.1158/1078-0432.CCR-10-2509
PMCID: PMC3077819  PMID: 21278247
DNA Methylation; Extracellular Matrix Pathway; Prognostic Biomarker; Colorectal cancer
24.  Cancer -related Epigenome Changes Associated with Reprogramming to Induced Pluripotent Stem Cells 
Cancer research  2010;70(19):7662-7673.
The ability to induce pluripotent stem cells from committed, somatic, human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome wide assays we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer-specific, gene promoter, DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis and add to means of assessing iPS for safety.
doi:10.1158/0008-5472.CAN-10-1361
PMCID: PMC2980296  PMID: 20841480
reprogramming; induced pluripotent stem cells (iPS); embryonic stem cells (ESC); DNA methylation; chromatin; cancer
25.  Comprehensive molecular characterization of gastric adenocarcinoma 
Bass, Adam J. | Thorsson, Vesteinn | Shmulevich, Ilya | Reynolds, Sheila M. | Miller, Michael | Bernard, Brady | Hinoue, Toshinori | Laird, Peter W. | Curtis, Christina | Shen, Hui | Weisenberger, Daniel J. | Schultz, Nikolaus | Shen, Ronglai | Weinhold, Nils | Kelsen, David P. | Bowlby, Reanne | Chu, Andy | Kasaian, Katayoon | Mungall, Andrew J. | Robertson, A. Gordon | Sipahimalani, Payal | Cherniack, Andrew | Getz, Gad | Liu, Yingchun | Noble, Michael S. | Pedamallu, Chandra | Sougnez, Carrie | Taylor-Weiner, Amaro | Akbani, Rehan | Lee, Ju-Seog | Liu, Wenbin | Mills, Gordon B. | Yang, Da | Zhang, Wei | Pantazi, Angeliki | Parfenov, Michael | Gulley, Margaret | Piazuelo, M. Blanca | Schneider, Barbara G. | Kim, Jihun | Boussioutas, Alex | Sheth, Margi | Demchok, John A. | Rabkin, Charles S. | Willis, Joseph E. | Ng, Sam | Garman, Katherine | Beer, David G. | Pennathur, Arjun | Raphael, Benjamin J. | Wu, Hsin-Ta | Odze, Robert | Kim, Hark K. | Bowen, Jay | Leraas, Kristen M. | Lichtenberg, Tara M. | Weaver, Stephanie | McLellan, Michael | Wiznerowicz, Maciej | Sakai, Ryo | Getz, Gad | Sougnez, Carrie | Lawrence, Michael S. | Cibulskis, Kristian | Lichtenstein, Lee | Fisher, Sheila | Gabriel, Stacey B. | Lander, Eric S. | Ding, Li | Niu, Beifang | Ally, Adrian | Balasundaram, Miruna | Birol, Inanc | Bowlby, Reanne | Brooks, Denise | Butterfield, Yaron S. N. | Carlsen, Rebecca | Chu, Andy | Chu, Justin | Chuah, Eric | Chun, Hye-Jung E. | Clarke, Amanda | Dhalla, Noreen | Guin, Ranabir | Holt, Robert A. | Jones, Steven J.M. | Kasaian, Katayoon | Lee, Darlene | Li, Haiyan A. | Lim, Emilia | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Moore, Richard A. | Mungall, Andrew J. | Mungall, Karen L. | Nip, Ka Ming | Robertson, A. Gordon | Schein, Jacqueline E. | Sipahimalani, Payal | Tam, Angela | Thiessen, Nina | Beroukhim, Rameen | Carter, Scott L. | Cherniack, Andrew D. | Cho, Juok | Cibulskis, Kristian | DiCara, Daniel | Frazer, Scott | Fisher, Sheila | Gabriel, Stacey B. | Gehlenborg, Nils | Heiman, David I. | Jung, Joonil | Kim, Jaegil | Lander, Eric S. | Lawrence, Michael S. | Lichtenstein, Lee | Lin, Pei | Meyerson, Matthew | Ojesina, Akinyemi I. | Pedamallu, Chandra Sekhar | Saksena, Gordon | Schumacher, Steven E. | Sougnez, Carrie | Stojanov, Petar | Tabak, Barbara | Taylor-Weiner, Amaro | Voet, Doug | Rosenberg, Mara | Zack, Travis I. | Zhang, Hailei | Zou, Lihua | Protopopov, Alexei | Santoso, Netty | Parfenov, Michael | Lee, Semin | Zhang, Jianhua | Mahadeshwar, Harshad S. | Tang, Jiabin | Ren, Xiaojia | Seth, Sahil | Yang, Lixing | Xu, Andrew W. | Song, Xingzhi | Pantazi, Angeliki | Xi, Ruibin | Bristow, Christopher A. | Hadjipanayis, Angela | Seidman, Jonathan | Chin, Lynda | Park, Peter J. | Kucherlapati, Raju | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Kim, Sang-Bae | Lee, Ju-Seog | Lu, Yiling | Mills, Gordon | Laird, Peter W. | Hinoue, Toshinori | Weisenberger, Daniel J. | Bootwalla, Moiz S. | Lai, Phillip H. | Shen, Hui | Triche, Timothy | Van Den Berg, David J. | Baylin, Stephen B. | Herman, James G. | Getz, Gad | Chin, Lynda | Liu, Yingchun | Murray, Bradley A. | Noble, Michael S. | Askoy, B. Arman | Ciriello, Giovanni | Dresdner, Gideon | Gao, Jianjiong | Gross, Benjamin | Jacobsen, Anders | Lee, William | Ramirez, Ricardo | Sander, Chris | Schultz, Nikolaus | Senbabaoglu, Yasin | Sinha, Rileen | Sumer, S. Onur | Sun, Yichao | Weinhold, Nils | Thorsson, Vésteinn | Bernard, Brady | Iype, Lisa | Kramer, Roger W. | Kreisberg, Richard | Miller, Michael | Reynolds, Sheila M. | Rovira, Hector | Tasman, Natalie | Shmulevich, Ilya | Ng, Santa Cruz Sam | Haussler, David | Stuart, Josh M. | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Verhaak, Roeland G.W. | Mills, Gordon B. | Leiserson, Mark D. M. | Raphael, Benjamin J. | Wu, Hsin-Ta | Taylor, Barry S. | Black, Aaron D. | Bowen, Jay | Carney, Julie Ann | Gastier-Foster, Julie M. | Helsel, Carmen | Leraas, Kristen M. | Lichtenberg, Tara M. | McAllister, Cynthia | Ramirez, Nilsa C. | Tabler, Teresa R. | Wise, Lisa | Zmuda, Erik | Penny, Robert | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Curely, Erin | Mallery, David | Morris, Scott | Paulauskis, Joseph | Shelton, Troy | Shelton, Candace | Sherman, Mark | Benz, Christopher | Lee, Jae-Hyuk | Fedosenko, Konstantin | Manikhas, Georgy | Potapova, Olga | Voronina, Olga | Belyaev, Smitry | Dolzhansky, Oleg | Rathmell, W. Kimryn | Brzezinski, Jakub | Ibbs, Matthew | Korski, Konstanty | Kycler, Witold | ŁaŸniak, Radoslaw | Leporowska, Ewa | Mackiewicz, Andrzej | Murawa, Dawid | Murawa, Pawel | Spychała, Arkadiusz | Suchorska, Wiktoria M. | Tatka, Honorata | Teresiak, Marek | Wiznerowicz, Maciej | Abdel-Misih, Raafat | Bennett, Joseph | Brown, Jennifer | Iacocca, Mary | Rabeno, Brenda | Kwon, Sun-Young | Penny, Robert | Gardner, Johanna | Kemkes, Ariane | Mallery, David | Morris, Scott | Shelton, Troy | Shelton, Candace | Curley, Erin | Alexopoulou, Iakovina | Engel, Jay | Bartlett, John | Albert, Monique | Park, Do-Youn | Dhir, Rajiv | Luketich, James | Landreneau, Rodney | Janjigian, Yelena Y. | Kelsen, David P. | Cho, Eunjung | Ladanyi, Marc | Tang, Laura | McCall, Shannon J. | Park, Young S. | Cheong, Jae-Ho | Ajani, Jaffer | Camargo, M. Constanza | Alonso, Shelley | Ayala, Brenda | Jensen, Mark A. | Pihl, Todd | Raman, Rohini | Walton, Jessica | Wan, Yunhu | Demchok, John A. | Eley, Greg | Mills Shaw, Kenna R. | Sheth, Margi | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean Claude | Davidsen, Tanja | Hutter, Carolyn M. | Sofia, Heidi J. | Burton, Robert | Chudamani, Sudha | Liu, Jia
Nature  2014;513(7517):202-209.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
doi:10.1038/nature13480
PMCID: PMC4170219  PMID: 25079317

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