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Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas
Liu, Yang,Sethi, Nilay S.,Hinoue, Toshinori,Schneider, Barbara G.,Cherniack, Andrew D.,Sanchez-Vega, Francisco,Seoane, Jose A.,Farshidfar, Farshad,Bowlby, Reanne,Islam, Mirazul,Kim, Jaegil,Chatila, Wa Elsevier 2018 Cancer cell Vol.33 No.4
<P><B>Summary</B></P> <P>We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of <I>MLH1</I> in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in <I>POLE</I>. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in <I>KRAS</I>, <I>SOX9</I>, and <I>PCBP1</I>.</P> <P><B>Highlights</B></P> <P> <UL> <LI> GI adenocarcinomas comprised five molecular subtypes: EBV, MSI, HM-SNV, CIN, and GS </LI> <LI> Hypermutated tumors had diverse immune features varying by tissue and subtype </LI> <LI> CIN tumors displayed more fragmented copy-number alterations in the upper GI tract </LI> <LI> Genome-stable CRC subtype was enriched for recurrent mutations in <I>SOX9</I> and <I>PCBP1</I> </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Liu, Jianfang,Lichtenberg, Tara,Hoadley, Katherine A.,Poisson, Laila M.,Lazar, Alexander J.,Cherniack, Andrew D.,Kovatich, Albert J.,Benz, Christopher C.,Levine, Douglas A.,Lee, Adrian V.,Omberg, Lars Elsevier 2018 Cell Vol.173 No.2
<P><B>Summary</B></P> <P>For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Generation of TCGA Clinical Data Resource for 11,160 patients over 33 cancer types </LI> <LI> Analysis of clinical outcome endpoints with usage recommendations for each cancer </LI> <LI> Demonstration of data validity and utility for large-scale translational research </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma
The Cancer Genome Atlas Research Network,Davis, Caleb F.,Ricketts, C.J.,Wang, M.,Yang, L.,Cherniack, Andrew D.,Shen, H.,Buhay, C.,Kang, H.,Kim, S.,Fahey, Catherine C.,Hacker, Kathryn E.,Bhanot, G.,Gor Cell Press 2014 Cancer Cell Vol.26 No.3
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
Genomic and Functional Approaches to Understanding Cancer Aneuploidy
Taylor, Alison M.,Shih, Juliann,Ha, Gavin,Gao, Galen F.,Zhang, Xiaoyang,Berger, Ashton C.,Schumacher, Steven E.,Wang, Chen,Hu, Hai,Liu, Jianfang,Lazar, Alexander J.,Cherniack, Andrew D.,Beroukhim, Ram Elsevier Science B.V., Amsterdam 2018 Cancer cell Vol.33 No.4
Pathogenic Germline Variants in 10,389 Adult Cancers
Huang, Kuan-lin,Mashl, R. Jay,Wu, Yige,Ritter, Deborah I.,Wang, Jiayin,Oh, Clara,Paczkowska, Marta,Reynolds, Sheila,Wyczalkowski, Matthew A.,Oak, Ninad,Scott, Adam D.,Krassowski, Michal,Cherniack, And Elsevier 2018 Cell Vol.173 No.2
<P><B>Summary</B></P> <P>We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of <I>SDHA</I> in melanoma and <I>PALB2</I> in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including <I>ATM</I>, <I>BRCA1</I>, and <I>NF1</I>, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in <I>MET</I>, <I>RET</I>, and <I>PTPN11</I> associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 871 predisposition variants/CNVs discovered in 8% of 10,389 cases of 33 cancers </LI> <LI> Pan-cancer approach identified shared variants and genes across cancers </LI> <LI> 33 variants affecting activating domains of oncogenes showed high expression </LI> <LI> 47 VUSs prioritized using cancer enrichment, LOH, expression and other evidence </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>