Abstract 2969: Progress in The Cancer Genome Atlas bladder cancer project
Authors: Weinstein John N. , Kim Jaegil , Creighton Chad J. , Akbani Rehan , Hoadley Katherine A. , Kim William Y. , Morgan Margaret B. , Hinoue Toshinori , Cherniack Andrew , Su Xiaoping , Mungall Andrew J. , Ryan Michael C. , Bajorin Dean F. , Rosenberg Jonathan E. , Czerniak Bogdan , Hansel Donna , Reuter Victor E. , Robinson Brian D. , Al-Ahmadie Hikmat A. , Damrauer Jeffrey S. , Zhang Wei , Liu Yuexin , Gordenin Dmitry R. , Stuart Joshua M. , Schultz Nikolaus , Robertson Gordon , Jones Steven JM , Kucherlapati Raju R. , McConkey David J. , Laird Peter W. , Mills Gordon B. , Kwiatkowski David J. , Lerner Seth P. ,   TCGA Bladder Cancer Working Group, TCGA Research Network
Published: August 2015

In 2014, as part of The Cancer Genome Atlas (TCGA) Project, we reported molecular profiling of 131 chemotherapy-naive, muscle-invasive urothelial bladder cancers for DNA copy number variants (CNVs), somatic mutations by whole exome sequencing (WES), DNA methylation, mRNA expression, microRNA expression, protein expression and phosphorylation, transcript splicing, gene fusion, viral integration, pathway perturbation, clinical correlates, and histopathology (TCGA Research Network, Nature 507:315, 2014). Since that time, the number of tumors (from 19 tissue source sites) profiled comprehensively has doubled, and the final analyzed cohort will total 412 by February 2015. Unsupervised consensus clustering for the data from miRNAseq on the first 310 tumor samples shows five robust clusters, with miR-99a, miR-100, and miR-200 family members differentially abundant across the clusters. mRNA clusters I-IV remained stable as well. For the 266 tumour samples for which we have both miRNA and mRNA data, potential miRNA-mRNA targeting relationships supported by functional validation publications include miR-100-5p targeting FGFR3. The data also highlight the miR-200 family, miR-29abc, miR-17-92 and 106b-25 complexes, as well as miR-34a, miR-155, and miR-21. At this time, mutation analysis of WES data has been completed for 238 samples (including the first 131). Seven additional significantly mutated genes (using MutSig) have been identified: ASXL2 (11%), HSP90AA1 (7%), PSIP1 (5%), ZFP36L2 (5%), ZNF513 (5%), PTEN (4%), CEBPB (2%) (mutant frequency in parentheses). A sample with a POLE exonuclease domain mutation (P286R) exhibited an ultra-mutant phenotype (mutation rate ∼100 per MB). Many of the 38 (total) SMGs have not previously been described in bladder cancer. Combining copy number variation and somatic mutation data, 69% of tumors harbor one or more potentially actionable targets. Three mutation clusters were identified and characterized as: 1) “Focally amplified” - enriched in focal copy number alterations (e.g., 3p loss/PPARG) and MLL2 mutations; 2) Enriched for TP53 and RB1 mutations, E2F3 amplifications; and 3) Papillary histology, FGFR3 mutant CDKN2A-deficient.

This work was supported by the following grants from the United States National Institutes of Health: U54HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025 and P01 CA120964, as well as multiple other funding sources for the individual authors.

Citation Format: John N. Weinstein, Jaegil Kim, Chad J. Creighton, Rehan Akbani, Katherine A. Hoadley, William Y. Kim, Margaret B. Morgan, Toshinori Hinoue, Andrew Cherniack, Xiaoping Su, Andrew J. Mungall, Michael C. Ryan, Dean F. Bajorin, Jonathan E. Rosenberg, Bogdan Czerniak, Donna Hansel, Victor E. Reuter, Brian D. Robinson, Hikmat A. Al-Ahmadie, Jeffrey S. Damrauer, Wei Zhang, Yuexin Liu, Dmitry R. Gordenin, Joshua M. Stuart, Nikolaus Schultz, Gordon Robertson, Steven JM Jones, Raju R. Kucherlapati, David J. McConkey, Peter W. Laird, Gordon B. Mills, David J. Kwiatkowski, Seth P. Lerner, TCGA Bladder Cancer Working Group, TCGA Research Network. Progress in The Cancer Genome Atlas bladder cancer project. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2969. doi:10.1158/1538-7445.AM2015-2969