Abstract 136: Refining the molecular profile of colorectal tumors to expand prevention and treatment opportunities
Authors: Grasso Catherine S. , Shinbrot Eve , Yu Ming , Liesersen Max , Chaisson Mark , Chan Andrew , Connolly Charles , Dai James , Du Margaret , Fuchs Charles , Garraway Levi , Giannakis Marios , Harrison Tabitha , Hsu Li , Huyghe Jeroen , Mu Jasmine , Ogino Shuji , Pritchard Colin , Salipante Stephen , Sun Wei , Zaidi Syed H. , Zhao Ni , Grady William , Raphael Ben , Hudson Thomas , Wheeler David , Peters Ulrike 
Published: July 2016

The completion of The Cancer Genome Atlas (TCGA) project for colorectal cancer (CRC) is ushering in a new phase of identifying treatment strategies tailored to the molecular profile of each person's tumor. Precision medicine approaches to cancer treatment rely on the identification of molecular profiles that can be used to identify effective therapies and can be used in a targeted sequencing setting to make treatment decisions.

The initial TCGA colorectal effort included 276 samples and focused on integrating data from exome sequencing with genome-wide DNA copy number alterations (CNAs), DNA methylation, and mRNA and microRNA expression. Since then a total of 626 samples have been completed with the potential to refine CRC subtypes, identify novel mutated pathways, and further functional understanding. Such a large data set presents opportunities to identify new recurrent drug targets and to stratify patients into groups that are predictive of treatment response. However, large data sets also present substantial challenges, since hand-curation becomes intractable, while computational tools can be overwhelmed by hypermutation and copy number changes.

Here we present a comprehensive molecular analysis of all 626 TCGA colorectal cancer samples, including exome sequencing, CNAs, DNA methylation, and mRNA expression. For each data type, we identified recurrently altered genes. Using MutSigCV on 525 samples yielded 27 and 87 significantly mutated genes in non-hypermutated and hypermutated samples, respectively, a substantial increase over the 15 and 17 somatically recurrently mutated genes identified using MutSig in non-hypermutated and hypermutated samples, respectively, in the previously published TCGA colorectal study. For example, PTEN, a known tumor suppressor, was not reported as significantly recurrently mutated in the initial TCGA non-hypermutated set; however, it was in the larger non-hypermutated set, demonstrating the power of a larger data set for assessing the significance and relative frequency of mutations in the context of known subtypes.

In addition, we integrated the somatic mutation data, copy number data, LOH data, and hyper-methylation data to identify genes, like MLH1, that are recurrently disrupted by different mechanisms. We also considered somatic mutations that are likely gain-of-function mutations based on nonrandom clustering; and we used recurrent indels to identify loss-of-function drivers in samples positive for microsatellite instability (MSI). We further classified each sample using the previously identified subtypes – BRAF+, KRAS+, APC+, CTNNB1+ (beta-catenin+), TGFBR2/SMAD4+, PTEN+ and PIK3CA+, and R-spondin fusion positive, as well as CpG Island Methylator Phenotype (CIMP) and MSI - in order to refine the relevant molecular signatures driving CRC etiology and thereby prevention and treatment paradigms.

Citation Format: Catherine S. Grasso, Eve Shinbrot, Ming Yu, Max Liesersen, Mark Chaisson, Andrew Chan, Charles Connolly, James Dai, Margaret Du, Charles Fuchs, Levi Garraway, Marios Giannakis, Tabitha Harrison, Li Hsu, Jeroen Huyghe, Jasmine Mu, Shuji Ogino, Colin Pritchard, Stephen Salipante, Wei Sun, Syed H. Zaidi, Ni Zhao, William Grady, Ben Raphael, Thomas Hudson, David Wheeler, Ulrike Peters. Refining the molecular profile of colorectal tumors to expand prevention and treatment opportunities. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 136.