Abstract 149: Integrated analysis of intratumor heterogeneity with genetic and epigenetic aberrations during colorectal cancer evolution

Abstract

Abstract [background] Intratumor heterogeneity (ITH) is presumably generated by branching clonal evolution of cancer cells. Recently, a multiregional sequencing approach, which sequences DNA sampled from geographically separated regions of a single tumor, has revealed branched evolution and ITH. In this study, we present genetic and epigenetic analysis of ITH in a series of nine colorectal cancers [material and method] We conducted analysis of samples from geographically separated regions from nine colorectal tumors. From each of the nine tumor, we obtained 5-21 multiregional samples, which were 75 samples in total, together with 9 paired normal mucosa samples. For two cases, samples from liver metastases were obtained. We performed exome sequencing and copy number (CN), methylation, and mRNA expression array profiling. [Result] Each of the multiregional mutation profiles harbored founder and progressor mutations; founder mutations are shared by all regions while progressor mutations are not. We found that mutations in well-known driver genes such as APC, KRAS, and FBWX7 were acquired as founder mutations, while mutations in PIK3CA recurrently occurred as progressor mutations, suggesting that PIK3CA mutations are a late event in the evolution of colorectal cancer. We counted each category of mutation and then identified a correlation between the number of founder mutations and the age of the patients. Our analysis showed that C > T transitions at CpG sites are more prominent in founder mutations than in progressor mutations. Then, the multiregional CN profiles showed that amplifications of 7p, 13q, 10q, 20p, and 20q frequently occurred across all samples in multiple tumors, namely as founder CN alterations. Finally, our data showed that hypermethylations in CpG islands were more prominent in founder methylations than in progressor methylations, suggesting that CpG island hypermethylations mainly occur in the early phase of colorectal cancer evolution. [Conclusion] In this study, our integrated analysis revealed not only extensive ITH, but also the evolutionary histories of the nine tumors. In particular, by focusing on founder and progressor mutations, we identified clues for decoding the life history of the tumors. Citation Format: Shinya Kidogami, Atsushi Niida, Ryutaro Uchi, Yusuke Takahashi, Masaki Mori, Satoru Miyano, Koshi Mimori. Integrated analysis of intratumor heterogeneity with genetic and epigenetic aberrations during colorectal cancer evolution. [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 149.