Abstract 5174: Toward understanding the genomic alterations in human gastric cancer

Abstract

Abstract Gastric cancer is one of the most prevalent and aggressive cancers worldwide, and its molecular mechanism remains largely elusive. Although recent genome sequencing studies have uncovered rich information on cancer evolutions of many types, little is known about the genetic basis of gastric cancer due to its complexity. Here we report genomic mutations in primary gastric adenocarcinoma of human, based on the whole genome sequences of five pairs of cancer and matching normal samples. In total, 407 non-synonymous somatic point mutations have been identified in these genomes and the most recurrent mutations were harbored by genes such as Mucins (MUC3A and MUC12) and transcription factors (ZNF717, ZNF595 and TP53). 679 genomic rearrangements were detected which affect 355 protein-coding genes; and 76 genes show copy number changes. The focus of the functional analysis is to validate the biological relevance of each variant to cancer formation and progression, particularly to explore the to-be-determined causal relationships between the observed mutations in cancer genomes and cancer development. Additionally, we have attempted to investigate the mechanism of how these variants form in each tumor and discuss about multiple possible factors that may affect the susceptibility to each specific chromosomal changes. For examples, structural correlation between two boundaries of most rearrangements was observed based on the Hi-C data analysis, which indicate these rearrangements may happen among DNA fragments in close spatial proximity, especially when two endpoints stay in a similar replication phase. Sequence analysis on the flacking region of those rearrangements also showed clear evidences that about half of these genomic changes may be involved in the mechanism of microhomology-mediated break induced replication (MMBIR). Furthermore, DNA integrations from Helicobacter pylori have been detected for the first time, for instance, in the gene region of PREX2, which may reflect a new mechanism about how H. pylori induce cancer development. Overall, the in-depth analyses on these sequenced genomes lead to the detection of a myriad of novel genomic variations in gastric cancer, which in turn bring new insights in our understanding of the genetic basis and indicate new molecular mechanism of the gastric tumorigenesis. Citation Format: Juan Cui, Ying Xu. Toward understanding the genomic alterations in human gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5174. doi:10.1158/1538-7445.AM2014-5174