Abstract 2970: Whole genome sequencing analysis of multiple liver cancer nodules for determination of causal events for multi-occurrence

Abstract

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite the recent progress in diagnostic accuracy and therapeutic efficacy, its five-year survival rate is still low. Characteristically, HCC shows a high rate of intrahepatic metastasis (IM) or multi-centric (MC) occurrence within the liver, and discrimination of IM/MC is difficult and important for therapeutic decision. Previously we reported that there were no common somatic mutations between whole genomes of MC tumors, indicating that MC tumors independently developed in their genetic aspect (Nat Genet, 44: 760-764, 2012). Here we performed whole genome sequencing (WGS) analysis on 43 multiple liver cancer nodules derived from 20 patients, which were clinically defined as IM or MC occurrence. We first analyzed common and unique somatic mutations in each individual and divided the cases into IM or MC by using the information of common somatic mutations between the multiple nodules. Interestingly, the clinical and pathological diagnoses of MC/IM in five of 20 cases were not concordant with the judgments from WGS, indicating the usefulness of WGS for a precise IM/MC judgment. Analysis of common somatic alterations in IM tumors enabled to extract early and late event in hepatocarcinogenesis among a large number of somatic events in each cases, while MC pairs shared only a few numbers of common alterations, including false positives. Importantly, one somatic mutation in non-coding region was exceptionally detected commonly among MC tumor pairs from three cases. Sanger sequencing confirmed that this mutation was also commonly detected in 10.9% (35/321) of liver cancer samples somatically. These results indicate the significance of this function-unknown and recurrent mutation in liver cancer development. To illuminate common driver events in MC tumors, we analyzed all detectable genetic alterations, including copy number alterations and rearrangements, on multi-time point or MC tumors derived from same individuals and extracted significant genetic alterations from them, which can help the understanding of driver genetic alterations in liver cancers. Citation Format: Mayuko Furuta, Akihiro Fujimoto, Masaki Ueno, Shinya Hayami, Yoshi-iku Kawakami, Kunihito Gotoh, Tatsuhiko Tsunoda, Satoru Miyano, Hideki Ohdan, Kazuaki Chayama, Hiroki Yamaue, Hidewaki Nakagawa. Whole genome sequencing analysis of multiple liver cancer nodules for determination of causal events for multi-occurrence. [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 2970. doi:10.1158/1538-7445.AM2015-2970