Genomic and Epigenomic Heterogeneity of Hepatocellular Carcinoma

被引：165

作者：

Lin, De-Chen ^{[1
,2
]}

Mayakonda, Anand ^{[3
]}

Dinh, Huy Q. ^{[4
]}

Huang, Pinbo ^{[1
,5
]}

Lin, Lehang ^{[1
]}

Liu, Xiaoping ^{[1
]}

Ding, Ling-wen ^{[3
]}

Wang, Jie ^{[1
,5
]}

Berman, Benjamin P. ^{[4
]}

Song, Er-Wei ^{[1
]}

Yin, Dong ^{[1
]}

Koeffler, H. Phillip ^{[2
,3
,6
]}

机构：

[1] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Res Ctr Med, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou, Guangdong, Peoples R China

[2] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Div Hematol Oncol, Los Angeles, CA 90048 USA

[3] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore

[4] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Ctr Bioinformat & Funct Genom,Biomed Sci, Los Angeles, CA 90048 USA

[5] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Hepatobiliary Surg, Guangzhou, Guangdong, Peoples R China

[6] Natl Univ Singapore Hosp, Natl Univ Canc Inst, Singapore, Singapore

来源：

CANCER RESEARCH | 2017年 / 77卷 / 09期

基金：

新加坡国家研究基金会;

关键词：

DNA METHYLATION; INTRATUMOR HETEROGENEITY; CLONAL EVOLUTION; GENETIC-HETEROGENEITY; RECURRENT MUTATIONS; SOMATIC MUTATIONS; CANCER; CLASSIFICATION; SIGNATURES; PATTERNS;

D O I：

10.1158/0008-5472.CAN-16-2822

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Understanding the intratumoral heterogeneity of hepatocellular carcinoma is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 hepatocellular carcinoma cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions, that is, located on the " trunk" of the evolutionary tree. In addition, we foundthat variants within several drug targets such as KIT, SYK, and PIK3CA were mutated in a fully clonal manner, indicating their therapeutic potentials for hepatocellular carcinoma. Temporal dissection of mutational signatures suggested that mutagenic processes associated with exposure to aristolochic acid and aflatoxin might play a more important role in early, as opposed to late, stages of hepatocellular carcinoma development. Moreover, we observed extensive intratumoral epigenetic heterogeneity in hepatocellular carcinoma based on multiple independent analytical methods and showed that intratumoral methylation heterogeneity might play important roles in the biology of hepatocellular carcinoma cells. Our results also demonstrated prominent heterogeneity of intratumoral methylation even in a stable hepatocellular carcinoma genome. Together, these findings highlight widespread intratumoral heterogeneity at both the genomic and epigenomic levels in hepatocellular carcinoma and provide an important molecular foundation for better understanding the pathogenesis of this malignancy. (C) 2017 AACR.

引用

页码：2255 / 2265

页数：11

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