Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.

TitleTrans-ancestry mutational landscape of hepatocellular carcinoma genomes.
Publication TypeJournal Article
Year of Publication2014
AuthorsTotoki, Y, Tatsuno, K, Covington, KR, Ueda, H, Creighton, CJ, Kato, M, Tsuji, S, Donehower, LA, Slagle, BL, Nakamura, H, Yamamoto, S, Shinbrot, E, Hama, N, Lehmkuhl, M, Hosoda, F, Arai, Y, Walker, K, Dahdouli, M, Gotoh, K, Nagae, G, Gingras, M-C, Muzny, DM, Ojima, H, Shimada, K, Midorikawa, Y, Goss, JA, Cotton, R, Hayashi, A, Shibahara, J, Ishikawa, S, Guiteau, J, Tanaka, M, Urushidate, T, Ohashi, S, Okada, N, Doddapaneni, HV, Wang, M, Zhu, Y, Dinh, H, Okusaka, T, Kokudo, N, Kosuge, T, Takayama, T, Fukayama, M, Gibbs, RA, Wheeler, DA, Aburatani, H, Shibata, T
JournalNat Genet
Volume46
Issue12
Pagination1267-73
Date Published2014 Dec
ISSN1546-1718
KeywordsAlgorithms, Asian Continental Ancestry Group, Carcinoma, Hepatocellular, CpG Islands, DNA Mutational Analysis, European Continental Ancestry Group, Exome, Gene Expression Regulation, Neoplastic, Genome, Human, Genome, Viral, Hepacivirus, Hepatitis B virus, Humans, Japan, Liver Neoplasms, Models, Statistical, Mutation, Principal Component Analysis, Telomerase, TOR Serine-Threonine Kinases, United States
Abstract

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

DOI10.1038/ng.3126
Alternate JournalNat. Genet.
PubMed ID25362482
Grant List5U54HG003273 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
P30 AI036211 / AI / NIAID NIH HHS / United States
HHSN261201000053C / / PHS HHS / United States