Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ∼50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.
Center for Genomic Medicine, RIKEN, Yokohama, Japan.
Akihiro
A
Fujimoto
Yasushi
Y
Totoki
Tetsuo
T
Abe
Keith A
KA
Boroevich
Fumie
F
Hosoda
Ha Hai
HH
Nguyen
Masayuki
M
Aoki
Naoya
N
Hosono
Michiaki
M
Kubo
Fuyuki
F
Miya
Yasuhito
Y
Arai
Hiroyuki
H
Takahashi
Takuya
T
Shirakihara
Masao
M
Nagasaki
Tetsuo
T
Shibuya
Kaoru
K
Nakano
Kumiko
K
Watanabe-Makino
Hiroko
H
Tanaka
Hiromi
H
Nakamura
Jun
J
Kusuda
Hidenori
H
Ojima
Kazuaki
K
Shimada
Takuji
T
Okusaka
Masaki
M
Ueno
Yoshinobu
Y
Shigekawa
Yoshiiku
Y
Kawakami
Koji
K
Arihiro
Hideki
H
Ohdan
Kunihito
K
Gotoh
Osamu
O
Ishikawa
Shun-Ichi
S
Ariizumi
Masakazu
M
Yamamoto
Terumasa
T
Yamada
Kazuaki
K
Chayama
Tomoo
T
Kosuge
Hiroki
H
Yamaue
Naoyuki
N
Kamatani
Satoru
S
Miyano
Hitoshi
H
Nakagama
Yusuke
Y
Nakamura
Tatsuhiko
T
Tsunoda
Tatsuhiro
T
Shibata
Hidewaki
H
Nakagawa
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002843:Chromatin / Q000235:genetics*; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D006509:Hepatitis B / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019098:Telomerase / Q000235:genetics; D016662:Virus Integration / Q000235:genetics
D002843:Chromatin; C509186:TERT protein, human; D019098:Telomerase