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2012年5月21日月曜日
ARID遺伝子変異をめぐる小論
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(1) 肝癌27例のdeep sequenceによる遺伝子変異解析であり、理化学研究所を中心とする研究グループによるものである。多発肝癌それぞれが変異に関してはindependentと書いてある。肝癌では昨年ARID2の変異報告が米国からあり、その論文ではアジアの肝癌（実際には中国の肝癌であった）にはその変異がほとんど認められないとあったが、今回の報告では
ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ~50% of the tumors
とある。米国の報告ではnon-アジアで10%程度であったはずだけど、今回の日本人肝癌ARID2だけだと、％はいかほどなのだろう？
Nature Genetics
(2012)Received 17 January 2012
Accepted 30 April 2012
Published online 27 May 2012
Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators
Akihiro Fujimoto,Yasushi Totoki,Tetsuo Abe,Keith A Boroevich,Fumie Hosoda,Ha Hai Nguyen,Masayuki Aoki,Naoya Hosono,Michiaki Kubo, Fuyuki Miya,Yasuhito Arai,Hiroyuki Takahashi,Takuya Shirakihara,Masao Nagasaki, Tetsuo Shibuya,Kaoru Nakano,Kumiko Watanabe-Makino,Hiroko Tanaka,Hiromi Nakamura,Jun Kusuda,Hidenori Ojima,Kazuaki Shimada,Takuji Okusaka,Masaki Ueno,Yoshinobu,Shigekawa,Yoshiiku Kawakami,Koji Arihiro,Hideki Ohdan,Kunihito Gotoh, Osamu Ishikawa,Shunichi,Ariizumi,Masakazu Yamamoto,Terumasa Yamada,Kazuaki Chayama,Tomoo Kosuge,Hiroki Yamaue,Naoyuki Kamatani,Satoru Miyano,Hitoshi Nakagama,Yusuke Nakamura,Tatsuhiko Tsunoda,Tatsuhiro Shibata& Hidewaki NakagawaHepatocellular 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.
（２）昔からB型肝炎ウイルスは肝炎・肝硬変で肝細胞のゲノムDNAに挿入されていることが知られており、その時代の技術に応じた解析報告が時代ごとにしつこく頻回にこれまでもなされていた。小生は興味をもって学会会場に足を運んだものだ。はっきり言って説得力のある研究は皆無に近かったと思うぞ。これほどその詳細報告が待たれていた研究はないのではないか？2012年レベルでの一応の解答が下記であり、上の日本からの報告である。その結果はどれほどのものであったのか？
Nature Genetics
(2012)Received 23 January 2012
Accepted 30 April 2012
Published online 27 May 2012
Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma
To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.
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