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Vol. 84, Suppl. 1, 2013
Issue release date: February 2013
Oncology 2013;84(suppl 1):93-97

Recent Advancements in Comprehensive Genetic Analyses for Human Hepatocellular Carcinoma

Nishida N. · Kudo M.
Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osakasayama, Japan

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Hepatocellular carcinoma (HCC) typically develops in the liver with chronic hepatitis and cirrhosis, and activation of oncogenes and inactivation of tumor suppressor genes occurs during carcinogenesis via genetic and epigenetic mechanisms. Recent advancements in the development of analyses for examining the cancer genome have revealed information regarding genetic alterations in HCC tissues. According to previous studies, the incidence of recurrent genetic alterations in individual genes was thought to be relatively rare and limited to a subset of a few cancer-specific genes such as tumor suppressor p53, RB genes and oncogenes such as CTNNB1. However, recent whole-genome analyses and exome sequencing of tumor DNA have revealed numerous novel alterations of cancer-related genes and pathways critical for HCC development. In addition, various risk factors for HCC, such as the presence or absence of hepatitis B and C virus, may affect the mutation profile of the corresponding cancer genome. On the other hand, genome-wide association studies have also identified important single-nucleotide polymorphisms involved in HCC development, which may allow detection of a group at high risk of HCC emergence. Such analyses will clarify how this malignancy can be treated, diagnosed and prevented more effectively.

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  1. Kim DY, Han K: Epidemiology and surveilance of hepatocellular carcinoma. Liver Cancer 2012;1:2-14.

    External Resources

  2. Nishida N, Fukuda Y, Kokuryu H, Toguchida J, Yandell DW, Ikenega M, Imura H, Ishizaki K: Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res 1993;53:368-372.
  3. Nishida N, Fukuda Y, Komeda T, Kita R, Sando T, Furukawa M, Amenomori M, Shibagaki I, Nakao K, Ikenaga M, et al: Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res 1994;54:3107-3110.
  4. Nishida N, Fukuda Y, Ishizaki K, Nakao K: Alteration of cell cycle-related genes in hepatocarcinogenesis. Histol Histopathol 1997;12:1019-1025.
  5. Nishida N, Nishimura T, Ito T, Komeda T, Fukuda Y, Nakao K: Chromosomal instability and human hepatocarcinogenesis. Histol Histopathol 2003;18:897-909.
  6. Nishida N, Nagasaka T, Nishimura T, Ikai I, Boland CR, Goel A: Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology 2008;47:908-918.
  7. Nishida N: Impact of hepatitis virus and aging on DNA methylation in human hepatocarcinogenesis. Histol Histopathol 2010;25:647-654.
  8. Nishida N, Goel A: Genetic and epigenetic signatures in human hepatocellular carcinoma: a systematic review. Curr Genomics 2011;12:130-137.
  9. Toffanin S, Cornella H, Harrington A, Llovet JM: Next-generation sequencing: path for driver discovery in hepatocellular carcinoma. Gastroenterology 2012;143:1391-1393.
  10. Zhang Z: Genomic landscape of liver cancer. Nat Genet 2012;44:1075-1077.
  11. Hoshida Y, Fuchs BC, Tanabe KK: Genomic risk of hepatitis C-related hepatocellular carcinoma. J Hepatol 2012;56:729-730.
  12. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC: Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 1991;350:427-428.
  13. Bressac B, Kew M, Wands J, Ozturk M: Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991;350:429-431.
  14. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Cle-ment B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouze E, Calvo F, Zucman-Rossi J: Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012;44:694-698.
  15. Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, Zhu ZD, Zhou B, Liu XY, Liu RF, Fei QL, Chen H, Cai B, Xiao HS, Qin LX, Han ZG: Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet 2012;44:1117-1121.
  16. Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, Tsutsumi S, Sonoda K, Totsuka H, Shirakihara T, Sakamoto H, Wang L, Ojima H, Shimada K, Kosuge T, Okusaka T, Kato K, Kusuda J, Yoshida T, Aburatani H, Shibata T: High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet 2011;43:464-469.
  17. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, Aoki M, Hosono N, Kubo M, Miya F, Arai Y, Takahashi H, Shirakihara T, Nagasaki M, Shibuya T, Nakano K, Watanabe-Makino K, Tanaka H, Nakamura H, Kusuda J, Ojima H, Shimada K, Okusaka T, Ueno M, Shigekawa Y, Kawakami Y, Arihiro K, Ohdan H, Gotoh K, Ishikawa O, Ariizumi S, Yamamoto M, Yamada T, Chayama K, Kosuge T, Yamaue H, Kamatani N, Miyano S, Nakagama H, Nakamura Y, Tsunoda T, Shibata T, Nakagawa H: Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012;44:760-764.
  18. Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW: Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 2011;43:828-829.
  19. Huang Q, Lin B, Liu H, Ma X, Mo F, Yu W, Li L, Li H, Tian T, Wu D, Shen F, Xing J, Chen ZN: RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma. PLoS One 2011;6:e26168.
  20. Nishida N, Fukuda Y, Kokuryu H, Sadamoto T, Isowa G, Honda K, Yamaoka Y, Ikenaga M, Imura H, Ishizaki K: Accumulation of allelic loss on arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma. Int J Cancer 1992;51:862-868.
  21. Nishida N, Fukuda Y, Komeda T, Ito T, Nishimura T, Minata M, Kuno M, Katsuma H, Ikai I, Yamaoka Y, Nakao K: Prognostic impact of multiple allelic losses on metastatic recurrence in hepatocellular carcinoma after curative resection. Oncology 2002;62:141-148.
  22. Nishida N, Nishimura T, Nagasaka T, Ikai I, Goel A, Boland CR: Extensive methylation is associated with beta-catenin mutations in hepatocellular carcinoma: evidence for two distinct pathways of human hepatocarcinogenesis. Cancer Res 2007;67:4586-4594.
  23. Gozuacik D, Murakami Y, Saigo K, Chami M, Mugnier C, Lagorce D, Okanoue T, Urashima T, Brechot C, Paterlini-Brechot P: Identification of human cancer-related genes by naturally occurring hepatitis B virus DNA tagging. Oncogene 2001;20:6233-6240.
  24. Paterlini-Brechot P, Saigo K, Murakami Y, Chami M, Gozuacik D, Mugnier C, Lagorce D, Brechot C: Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 2003;22:3911-3916.
  25. Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Brechot C, Paterlini-Brechot P: Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 2005;54:1162-1168.
  26. Saigo K, Yoshida K, Ikeda R, Sakamoto Y, Murakami Y, Urashima T, Asano T, Kenmochi T, Inoue I: Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma. Hum Mutat 2008;29:703-708.
  27. Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, Lee NP, Lee WH, Ariyaratne PN, Tennakoon C, Mulawadi FH, Wong KF, Liu AM, Poon RT, Fan ST, Chan KL, Gong Z, Hu Y, Lin Z, Wang G, Zhang Q, Barber TD, Chou WC, Aggarwal A, Hao K, Zhou W, Zhang C, Hardwick J, Buser C, Xu J, Kan Z, Dai H, Mao M, Reinhard C, Wang J, Luk JM: Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012;44:765-769.
  28. Jiang S, Yang Z, Li W, Li X, Wang Y, Zhang J, Xu C, Chen PJ, Hou J, McCrae MA, Chen X, Zhuang H, Lu F: Re-evaluation of the car-cinogenic significance of hepatitis B virus integration in hepatocarcinogenesis. PLoS One 2012;7:e40363.
  29. Tao Y, Ruan J, Yeh SH, Lu X, Wang Y, Zhai W, Cai J, Ling S, Gong Q, Chong Z, Qu Z, Li Q, Liu J, Yang J, Zheng C, Zeng C, Wang HY, Zhang J, Wang SH, Hao L, Dong L, Li W, Sun M, Zou W, Yu C, Li C, Liu G, Jiang L, Xu J, Huang H, Mi S, Zhang B, Chen B, Zhao W, Hu S, Zhuang SM, Shen Y, Shi S, Brown C, White KP, Chen DS, Chen PJ, Wu CI: Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data. Proc Natl Acad Sci USA 2011;108:12042-12047.
  30. Kato N, Ji G, Wang Y, Baba M, Hoshida Y, Otsuka M, Taniguchi H, Moriyama M, Dharel N, Goto T, Shao RX, Matsuura T, Ishii K, Shiina S, Kawabe T, Muramatsu M, Omata M: Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Hepatology 2005;42:846-853.
  31. Tomoda T, Nouso K, Sakai A, Ouchida M, Kobayashi S, Miyahara K, Onishi H, Nakamura S, Yamamoto K, Shimizu K: Genetic risk of hepatocellular carcinoma in patients with hepatitis C virus: a case control study. J Gastroenterol Hepatol 2012;27:797-804.
  32. Miki D, Ochi H, Hayes CN, Abe H, Yoshima T, Aikata H, Ikeda K, Kumada H, Toyota J, Morizono T, Tsunoda T, Kubo M, Nakamura Y, Kamatani N, Chayama K: Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet 2011;43:797-800.
  33. Kanehira M, Harada Y, Takata R, Shuin T, Miki T, Fujioka T, Nakamura Y, Katagiri T: Involvement of upregulation of DEPDC1 (dep domain containing 1) in bladder carcinogenesis. Oncogene 2007;26:6448-6455.
  34. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Omata M, Nakagawa H, Koike K, Kamatani N, Kubo M, Nakamura Y, Matsuda K: Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011;43:455-458.
  35. Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, Ma F, Huang W, Yu L, Yue W, Wang Z, Li P, Zhang Y, Liang R, Wei Z, Cui Y, Xie W, Cai M, Yu X, Yuan Y, Xia X, Zhang X, Yang H, Qiu W, Yang J, Gong F, Chen M, Shen H, Lin D, Zeng YX, He F, Zhou G: Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet 2010;42:755-758.

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