Genetically Distinct and Clinically Relevant Classification of Hepatocellular Carcinoma: Putative Therapeutic Targets

Hiroto Katoh, Hidenori Ojima, Akiko Kokubu, Shigeru Saito, Tadashi Kondo, Tomoo Kosuge, Fumie Hosoda, Issei Imoto, Johji Inazawa, Setsuo Hirohashi, Tatsuhiro Shibata

研究成果: Article査読

72 被引用数 (Scopus)

抄録

Background & Aims: The biological aggressiveness of hepatocellular carcinoma (HCC) and the lack of optimal therapeutic strategies have rendered the disease a major challenge. Highly heterogeneous genetic alteration profiles of HCC have made it difficult to identify effective tailor-made molecular therapeutic targets. Therefore, classification of HCC into genetically homogeneous subclasses would be of great worth to develop novel therapeutic strategies. Methods: We clarified genome-scale chromosomal copy number alteration profiles and mutational statuses of p53 and β-catenin in 87 HCC tumors. We investigated the possibility that HCC might be classifiable into a number of homogeneous subclasses based solely on their genetic alteration profiles. We also explored putative molecular therapeutic targets specific for each HCC subgroup. Results: Unsupervised hierarchical cluster analysis based on chromosomal alteration profiles suggested that HCCs with heterogeneous genetic backgrounds are divisible into homogeneous subclasses that are highly associated with a range of clinicopathologic features of the tumors and moreover with clinical outcomes of the patients (P < .05). These genetically homogeneous subclasses could be characterized distinctively by pathognomonic chromosomal amplifications (eg, c-Myc-induced HCC, 6p/1q-amplified HCC, and 17q-amplified HCC). An in vitro experiment raised a possibility that Rapamycin would significantly inhibit the proliferative activities of HCCs with 17q amplification. Conclusions: HCC is composed of several genetically homogeneous subclasses, each of which harbors characteristic genetic alterations that can be putative tailor-made molecular therapeutic targets for HCCs with specific genetic backgrounds. Our results offer an opportunity for developing novel individualized therapeutic modalities for distinctive genome types of HCC.

本文言語English
ページ(範囲)1475-1486
ページ数12
ジャーナルGastroenterology
133
5
DOI
出版ステータスPublished - 2007 11月
外部発表はい

ASJC Scopus subject areas

  • 肝臓学
  • 消化器病学

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