Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets.
OBJECTIVE
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 beta-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.
Katoh
Hiroto
H
Cancer Genomics Project, National Cancer Center Research Institute, Tokyo, Japan; Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Ojima
Hidenori
H
Kokubu
Akiko
A
Saito
Shigeru
S
Kondo
Tadashi
T
Kosuge
Tomoo
T
Hosoda
Fumie
F
Imoto
Issei
I
Inazawa
Johji
J
Hirohashi
Setsuo
S
Shibata
Tatsuhiro
T
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016172:DNA Fingerprinting; D005260:Female; D051858:Forkhead Transcription Factors; D018628:Gene Dosage; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
D018797:Cell Cycle Proteins; C106158:FOXN3 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D053148:Caspase 3