Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.
Genomic changes frequently occur in cancer cells during tumorigenesis from normal cells. Using the Illumina Human NS-12 single-nucleotide polymorphism (SNP) chip to screen for gene copy number changes in primary hepatocellular carcinomas (HCCs), we initially detected amplification of 35 genes from four genomic regions (1q21-41, 6p21.2-24.1, 7p13 and 8q13-23). By integrated screening of these genes for both DNA copy number and gene expression in HCC and colorectal cancer, we selected CENPF (centromere protein F/mitosin), GMNN (geminin, DNA replication inhibitor), CDK13 (cyclin-dependent kinase 13), and FAM82B (family with sequence similarity 82, member B) as common cancer genes. Each gene exhibited an amplification frequency of ~30% (range, 20-50%) in primary HCC (n = 57) and colorectal cancer (n = 12), as well as in a panel of human cancer cell lines (n = 70). Clonogenic and invasion assays of NIH3T3 cells transfected with each of the four amplified genes showed that CENPF, GMNN, and CDK13 were highly oncogenic whereas FAM82B was not. Interestingly, the oncogenic activity of these genes (excluding FAM82B) was highly correlated with gene-copy numbers in tumor samples (correlation coefficient, r>0.423), indicating that amplifications of CENPF, GMNN, and CDK13 genes are tightly linked and coincident in tumors. Furthermore, we confirmed that CDK13 gene copy number was significantly associated with clinical onset age in patients with HCC (P = 0.0037). Taken together, our results suggest that coincidently amplified CDK13, GMNN, and CENPF genes can play a role as common cancer-driver genes in human cancers.
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
Hye-Eun
HE
Kim
Dae-Ghon
DG
Kim
Kyung Jin
KJ
Lee
Jang Geun
JG
Son
Min-Young
MY
Song
Young-Mi
YM
Park
Jae-Jung
JJ
Kim
Sung-Won
SW
Cho
Sung-Gil
SG
Chi
Hyun Sub
HS
Cheong
Hyoung Doo
HD
Shin
Sang-Wook
SW
Lee
Jong-Keuk
JK
Lee
D017668:Age of Onset; D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D064248:Geminin; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009857:Oncogenes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C577995:GMNN protein, human; D064248:Geminin; D008840:Microfilament Proteins; C094772:centromere protein F; D016203:CDC2 Protein Kinase; C072262:CDK13 protein, human