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Prognostic value of DNA alterations on chromosome 17p13.2 for intrahepatic cholangiocarcinoma.

ABSTRACT: AIM:To characterize and evaluate DNA alterations among intrahepatic cholangiocarcinoma (ICC) patients. METHODS:DNA from tumor and corresponding normal tissues of 52 patients was amplified with 33 arbitrary primers. The DNA fragment that alters most frequently in ICC was cloned, sequenced, and identified by comparison with known nucleotide sequences in the genome database (www.ncbi.nlm.nih.gov). The DNA copy numbers of the allelic alterations in cholangiocarcinoma were determined by quantitative real-time PCR and interpreted as allelic loss or DNA amplification by comparison with the reference gene. Associations between allelic imbalance and clinicopathological parameters of ICC patients were evaluated by chi2-test. The Kaplan-Meier method was used to analyze survival rates. RESULTS:From 33 primers, an altered DNA fragment (518 bp) amplified from BC17 random primer was found frequently in the tumors analyzed and mapped to chromosome 17p13.2. Sixteen of 52 (31%) cases showed DNA amplification, while 7 (13%) showed allelic loss. Interestingly, DNA amplification on chromosome 17p13.2 was associated with a good prognosis, median survival time (wk) of amp vs no amp was 44.14 vs 24.14, P = 0.002; whereas allelic loss of this DNA sequence corresponded with a poor prognosis, median survival time (wk) of loss vs no loss was 18.00 vs 28.71, P = 0.019). Moreover, Kaplan-Meier curves comparing the DNA alterations with survival depicted highly significant separation that the median survival time equal to DNA amplification, allelic loss, and normal was 44.14 wk, 18.00 wk, and 24.29 wk, respectively (P = 0.005). CONCLUSION:Alterations in the DNA sequence on chromosome 17p13.2 may be involved in cholangio-carcinogenesis, and could be used as a prognostic marker in the treatment of ICC patients.

SUBMITTER: Chuensumran U

PROVIDER: S-EPMC4171154 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Prognostic value of DNA alterations on chromosome 17p13.2 for intrahepatic cholangiocarcinoma.

Chuensumran Ubol U Wongkham Sopit S Pairojkul Chawalit C Chauin Siri S Petmitr Songsak S

World journal of gastroenterology 20070601 21

<h4>Aim</h4>To characterize and evaluate DNA alterations among intrahepatic cholangiocarcinoma (ICC) patients.<h4>Methods</h4>DNA from tumor and corresponding normal tissues of 52 patients was amplified with 33 arbitrary primers. The DNA fragment that alters most frequently in ICC was cloned, sequenced, and identified by comparison with known nucleotide sequences in the genome database (www.ncbi.nlm.nih.gov). The DNA copy numbers of the allelic alterations in cholangiocarcinoma were determined b ...[more]

PMID: 17589952

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Project description:Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. It is defined by cholangiocytic differentiation and has poor prognosis. Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis. We performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with a specific focus on DNA methylation components. We found recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and focal alterations such as deletion of 3p21 or amplification of 12q15, which affect BRCA1 Associated Protein 1, polybromo 1, and mouse double minute 2 homolog. DNA methylome analysis revealed excessive hypermethylation of iCCA, affecting primarily the bivalent genomic regions marked with both active and repressive histone modifications. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H), medium (M), and low (L) alteration groups. The IDH group consisted of all samples with IDH1 or IDH2 mutations and showed, together with the H group, a highly disrupted genome, characterized by frequent deletions of chromosome arms 3p and 6q. Both groups showed excessive hypermethylation with distinct patterns. The M group showed intermediate characteristics regarding both genetic and epigenetic marks, whereas the L group exhibited few methylation changes and mutations and a lack of CNAs. Methylation-based latent component analysis of cell-type composition identified differences among these four groups. Prognosis of the H and M groups was significantly worse than that of the L group. Conclusion: Using an integrative genomic and epigenomic analysis approach, we identified four major iCCA subgroups with widespread genomic and epigenomic differences and prognostic implications. Furthermore, our data suggest differences in the cell-of-origin of the iCCA subtypes.

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Prognostic value of DNA alterations on chromosome 17p13.2 for intrahepatic cholangiocarcinoma.

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Prognostic value of DNA alterations on chromosome 17p13.2 for intrahepatic cholangiocarcinoma.

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