Multiple genetic alterations involved in the tumorigenesis of human cholangiocarcinoma: a molecular genetic and clinicopathological study

Purpose: Cholangiocaroinoma (CC) is the second most common malignant tumor in the liver and the molecular genetic alterations involved in the tumorige nesis of CC have not been well studied. Patients and methods: The authors a nalyzed the loss of heterozygosity (LOH) in four tumor suppressor genes- in cluding the adenomatous polyposis coli (APC) gene, the deleted in colon can cer (DCC) gene. the 8-hydroguanine-specific DNA glycosylase (OGG1) gene, an d the p53 gene in 22 surgically resected primary CCs by using microdissecti on-based PCR amplification and direct DNA sequencing. Results: A total of 1 9 (86.49%) out of 22 CCs exhibited genetic alterations, of which 11 (57.9%) and eight (42.1%) cases showed one and more than one gene alterations, res pectively. The frequency of genetic alterations of the four genes studied r anged in order from high to low as APC (68.8%) > DCC (46.2%) > OGC1 (41.7%) > p53 (37.5%). Based on the pattern of altered genes and their correlation with clinical and pathological parameters, the genetic alterations were cl assified into three groups: group I: no detectable genetic alterations (n = 3. 13.6%): group II: LOH in APC and/or DCC (n = 9, 40.9%); and group III: LOH in OGG1 and/or p53 occurred separately or combined with LOH in APC and/ or DCC (n = 10, 45.5%). The 23-year survival rates between group II and gro up III are 88.9% and 30%, respectively (P < 0.05). No significant differenc es were found between genetic alterations and tumor size, tumor type, tumor invasion, TNM staging, and tumor differentiation (P > 0.05). Conclusion: A ccumulation of multiple genetic alterations are involved in the tumorigenes is of CC, of which, genetic alterations of APC and DCC occur at a relativel y early stage, and of OGG1 and p53 occur at a relatively late stage during development of CC.