Cyclin D1 G870A Variant is Associated with Increased Risk of Microsatellite Instability-Positive Colorectal Cancer in Young Male Patients

Cyclin D1 (CCND1) is a cell cycle regulatory protein, which is often over expressed in human tumors and is associated with cell proliferation and poor prognosis. A common G870A single nucleotide polymorphism at codon 242 in exon 4 of the CCND1 gene is associated with an altered messenger RNA transcript and increased risk of colorectal cancer (CRC) and adenoma in some studies. Over expression of CCND1 modifies the effect of mutations in mismatch repair (MMR) genes, enhances microsatellite instability (MSI), and influences the age ofonset of hereditary non polyposis colorectal cancer (HNPCC). We have extended our study that indicated that the CCND1 A variant may influence the age of onset of CRC in the Macedonian population only in patients who exhibit MSI tumors by a case control study of 331 randomly selected CRC patients and 101 controls without clinical diagnosis of CRC. We did not observe a significant difference in overall allelic frequencies and genotype distribution of affected and unaffected mutation carriers, but found a statistically significant risk of CRC in carriers of the CCND1 A allele when patients were grouped according to gender, age and MSI status. A higher risk was observed in patients with MSI-positive tumors and particularly in male patients under 60 years of age. The consequences of the above observation were reversed in female patients. These results indicate that the CCND1 A variant may enhance CRC progression through a pathway influenced by estrogens in colonic epithelia.