Cyclin D1 plays a key role in cell cycle regulation, particularly in the transition from G1 to S phase, which is regulated by cyclin-dependent kinases (CDK). The predominant action of cyclin D1 is believed to result from interactions with CDK4 and/or CDK6 which promote phosphorylation and inactivation of retinoblastoma (RB) tumor suppressor protein, and thus facilitate of cell cycle progression [1]. Although somatic mutations in the Cyclin D1 gene (CCND1, also known as PRAD1) are rare, a common G.A polymorphism may influence cancer risk and outcome [2-9]. The G870A polymorphism in exon 4 with in the spliced donor site results in two splice variants, “transcript a” preferentially associated with the G allele and truncated “transcript b” lacking exon 5, which is associated with the A allele [10]. However, individuals with the A/A genotype can still produce “transcript a” [11], indicating that the 870-A allele is not completely penetrant for “transcript b” production. The “transcript b” results in a 274 amino acid product that lacks the C-terminal PEST domain and residue Thr 286 that regulates cyclin D1 stability, and the variant protein would be expected to have a longer half-life. However the half-life of cyclin D1b is only slightly greater than that of the fulllength variant (cyclin D1a) and cyclin D1b is a poor activator of CDK4 and RB phosphorylation [12,13]. Nevertheless, cyclin D1b harbors an increased transforming capability (as compared to cyclin D1a) thus indicating that it may serve as a more potent oncogene in human cancers [12-15].

Microsatellite instability (MSI) in hereditary and in sporadic colorectal cancer (CRC) occurs through two mechanisms. In hereditary cases (e.g., hereditary non poly posis colorectal cancer-HNPCC), a germline mutation of one of the three main mismatch repair (MMR) genes (MLH1, MSH2, and MSH6), leads to mutational inactivation and deficient MMR. However, many CRCs show MSI without evidence of germline abnormalities. In sporadic CRC exhibiting MSI, instability in microsatellite se quences is often due to loss of expression of MMR genes (most commonly MLH1) that is caused by epigenetic silencing.

Most studies link the A allele to increased CRC risk and poor disease outcome, with the largest associations being observed with the A/A genotype. However, some studies have implicated the G allele with increased cancer risk [16], while others have attributed no significant value to any allele of the G/A870 polymorphism [17]. There are conflicting reports on the implication of the CCND1 G870A polymorphism with the age of onset of HNPCC [2,3,11,18].

Our initial study on a limited number of patients from the Macedonian population indicated that the CCND1 A variant may influence the age of onset of CRC only in patients who exhibit MSI-positive tumors [19]. We have extended our study of the role of CCND1 polymorphism in tumorogenesis by a case control study of 331 randomly selected CRC patients and 101 controls without clinical diagnosis of CRC. The main aim of the study was to assess the CCND1 G870A polymorphism as a risk factor for CRC in the Macedonian population, and to elucidate the association between the CCND1 G870A polymorphism and MSI.