Although the molecular basis of HNPCC is well known, there is no explanation for the wide range of phenotypes observed, e.g., the wide variety in age of onset (19-90 years) of CRC. Thus, other environmental or genetic factors must be considered as modifying the HNPCC phenotype. The first genetic modifier reported to be associated with age of onset in HNPCC was the CCND1 G870A polymorphism [2,3], but other studies failed to detect any significant association in a larger HNPCC population [11,18] (Table 5).

Table 2. Allele frequencies and genotype distribution of CCND1 G870A in colorectal cancer patients and controls.

We correlated the CCND1 G870A polymorphism with MSI status of the tumors and observed a statistically significant risk of CRC in MSI-positive carriers of the CCND1 A allele. After stratification by gender and age at diagnosis, we observed increased risk in male patients and particularly those under 60 years of age, as indicated by the increase of the ORs. The consequences of the above observation were reversed (although statistically not significant) in female patients (Tables 3 and 4). The effect of the CCND1 A allele on the risk of CRC apparently differs by gender which could be ex plained by the sex hormone divergence. The CCND1 870A variant may enhance CRC progression through a cell signalling pathway influenced by estrogens in colonic epithelia. It is well known that induction of cyclin D1 gene transcription by estrogen receptor a (ERa) plays an important role in estrogen-mediated proliferation in breast cancer [21,22]. However, estrogens decrease cyclin D1 gene expression when they bind to ERa. Strikingly, the presence of ERb completely inhibits cyclin D1 gene activation by estrogen and ERb, and even has the ability to block estrogen activation of the cyclin D1 gene mediated by ERb if the two receptors are present in the same cell [23], and seems to be essential for maintenance of cellular homeostasis and for driving cellular differentiation in the colon [24,25].

 Data are numbers with percentages in parentheses                                                                            OR = Odds Ratio                                                                                                                           CI = Confidence Interval

The fact that ERa, the predominant ER subtype in the human colon, is significantly decreased in CRCs compared with normal mucosa, led to our assumption that estrogen has a protective role in the regulation of colon tumor growth and CRC development. Indeed, the risk of both CRC and adenoma associated with a family history of CRC may be augmented by the CCND1 G870A genotype [5]. Moreover, the A870G genotype appears to enhance the protective effect of postmenopausal estrogen use on the development of colorectal neoplasia, whereas there was no effect of postmenopausal hormone use among those with the GG genotype [5]. Our findings led us to conclude that the CCND1 AA genotype may have a modifying effect in decreasing the age of onset in HNPCC, but only in males since they lack the protective effect of estrogen. If these results can be replicated in other case/control studies, the CCND1 G870A variant could be used in the future to provide additional information in genetic counseling of families with MSI-positive tumors.