CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer is associated with inherited defe cts in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributin g to the phenotype. We addressed the modifying role of the common A/G polym orphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin DI in a series of 146 affected carriers of 10 ML H1 and 3 MSH2 mutations. No correlation was observed between a particular a llele (A versus G) and age at onset. However, the presence of the variant t ranscript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0 .02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b tr anscripts may modify the age at onset of colon cancer in hereditary nonpoly posis colorectal cancer.