Cyclin D1 protein expression and gene polymorphism in colorectal cancer

Cyclin D1 is a key cell cycle regulatory protein, the expression and subcel lular localization of which is often altered in human tumor cells. A common A/G single nucleotide polymorphism (A870G) in exon 4 of the cyclin D1 gene , CCND1, is associated with the presence of 2 distinct mRNA transcripts for this G1/S regulatory protein, and CCND1 genotype has been related to progn osis in lung cancer and head and neck carcinoma. We have investigated both the expression of cyclin D1 protein and the CCND1 A870G polymorphism in 100 colorectal cancer patients. Immunohistochemistry demonstrated cyclin D1 pr otein expression in 55% of tumors, and while the absence of cyclin D1 prote in was not associated with outcome (p = 0.81), high levels of protein expre ssion (>50% of tumor cells expressing cyclin D1) correlated with significan tly shortened overall survival (p = 0.01). Using polymerase chain reaction restriction fragment length polymorphism analysis, we determined the freque ncy of each genotype and found that CCND1 genotype was not related to overa ll survival (p > 0.05). In addition, genotype was unrelated to the level of expression and localization of cyclin D1 protein, as well as other key G1/ S checkpoint proteins (p21, p27, p53, retinoblastoma) and tumor proliferati on markers (proliferating cell nuclear antigen). However, higher levels of p27, and to a lesser extent p21, were associated with reduced cytoplasmic c yclin D1 protein (p = 0.029 and p = 0.054, respectively). In conclusion, we have demonstrated that high levels of cyclin D1 protein expression are rel ated to outcome in colorectal cancer; however, the CCND1 A870G polymorphism is unrelated to either cyclin D1 protein expression or patient survival. ( C) 2000 Wiley-Liss, Inc.