Cyclin D1 polymorphism and increased risk of colorectal cancer at young age

Colorectal cancer is the third most common cause of cancer and cancer mortality among men and women in the United States. It is estimated that there will be approximately 130 400 new co-lorectal cancer cases and 56 700 deaths in the year 2001 (1). Cyclin D1 is involved both in normal regulation of the cell cycle and in neo-plasia, where it is frequently overex-pressed (2). It plays an important role in the transition from the G1 phase to the S phase of the cell cycle. Amplification or overexpression of the cyclin D1 gene (also known as CCND1) is common in a variety of different cancers and induces proliferation. The cyclin D1 gene has a G to A polymorphism at codon 242 in exon 4 that increases the frequency of alternate splicing (3). In the alternately spliced RNA, intron 4 is not spliced out. Both the normal and altered transcripts en-code a protein that contains amino acids 55–161, which are thought to be respon-sible for the cyclin D1 function (4). The protein encoded by the alternate transcript is missing the last 55 amino acids at the carboxy-terminus that are replaced by a shorter 43-amino-acid sequence encoded by intron 4. As a re-sult, the carboxy-terminal end of the al-ternate transcript is missing sequences important in protein turnover; therefore, it may have a longer half-life (3). Slight elevations in the levels of cyclin D1 might make the cells less sensitive to signals by the cell-cycle checkpoint machinery. The A allele leads to poorer clinical outcome in patients with non-small-cell lung cancer (3). In a previous study (5), we showed that patients with one or two copies of the polymorphic A allele of the cyclin D1 gene who also carried a mu-tation in a mismatch repair gene devel-oped hereditary nonpolyposis colorectal cancer (HNPCC) on the average of 11 years earlier than mismatch repair gene mutation carriers with the GG genotype. To extend our findings, we conducted a hospital-based case–control study of nonsyndromic colorectal cancer to de-termine if the cyclin D1 polymorphism influences risk for this disease. We studied a consecutive series of newly registered patients with nonsyn-dromic adenocarcinoma of the colon or rectum evaluated at The University o