Cyclin D1 Polymorphism and Increased Risk of Colorectal Cancer at Young Age
Authors: S. Kong, Q. Wei, C. I. Amos, P. M. Lynch, B. Levin, J. Zong, M. L. Frazier
Journal: JNCI Journal of the National Cancer Institute (2001)

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 colorectal 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 neoplasia, where it is frequently overexpressed (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 encode a protein that contains amino acids 55–161, which are thought to be responsible 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 result, the carboxy-terminal end of the alternate 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 mutation in a mismatch repair gene developed 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 determine if the cyclin D1 polymorphism influences risk for this disease. We studied a consecutive series of newly registered patients with nonsyndromic adenocarcinoma of the colon or rectum evaluated at The University of Texas M. D. Anderson Cancer Center, Houston, who agreed to participate in the study. Patients with nonsyndromic colorectal cancer are defined as individuals with no obvious physical characteristics such as occur in familial adenomatous polyposis coli (FAP) or Peutz–Jeghers syndrome. The patients were enrolled during an 11-month period that began in September 1994. From September 20, 1994, through August 17, 1995, a total of 321 patients with confirmed colon or rectal adenocarcinoma consented to participate in the study and provided a blood specimen, representing 69% of the patients originally contacted. Of these 321 patients, 188 (59%) were male and 133 (41%) were female. Most case subjects were Caucasian (75%), with AfricanAmerican, Hispanic, and other ethnic groups accounting for 16%, 8%, and 1%, respectively. Thirty-four percent (n 110) of the cases occurred in individuals less than 50 years old, and 23% (n 75) occurred in individuals less than 45 years old. Because of possible heterogeneity in susceptibility to colorectal cancer among different racial and ethnic groups, we limited our study to Caucasians. Among the Caucasians, we limited the study to case subjects under the age of 60 years, because environmental effects are likely to dominate over genetic effects in older case subjects. This restriction led to our final tally of 156 case subjects, 28 (18%) of whom had rectal cancer (with two subjects having both rectal and colon cancers), and 11 patients (7%) met the Amsterdam criteria (6).