Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

Abstract

Cyclin D1 (CCND1) plays a key role in cell cycle control, particularly in the transition from G 1 to S phase, which is regulated by cyclindependent kinases. A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies. Among subjects with hereditary nonpolyposis colorectal cancer, the A870G polymorphism has also been associated with a younger age of onset of colorectal cancer. We analysed 181 colorectal cancer cases and 475 matched controls and 524 adenoma cases and 517 matched controls within women in the Nurses' Health Study (NHS) cohort, 171 colorectal cancer cases and 347 matched controls and 372 adenoma cases and 712 matched controls nested within men in the Health Professionals' Follow-Up Study (HPFS) cohort, and 258 colorectal cancer cases and 415 matched controls within men in the Physicians' Health Study (PHS) cohort to assess the risk associated with the CCND1 A870G genotype. Moreover, we assessed whether CCND1 genotype modified the effect of a sporadic (nonsyndromic) family history of colorectal cancer as well as the effect of other dietary and lifestyle risk factors for colorectal cancer and adenoma. In all cohorts combined, the CCND1 polymorphism did not show statistically significant associations to risk of colorectal cancer (odds ratio (OR) for A allele carriers, 1.04; 95% confidence interval (95% CI), 0.82 -1.32) or adenoma (OR, 0.96; 95% CI, 0.79 -1.18). The CCND1 A870G genotype was associated with a modest, although nonsignificantly elevated risk of colorectal cancer (OR, 1.59; 95% CI, 0.98 -2.57) in women. In contrast, the polymorphism was not associated with increased risk of adenoma in either men or women. Among participants with the A870G genotype, a family history of colorectal cancer conferred a substantially greater risk of colorectal cancer in the women (P for interaction ¼ 0.06) and adenoma in the men (P for interaction ¼ 0.02). Current postmenopausal hormone (PMH) use was associated with a significant reduction in the risk of colorectal cancer and adenoma among women with the A870G genotype, whereas there was no effect of PMH use among those with the GG genotype. The CCND1 polymorphism appeared to confer a modest elevation in the risk of colorectal cancer among women. Moreover, the A870G genotype may enhance the protective effect of postmenopausal oestrogen use on the development of colorectal neoplasia.

Cyclin D1 Pro241Pro (CCND1-G870A) Polymorphism Is Associated with Increased Cancer Risk in Human Populations: A Meta-Analysis

“…Heterogeneity was explored using subgroup analysis (10) with ethnicity (Asians and Caucasians) and cancer types. We have classified the cancer types in nine different categories including breast (13)(14)(15)(16)(17)(18)(19), colorectal (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), gynecologic [ovarian (35), cervical (36), and endometrial (37)], digestive tract [oral (38)(39)(40), esophageal (41)(42)(43)(44), and stomach (45,46)], blood-related [acute lymphoblastic leukemia (47), mantle cell lymphoma (48), and non-Hodgkin's lymphoma (49)], genitourinary [bladder (50)(51)(52)(53), prostate (54,55), and kidney (56)], lung (57)(58)(59)…”

Cyclin D1 Gene G870A Variants and Primary Brain Tumors

“…Since PEST domain is critical for the protein degradation, 870A allele encoded protein has a longer half-life than its wild type variant. As a result, it is suggested that individuals with CCDN1 870A allele can more easily bypass G1-S checkpoint and more likely to develop cancer (Betticher et al, 1995;Weinstein et al, 1997;Sawa et al, 1998;Solomon et al, 2003;Schernhammer et al, 2006). This hypothesis has been tested in various cancer types with variable results.…”

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

“…[7][8][9] Also, carriers of the A allele appear to be more frequent among individuals who developed non-syndromic colorectal cancer before the age of 60, 10 subjects with familial colorectal cancer 11,12 and affected women. 13,14 Other reports, however, do not subscribe to rs9344 genotype being a modifier of the colorectal cancer phenotype. 15,16 Given the low odds ratios (OR) associated with common variants, such as rs9344, we have argued that genetic risk factors underlying complex diseases are more likely to be due to functionally relevant rare variants with moderate penetrance that will considerably increase susceptibility and will, therefore, sometimes justify prophylactic interventions.…”