Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation

Abstract

Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the ‘period’ (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9–4.8; 5/5 OR, 5.1; 95% CI, 1.4–18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7–5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample.

Case-control study of candidate gene methylation and adenomatous polyp formation

“…26–29 The PER3 gene contains a variable-number tandem repeat (VNTR) sequence (a component of SVA retrotransposons), 80,81 and individuals with the 5-repeat PER3 VNTR sequence had an increased odds of adenoma formation. 66 However, the PER3 VNTR did not modify the results obtained for hypomethylation of the PER3 promoter in the present study; thus it is uncertain whether these processes are related. A growing body of evidence indicates that dysregulation of the PER s or other clock genes may have a role in adenoma formation and CRC risk, possibly via epigenetic or retrotransposon pathways, however the specific mechanisms remain to be elucidated.…”

“…17,59 PER1 and PER2 mutations occur in human colorectal tumors, 60 and PER expression is reduced in colorectal adenomas or tumors relative to normal tissue. 61–66 Polymorphisms in the PER3 gene have been associated with inflammatory bowel disease, an established CRC risk factor, 67 and with increased odds of adenoma formation. 66 Aberrant methylation of PER genes has been observed among leukemia and other cancer patients.…”

“…61–66 Polymorphisms in the PER3 gene have been associated with inflammatory bowel disease, an established CRC risk factor, 67 and with increased odds of adenoma formation. 66 Aberrant methylation of PER genes has been observed among leukemia and other cancer patients. 68–72 However, to the authors’ knowledge, no studies have examined epigenetic modifications in the PER or other clock genes in relation to adenoma formation.…”

“…68–72 However, to the authors’ knowledge, no studies have examined epigenetic modifications in the PER or other clock genes in relation to adenoma formation. 46,66 …”

Rotating night shift work and colorectal cancer risk in the nurses’ health studies

“…In addition, melatonin – which is often suppressed in night workers – exhibits direct and indirect oncostatic properties specific to colorectal cancer; for example, melatonin can cause growth inhibition of cell lines derived from colon carcinomas in vitro and animal studies 17–19 . Short sleep duration (a common consequence of night shift work) and a length polymorphism in the PER3 clock gene (a genotype associated with morning chronotype and sleep disorders) have been associated with a higher risk for formation of colorectal adenoma, the precursor lesion to colorectal cancer 20, 21 . However, in a recent report, we found no evidence for an association between night shift work and risk for colorectal adenomas among female nurses 22 .…”