Abstract
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
Highlights
Almost every human cell contains an autonomous circadian clock that synchronizes gene transcription in a daily oscillation for many physiological processes allowing for adaptation to the 24 hour environmental day/night cycle
No SNPs were significantly associated with EOC invasiveness nor were any SNPs significantly associated with risk of mucinous or clear cell EOC after applying the criterion of false discovery rate (FDR) < 0.10
The current study examined variation in nine key genes involved in circadian rhythm regulation or their transcription (BMAL1, CRY2, casein kinase 1 epsilon (CSNK1E), Krüppel-like factor 10 (KLF10), NPAS2, PER3, REV1, SENP3, TIMELESS) as predictors of epithelial ovarian cancer risk, histopathologic subtype, and invasiveness
Summary
Almost every human cell contains an autonomous circadian clock that synchronizes gene transcription in a daily oscillation for many physiological processes allowing for adaptation to the 24 hour environmental day/night cycle. Disruption in circadian gene expression, whether due to genetic variants or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence and invasiveness of a variety of human cancers [2,3,4,5] such that in 2007 the International Agency for Research on Cancer classified shift work that involves circadian disruption as “a probable carcinogen” in humans [6]. A recent study found that working nightshifts (i.e., 12:00–4:00 AM) was associated with an increased risk of serious and mucinous, invasive and borderline ovarian tumors in women who were 50 years of age and older [8]. Some studies have failed to find an association between shiftwork and cancer risk [9,10,11]
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