Background: Circadian rhythms of biological processes are regulated by endogenous clock genes and clock-controlled genes. Aberrant expression of circadian clock genes may have important consequences on the transactivation of downstream targets that control the cell cycle and cellular proliferation potentially promoting carcinogenesis. Animal models indicate that several circadian rhythm genes are expressed in the ovaries, where they influence and are influenced by estrous cycles. The goal of the current study was to examine the association of circadian gene variants and epithelial ovarian cancer (EOC) risk.
Methods: Thirty-one SNPs from five circadian genes (i.e., ARNTL, CRY2, KLF10, NPAS2, PER3, TIMELESS) were genotyped in 14,736 cases and 23,448 control women of European ancestry from 43 studies in the Ovarian Cancer Association Consortium (OCAC), on a custom Illumina iSelect designed for the Collaborative Oncological Gene-Environment Study (COGS). Both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, SNP analyses were conducted using unconditional logistic regression under a log-additive model. All analyses were adjusted for study site and population substructure.
Results: Eleven SNPs were found to be associated with ovarian cancer risk. The SNPs most associated with serous cancer risk were KLF10 rs2513928 (OR=.95 p=6.1x103), rs2513927 (OR=1.05 p=6.1x103), rs2511703 (OR=1.05 p=9.8x103), rs3191333 (OR=1.05, p=1.5x102) and NPAS2 rs13012930 (OR=.95, p=3.5x102). Endometroid cancer risk was significantly associated with ARNTL SNPs rs10732458 (OR=1.3, p=1.0x102) and rs7117836 (OR=1.2, p=4.6x102), while clear cell cancer risk was associated with ARNTL rs1562438 (OR=.88, p=1.5x102), rs1026071 (OR=.89, p=1.8x102), and rs3816360 (OR=.91, p=4.8x102) and KLF10 rs2388232 (OR=1.1, p=3.3x102). No variants were significantly associated with mucinous cancer risk. Four SNPs in KLF10 were associated with cancer invasiveness; they were rs2513928 (OR=.95, p=1.8x103), rs3191333 (OR=1.04, p=1.4x102), rs2513927 (OR=1.04, p=1.9x102), and rs2511703 (OR=1.03, p=2.8x102).
Conclusions: Data from the current study suggest that polymorphisms in circadian genes ARNTL, KLF10, and NPAS2 are significantly associated with ovarian cancer histopathologic subtypes and invasiveness. These findings merit further investigation and replication.
Funding: R01 CA149429
Citation Format: Heather Jim, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Ellen L. Goode, Zhihua Chen, Ya-Yu Tsai, Julie M. Cunningham, Edward Iversen, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven A. Narod, Thomas A. Sellers, Paul Pharoah, Catherine M. Phelan. Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4850. doi:10.1158/1538-7445.AM2013-4850
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.