A different methylation profile of circadian genes promoter in breast cancer patients according to clinicopathological features

ABSTRACT

One of the supposed mechanisms that may lead to breast cancer (BC) is an alteration of circadian gene expression and DNA methylation. We undertook an integrated approach to identify methylation pattern of core circadian promoter regions in BC patients with regard to clinical features. We performed a quantitative methylation-specific real-time PCR analysis of a promoter methylation profile in 107 breast tumor and matched non-tumor tissues. A panel of circadian genes CLOCK, BMAL1, PERIOD (PER1, 2, 3), CRYPTOCHROME (CRY1, 2) and TIMELESS as well as their association with clinicopathological characteristics were included in the analysis. Three out of the eight analyzed genes exhibited marked hypermethylation (PER1, 2, 3), whereas CLOCK, BMAL1, CRY2 showed significantly lower promoter CpG methylation in the BC tissues when compared to the non-tumor tissues. Among variously methylated genes we found an association between the elevated methylation level of PERs promoter region and molecular subtypes, histological subtypes and tumor grading of BC. Methylation status may be associated with a gene expression level of circadian genes in BC patients. An aberrant methylation pattern in circadian genes in BC may provide information that could be used as novel biomarkers in clinics and molecular epidemiology as well as play an important role in BC etiology.

KEYWORDS:

• DNA methylation
• gene expression
• circadian rhythm
• clock genes
• breast cancer

Disclosure statement

No potential conflicts of interest were disclosed.

Supplementary material

The supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Science Center (Grant No. 2014/15/N/NZ5/01671) (to ML) and partially supported by Ministry of Science and Higher Education, Poland DIR/WK/2017/01 (to LK), Internal grant for statutory activity at Nofer Institute of Occupational Medicine 14.4/2018 (to ML) and Internal grant for statutory activity at Medical University of Gdansk ST-02-0013/07/114 (to JS).