Abstract
Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.
Highlights
Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported
We found that peripheral blood DNA methylation at the BRCA1 promoter was associated with an estimated 3.5-fold increased risk of breast cancer diagnosed before the age of 40 years[7]
After removing 3949 poorly performing CpG probes, β-values and M-values were obtained from a total of 481,563 analysable CpG probes across DNA samples from 210 individuals in 25 families (20 families participating in kConFab and 5 families participating in the Australian Breast Cancer Family Registry (ABCFR)). β-values denote % methylation levels obtained from the HM450K platform, where 0 indicates 0% methylation and 1 indicates 100% methylation
Summary
Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk. Several genome-wide studies of DNA methylation have found evidence that global methylation levels measured in blood-derived DNA is associated with breast cancer risk for women in the general population, and for women from families at high genetic risk[1,2,3]. We found that peripheral blood DNA methylation at the BRCA1 promoter was associated with an estimated 3.5-fold (95% CI, 1.4–10.5) increased risk of breast cancer diagnosed before the age of 40 years[7]. Flanagan et al.[12] performed methylation microarray analyses of peripheral blood DNA across several genes including BRCA1, BRCA2, CHEK2, ATM, TP53, CDH1, and MLH1, and demonstrated that gene body hypermethylation of ATM was associated with an estimated threefold increased risk of breast cancer[12]. Mikeska et al.[15] found little evidence of PALB2 methylation in high-grade serous ovarian cancers using a methylation-sensitive high-resolution melting assay[15]
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