The role of rare copy number variants and other candidate alleles in hereditary breast cancer susceptibility

Breast cancer is the most common cancer in women worldwide. Out of approximately every eight women, one will develop breast cancer during their lifetime. Based on the familial clustering of the disease, it has been estimated that up to 10% of all cases stem from a strong hereditary predisposition. Multiple pathogenic variants in high-risk genes (e.g., BRCA1, BRCA2 and PALB2), moderate-risk genes (e.g., ATM and CHEK2), and low-risk loci have been identified as risk factors. However, they still explain only around half of the inherited risk. The identification of new susceptibility factors has the potential to improve genetic counseling and personalized cancer screenings. The aim of this thesis was to identify new breast cancer predisposing variants by evaluating the prevalence of selected candidate alleles and recurrent copy number variants (CNVs) in the Northern Finnish breast cancer cohorts. In addition, risk estimations were refined for previously identified and locally enriched moderate-to-high risk variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, FANCM, MCPH1 and RAD50 DNA damage response (DDR) genes.
Enriched in Northern Finland, the protein-truncating variant NTHL1 p.Q90* and missense-variant CHEK2 Asp438Tyr were selected for evaluation based on their unclear clinical significance and potential association with breast cancer susceptibility implied by previous studies. Both variants turned out to be likely benign for breast cancer susceptibility with carrier frequencies similar to that in the general population.
The moderate-to-high risk variants in DDR genes had an overall prevalence of 7.1% in the breast cancer cohort and associated with specific breast cancer subtypes. The identification of several double carriers supports a multiplicative risk model for the moderate- and high-risk variants.
CNVs are defined as gains or losses of genomic segments with a size of ≥1 kilobase (kb) and, in this thesis, identified by utilizing read-depth data from 98 whole-exome sequenced high-risk cases. Three recurrent CNVs were identified: deletion co-occurring with a retrotransposon insertion in RAD52, deletion in HSD17B14, and a partial duplication of RAD51C. RAD52 and HSD17B14 CNVs were significantly enriched in the familial cases, indicating that CNVs should be considered alongside single nucleotide variants when searching for inherited risk factors for breast cancer.