Population-based study of recurrent DNA damage response gene variants in breast cancer cases.

Purpose: Several variants in DNA damage response (DDR) genes increase the probability to develop breast cancer and show enrichment in Northern Finland. Here, the population prevalence and risk estimations were refined for sixteen recurrent pathogenic/likely pathogenic DDR gene variants.

Methods: Variant genotyping was performed in 2343 unselected Northern Finnish breast cancer cases and 4607 cancer-free controls, and tumor features and family history of cancer for the carriers were examined.

Results: Based on their prevalence and carrier family history, the studied BRCA1 and BRCA2 variants, PALB2 c.1592delT, and ATM c.7570G > C were confirmed as high-risk alleles, whereas CHEK2 c.1100delC, MCPH1 c.909_921del, and RAD50 c.687delT were moderate-risk alleles. FANCM c.5101C > T and c.5791C > T did not associate with overall breast cancer risk. Double carriers were significantly more common in cases (0.5%, 11/2343) than controls (0.07%, 3/4601, OR 7.2). The BRCA1/2 and PALB2 c.1592delT carrier tumors all had high proliferation rates, PALB2 c.1592delT associating also with grade 3 tumors (p = 0.002). Progesterone receptor (p < 0.05) and estrogen receptor positive tumors were enriched in ATM c.7570G > C and CHEK2 c.1100delC carriers, whereas MCPH1 c.904_916del carriers had a significantly high percentage of multifocal tumors (38%, p = 0.001). Moreover, one FANCM c.5101C > T homozygote case suffered severe side effects from chemotherapy.

Conclusion: The studied DDR gene variants were present in 9% of the unselected cases. As the presence of germline pathogenic variants can provide additional value for surgical decision-making and affect the choice of oncological treatments, the results promote the benefits of genetic testing as a part of breast cancer diagnostics.