Rare genetic variants in DNA repair genes in BRCA1 mutation carriers with early and late age at onset of breast cancer

Breast cancer is one of the major causes of cancer death among women with almost 31% heritability. Women carrying a mutation in BRCA1 have 57-65% risk of developing breast cancer by age 70. The lifetime risk varies between families and even within affected individuals of the same family. To find the cause for this variability in age at onset (AAO), we investigated the role of rare variants in different DNA-repair pathways in BRCA1 mutation carriers. DNAs were obtained from 139 carriers of BRCA1 mutation and either AAO below 35 (Early AAO cohort) or AAO above 60 (Late AAO cohort). Germline mutations in 311 DNA-repair genes were investigated by Next generation sequencing, using a customized sequencing panel. Forty-two truncating variants were found in 36 DNA-repair genes from different pathways. 25 patients in early AAO cohort (34.2 %; 95 %-CI 23.5 % - 46.3 %) carried at least one truncating variant compared to 18 women of the late AAO cohort (27.3 %; 95%-CI 17.0 % to 39.6 %). Germline DNA repair mutations load did not differ between the two cohorts (odds ratio: 1.4; 95 %-CI 0.7 to 2.9; p-value = 0.46). Additional truncating variants in DNA-repair genes did not explain the differences in AAO in this study. Further studies and larger cohorts are needed to further clarify the role of DNA-repair gene mutations on the age at onset among BRCA mutation carriers.

Keywords:

Hereditary Breast cancer , DNA-repair , Age at onset , Next Generation Sequencing , BRCA1 , extreme phenotypes