Exome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles

Abstract

Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.

Author Summary

Currently, we know that a woman who inherits a fault in one of two genes, BRCA1 or BRCA2, has a high risk of developing both breast and ovarian cancer. However, such faults account for only half of all families with a strong family history of breast cancer. In this study, we planned to identify new genes that may be associated with an increased risk of developing breast cancer by looking for faults in every gene in the blood DNA of multiple women with breast cancer from large families with a strong family history of the condition over multiple generations. We can then track which gene fault is present in all the women with breast cancer in that family and in other families, but is not found in the women who did not develop breast cancer or have no family history. Using this approach, we identified faults in two genes, Fanconi C and Bloom helicase, in six families. Faults in these genes appear to increase the risk of developing breast cancer. Both these genes work in a similar way as BRCA1 and BRCA2, and this highlights the importance of these functions in preventing breast cancer. Further studies need to be done to confirm our results.