Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer

Abstract

Background: Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family.

Methods: In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer.

Results: We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation.

Conclusions: Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions.

Figure 1

Pedigrees of the three families used in the study. BC (breast cancer), Bt (brain tumor), CRC (colorectal cancer), Lu (lung cancer), En (endometrium cancer), Ki (kidney cancer), Lym (lymphoma), NHL (non-Hodgkin lymphoma), OC (ovarian cancer), Pro (prostate cancer). Sar (sarcoma), Sk (skin cancer).

Figure 2

Comparison of the variants in BRCAx families and probands. A. Comparison in the three families. B. Comparison in the probands. The results show that the variants detected in the cancer-affected family members are highly family-specific. The higher rate (18%) of the shared variants in the probands are likely due to the remaining normal variants not filtered in the probands and the larger number of families represented by the probands than the three families.

Figure 3

A model for the genetic predispositions in familial breast cancer. The known predisposition in BRCA1 has the highest sharing frequency in the disease population, other known predispositions decrease their frequencies towards extreme rarity in the disease populations, and the family-specific predispositions are enriched in many disease families without known predispositions. The biggest circle represents the entire genetic predispositions in familial breast cancer. The open circles represent the shared, known predispositions, and the black circles represent the family-specific predispositions.