Familial Breast Cancer Study (FBCS)

Breast cancer has a significant genetic component. The strongest epidemiologic risk factor is family history of the disease. Familial studies have identified a number of genes contributing to increased risk. Of these, the highly penetrant BRCA1 and BRCA2 genes account for the majority of families in whom disease-causal mutations have been identified. However, mutations in other genes have been associated with predisposition to breast or breast and ovarian cancer including (CHEK2, ATM, PALB2, RAD51C, RAD51D). Together these genes account for less than 20% of excess familial breast cancer risk and do not explain ~50% of high-risk families referred for genetic testing. This significant gap in our understanding of the genetic basis of breast cancer poses a significant barrier to our ability to identify women at increased risk, who would benefit greatly from appropriate clinical management. To identify additional breast cancer predisposition genes whole exome sequencing of familial high-risk breast cancer patients was undertaken. DNA samples from 50 pairs of breast cancer patients from high-risk breast cancer families with no pathogenic mutations in the BRCA1 or BRCA2 breast cancer predisposition genes were subjected to whole exome sequencing. The goal was to select candidate predisposition genes for further validation studies based on sharing of putative protein inactivating mutations among both members of each family and/or the frequency of inactivating mutations among the 50 families.]]>
Familial Breast Cancer Study (FBCS)Inclusion criteria for families: Family history of breast cancer with three or more women diagnosed with breast cancer under age 60 among first and second-degree relatives of probands. Clear evidence of Mendelian segregation of disease. Germline DNA samples available from at least two second-degree relatives affected with breast cancer under age 60. No BRCA1 or BRCA2 pathogenic mutation identified from complete screen of coding sequences and intron-exon junctions. Exclusion criteria: ≤3 women diagnosed under age 60 years among first and second-degree relatives of proband. Male breast case in family. BRCA1 or BRCA2 pathogenic mutation present in germline DNA from any family member. Inactivating mutation in any other known breast cancer predisposition gene. No first or second degree relative pairs affected with breast cancer with available DNA samples. ]]>