Purpose Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear. Patients and Methods We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer–associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared. Results Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 × 10−16). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 × 10−6). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio [OR]= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk. Conclusion Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored.
PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo
