To the Editor: We read the article by Antoniou et al. (August 7 issue)¹ because we like to know the penetrance of breast-cancer genes before we recommend surgery. After reading the article, we are unsure of what to tell patients. The simplest message would be that the risk up to 70 years of age is 35%, but this is based on an analysis of patients who received a diagnosis of breast cancer from 1930 to the present. The relevant risk value is that for a woman without breast cancer who is found to have a PALB2 mutation today. Most patients . . .

Women who have inherited mutations in BRCA1 (17q21, chromosome 17: base pairs 43,044,294 to 43,125,482) or BRCA2 (13q12.3, chromosome 13: base pairs 32,315,479 to 32,399,671) have an increased risk of breast and ovarian cancers.^1,2 Little is known about how cancer risks differ by BRCA1 or BRCA2 (BRCA1/2) mutation type. An “ovarian cancer cluster region” (OCCR) has been reported in both BRCA1 and BRCA2 using small sample sets. For BRCA1, initially mutations after exon 11 were associated with a 20% lower ovarian cancer risk than mutations in exons 1 through 11.³ Following that observation, Thompson et al⁴ reported an increased risk of ovarian vs breast cancer specifically was associated with mutations in the central portion of exon 11. This association was attributed to both a decrease in breast cancer risk and an increase in ovarian cancer risk in this region. Mutations in exon 11 of BRCA2 also have been associated with higher ovarian vs breast cancer risk than in other regions of the gene.⁵ It was hypothesized that this risk variation might be explained by the failure of BRCA1/2 exon 11 truncating mutations to trigger nonsense-mediated messenger RNA (mRNA) decay (NMD) because of their extremely large size, contrary to truncating mutations in smaller exons. However, this postulate was not supported by the measures of the relative amounts of mRNA transcript encoded by BRCA1/2 alleles.^6,7 Murine models of different mutations in BRCA1/2 also suggest that genotype-phenotype correlations exist.^8,9 Quiz Ref ID To our knowledge, no study has reported whether BRCA1/2 mutation type is associated with differences in breast and ovarian cancer risk. Thus, we evaluated whether BRCA1 and BRCA2 mutation type or location is associated with variation in breast and ovarian cancer risk.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1. To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population. Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.