PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. Significance: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs. Cancer Discov; 2(11); 1036–47. ©2012 AACR. Read the Commentary on this article by Rehman et al., p. 982. This article is highlighted in the In This Issue feature, p. 961

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.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10⁻⁸, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10⁻⁸, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10⁻⁸, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10⁻⁴). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.

Georgia Chenevix-Trench and colleagues report meta-analyses of genome-wide association studies identifying six loci newly associated with epithelial ovarian cancer (EOC). They also test variants at the 12 known and 6 new EOC susceptibility loci for association in BRCA1 and BRCA2 mutation carriers. Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10−8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Familial susceptibility to breast cancer accounts for <25% of all breast cancer cases. BRCA1 and BRCA2 are high-penetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutations in BRCA1/2 explain ∼20% of the familial clustering of breast cancer. Germline mutations in the other high-risk genes TP53, PTEN and STK11 are identified in 70% of the familial breast cancer cases still remains unexplained.