Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ.

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.

Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition.

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. ©2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Self administered screening for hereditary cancers in conjunction with mammography and ultrasound.

We evaluated the feasibility of an automated tablet computer application providing a family and personal history based cancer risk assessment for hereditary breast, ovarian, endometrial and colorectal cancers. 1,002 women presenting for screening mammography and 1,000 presenting for ultrasound were offered screening. The application calculated the risk of BRCA mutations using BRCAPRO, Myriad and Tyrer-Cuzick risk assessment models. Lifetime risk of breast and ovarian cancer was assessed with the BRCAPRO, Claus and Tyrer-Cuzick models. Colorectal and endometrial cancer risk was calculated via the MMRpro model. Patients were identified as high-risk based on thresholds 10% or greater risk for carrying genetic mutations or 20% or greater lifetime risk of breast or ovarian cancer. The percent of women found to be high-risk by a single risk assessment tool ranged from 0.5 to 5.3%. Combining assessment tools found 9.3% of women to be high-risk. The risk assessments performed similarly for the mammography and ultrasound cohorts with yields (combining assessment tools) of 9.2 and 9.4% respectively. The average ages of all the high-risk women were 45.8 and 39.6 years for the mammography and ultrasound cohorts respectively. Difficulties encountered included a need for software upgrade, wireless network unreliability and hardware theft. Automated family history screening can identify women probably at high-risk for hereditary cancers efficiently. The number of women identified is increased by employing multiple risk assessment models simultaneously. Surveying women in conjunction with ultrasound identified women at increased risk as effectively and at a younger age than with screening mammography.