Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

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.

Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Chronic inflammation plays an important role in tumor progression. The aim of this analysis was to evaluate whether inflammatory biomarkers such as the Glasgow prognostic score (GPS), the neutrophil‐lymphocyte ratio (NLR), the platelet‐lymphocyte ratio (PLR), and the lymphocyte‐monocyte ratio (LMR) could predict the prognosis of nasopharyngeal carcinoma (NPC). In this analysis, pretreatment GPS, NLR, PLR, LMR of 388 patients who were diagnosed as nonmetastatic NPC and recruited prospectively in the 863 Program No. 2006AA02Z4B4 were assessed. Of those, the 249 cases enrolled between December 27th 2006 and July 31st 2011 were defined as the development set. The rest 139 cases enrolled between August 1st 2011 and July 31st 2013 were defined as the validation set. The variables above were analyzed in the development set, together with age, gender, Karnofsky performance score, T stage, and N stage, with respect to their impact on the disease‐specific survival (DSS) through a univariate analysis. The candidate prognostic factors then underwent a multivariate analysis. A nomogram was established to predict the DSS, by involving the independent prognostic factors. Its predction capacity was evaluated through calculating Harrell's concordance index (C‐index) in the validation set. After multivariate analysis for the development set, age (≤50 vs. >50 years old), T stage (T1–2 vs. T3–4), N stage (N0–1 vs. N2–3) and pretreatment GPS (0 vs. 1–2), NLR (≤2.5 vs. >2.5), LMR (≤2.35 vs. >2.35) were independent prognostic factors of DSS (P values were 0.002, 0.008, <0.001, 0.004, 0.018, and 0.004, respectively). A nomogram was established by involving all the factors above. Its C‐index for predicting the DSS of the validation set was 0.734 (standard error 0.056). Pretreatment GPS, NLR, and LMR were independent prognostic factors of NPC. The nomogram based on them could be used to predict the DSS of NPC patients.

Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10−22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10−12) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.