BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.

Background and Purpose-Chronic infectious diseases may increase the risk of stroke. We investigated whether periodontal disease, including periodontitis and gingivitis, is a risk factor for cerebral ischemia. Methods-We performed a case-control study with 303 patients examined within 7 days after acute ischemic stroke or transient ischemic attack, 300 population controls, and 168 hospital controls with nonvascular and noninflammatory neurological diseases. All subjects received a complete clinical and radiographic dental examination. The individual mean clinical attachment loss measured at 4 sites per tooth served as the main indicator for periodontitis. Results-Patients had higher clinical attachment loss than population (PϽ0.001) and hospital (Pϭ0.010) controls. After adjustment for age, sex, number of teeth, vascular risk factors and diseases, childhood and adult socioeconomic conditions, and lifestyle factors, the risk of cerebral ischemia increased with more severe periodontitis. Subjects with severe periodontitis (mean clinical attachment loss Ͼ6 mm) had a 4.3-times-higher (95% confidence interval, 1.85 to 10.2) risk of cerebral ischemia than subjects with mild or without periodontitis (Յ3 mm). Severe periodontitis was a risk factor in men but not women and in younger (Ͻ60 years) but not older subjects. Periodontitis increased the risk of cerebral ischemia caused by large-artery atherosclerosis, cardioembolism, and cryptogenic etiology. Gingivitis and severe radiologic bone loss were also independently associated with the risk of cerebral ischemia, whereas caries was not. Conclusions-Our study indicates that periodontal disease, a treatable condition, is an independent risk factor for cerebral ischemia in men and younger subjects.

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The authors examined cancer mortality in a historical cohort study of 21,863 male and female workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols, and dioxins in 12 countries. Subjects in this updated and expanded multinational study coordinated by the International Agency for Research on Cancer were followed from 1939 to 1992. Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins, mortality from soft-tissue sarcoma (6 deaths; standardized mortality ratio (SMR) = 2.03, 95% confidence interval (CI) 0.75-4.43) was higher than expected from national mortality rates. Mortality from all malignant neoplasms (710 deaths; SMR = 1.12, 95% CI 1.04-1.21), non-Hodgkin's lymphoma (24 deaths; SMR = 1.39, 95% CI 0.89-2.06), and lung cancer (225 deaths; SMR = 1.12, 95% CI 0.98-1.28) was slightly elevated. Risks for all neoplasms, for sarcomas, and for lymphomas increased with time since first exposure. In workers exposed to phenoxy herbicides with minimal or no contamination by TCDD and higher chlorinated dioxins, mortality from all neoplasms (398 deaths; SMR = 0.96, 95% CI 0.87-1.06), non-Hodgkin's lymphoma (9 deaths; SMR = 1.00), and lung cancer (148 deaths; SMR = 1.03) was similar to that expected, and mortality from soft-tissue sarcoma was slightly elevated (2 deaths; SMR = 1.35). In a Poisson regression analysis, workers exposed to TCDD or higher chlorinated dioxins had an increased risk for all neoplasms (rate ratio = 1.29, 95% CI 0.94-1.76) compared with workers from the same cohort exposed to phenoxy herbicides and chlorophenols but with minimal or no exposure to TCDD and higher chlorinated dioxins. These findings indicate that exposure to herbicides contaminated with TCDD and higher chlorinated dioxins may be associated with a small increase in overall cancer risk and in risk for specific cancers.