Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

Reduced expression of BRCA1 has been reported in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. Abnormal methylation leading to silencing of tumour suppressor genes has been implicated in tumorigenesis in a wide range of sporadic cancers. Therefore, we sought to determine the frequency of methylation within the BRCA1 promoter region in a large group of sporadic invasive breast (n=96) and ovarian (n=43) carcinomas using Southern analyses. Overall, methylation was detected in 11% of breast cancer cases and in 5% of ovarian tumours. Methylation of the BRCA1 promoter region was strongly correlated with lack of estrogen and progesterone receptor expression. It is clear from the frequency of abnormal methylation of the BRCA1 promoter region, that this cannot be the sole mechanism mediating the reduced expression of BRCA1 that has previously been reported to occur in the majority of invasive sporadic breast tumours. Nevertheless this study suggests that abnormal methylation of the BRCA1 promoter may be important in tumorigenesis in a subset of sporadic breast and ovarian cancers.

Background: The Immunoscore (IS), which prognostically classifies stage IeIII colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients. Patients and methods: Densities of CD3þ and CD8þ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance. Results: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int þ High [hazard ratio (HR) ¼ 1.54; 95% confidence interval (CI) 1.24e1.93, P ¼ 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23e70.94) for IS Low and 77.14% (95% CI 73.50e80.35) for IS Int þ High. In multivariable analysis, IS remained significantly independently associated with DFS (P ¼ 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P ¼ 0.057). IS Int þ High significantly predicted benefit of 6 months of treatment (HR ¼ 0.53; 95% CI 0.37e0.75; P ¼ 0.0004), including clinically low-and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6. Conclusions: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatinbased chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int þ High. These results will be validated in an external independent cohort.

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Background and Purpose-Lacunar infarcts are usually regarded as benign stroke, but population-based studies are required to assess the exact place of this stroke subtype in cerebrovascular pathology. Methods-We evaluated trends in incidence rates, risk factor profiles, and survival rates in symptomatic lacunar stroke from a prospective population-based registry from 1989 to 2006. Results-We recorded 2536 ischemic strokes. Among these, 715 (28%) were lacunar infarcts (354 men and 361 women).From 1989 to 2006, we observed a significant rise in the incidence of lacunar stroke in the 2 sexes considered together (relative risk, 1.02; 95% CI, 1.005 to 1.035; Pϭ0.007), whereas the variation was not significant in either men or women when considered separately. Incidence rates significantly increased in young patients under 65 years old (relative risk, 1.049; 95% CI, 1.0175 to 1.0817; Pϭ0.002). Concerning the distribution of cerebrovascular risk factors, lacunar stroke differed from nonlacunar stroke only with regard to the lower prevalence of a history of atrial fibrillation in the former (PϽ0.001). For lacunar infarcts, survival rates were 96% at 1 month (95% CI, 0.94 to 0.97), 86% at 1 year (95% CI, 0.83 to 0.89), and 78% at 2 years (95% CI, 0.75 to 0.81) and were significantly higher than those for nonlacunar stroke (hazard ratio, 2.05; 95% CI, 1.70 to 2.47; PϽ0.001). Conclusion-Our results suggest a significant increase in the incidence rates of lacunar stroke with a relatively good short-term prognosis in terms of survival. The association among hypertension, diabetes mellitus, and lacunar stroke was no stronger than the association between these 2 risk factors and nonlacunar stroke.