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The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.

The prevalence of germ line mutations in non‐ BRCA 1/2 genes associated with hereditary breast cancer ( BC ) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA 1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes ( ATM , CDH 1 , CHEK 2 , NBN , PALB 2 , RAD 51C , RAD 51D, and TP 53 ). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK 2 gene (2.5%), followed by ATM (1.5%) and PALB 2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM ( OR : 3.63, 95% CI : 2.67–4.94), CDH 1 ( OR : 17.04, 95% CI : 3.54–82), CHEK 2 ( OR : 2.93, 95% CI : 2.29–3.75), PALB 2 ( OR : 9.53, 95% CI : 6.25–14.51), and TP 53 ( OR : 7.30, 95% CI : 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk ( OR :1.39, 95% CI : 0.73–2.64). Due to their low mutation prevalence, the RAD 51C and RAD 51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK 2 and TP 53 in BC index patients. Compared with the overall sample, only TP 53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK 2 , PALB 2, and TP 53 genes with bilateral BC . Both, ATM and CHEK 2 , were negatively associated with triple‐negative breast cancer ( TNBC ) and estrogen receptor ( ER )‐negative tumor phenotypes. A particularly high CHEK 2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 ( HER 2)‐positive tumors.

Objective: To test the hypothesis that smooth muscle cells of the human umbilical vein have vasoconstricting endothelin B (ETB) receptors. Methods: In strip preparations of human umbilical veins isometric tension after exposure to the selective ETB receptor agonist sarafotoxin S6c (S6c) was compared to the tension before S6c exposure (set as 100%). Results: In intact preparations S6c induced vasoconstriction only at the highest concentration applied (10 –8 M; 149.5 ± 12.5 vs. 100%, p < 0.05). In contrast, in endothelium-denuded preparations S6c induced vasoconstriction already at the lowest S6c concentration investigated (10 –11 M; 111.7 ± 4.3 vs. 100%, p < 0.05). Conclusions: The vasoconstricting effect of S6c in endothelium-denuded human umbilical vein preparations points to smooth muscle cell ETB receptor activation.