Signatures of mutational processes in human cancer.

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy

Within Colour Dollops and Gender Statments : Invsetigating How Art Teachers Work with Gender in Classrooms

Syftet med denna studie är att undersöka hur lärare arbetar med genus i och under arbetet påbildlektioner. Likaså undersöks hur lärare bemöter elever och hur de hanterar genus i samband med bildundervisningen. För att svara på dessa frågor intervjuades gymnasiebildlärare om möj-ligheter och utmaningar kopplade till genus i undervisningen, och hur påverkas undervisningen av lärarens egen inställning och förståelse av genusfrågor deras förståelse av genus. Hur de an-vänder genus i inkluderingssyfte i klassrummet och hur grundskolans arbete med sexualitet, samtycke och relationer har påverkat deras arbete.Metoden för insamling av material är en semistrukturerad intervju av gymnasielärare. Resultatetav intervjuerna har sedan analyserats med en fenomenografisk utgångspunkt för att sedan tolkasefter feministisk teori.Genusfrågor förekommer aktivt bland respondenternas elever och i deras skolor. Det är en självklar del av bildundervisningen för respondenterna, även om inte alla har det som huvud-syfte i sina uppgifter. Eleverna uppges vara medvetna om genusfrågor och normbrytande identi-teter. Diskussionerna med eleverna är öppna, något som tillskrivs den positiva relationen lä-rarna har byggt med sina elever

The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer

PURPOSE: SMARCA4 mutations are among the most common recurrent alterations in NSCLC, but the relationship to other genomic abnormalities and clinical impact has not been established. EXPERIMENTAL DESIGN: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. RESULTS: In 4813 tumors from patients with NSCLC, we identified 8% (n= 407) patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: Class 1 mutations (truncating mutations, fusions and homozygous deletion) and Class 2 mutations (missense mutations). Protein expression loss was associated with Class 1 mutation (81% vs 0%, (P \u3c 0.001)). Both classes of mutation co-occured more frequently with KRAS, STK11, and KEAP1 mutations compared to SMARCA4 wildtype tumors (P \u3c 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with Class 1 alterations associated with shortest survival times (P \u3c 0.001). Conversely, we found that treatment with immune checkpoint inhibitors was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with Class 1 mutations having the best response to ICIs (p = 0.027). CONCLUSIONS: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy

The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer

Purpose: SMARCA4 mutations are among the most common recurrent alterations in non-small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. Experimental Design: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. Results: In 4,813 tumors from patients with NSCLC, we identified 8% (n ¼ 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P ¼ 0.01), with class 1 mutations having the best response to ICIs (P ¼ 0.027). Conclusions: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy