Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.

Development of a prognostic signature for esophageal cancer based on a novel 7-DNA damage repair genes signature

Esophageal cancer(EC)was an aggressive malignant neoplasm characterized by high morbidity and poor prognosis.Identifying the changes in DNA damage repair genes helps to better understand the mechanisms of carcinoma progression.In this study,by comparing EC samples and normal samples,we found a total of 132 DDR expression with a significant difference.Moreover,we revealed higher expression of POLN,PALB2,ATM,PER1,TOP3B and lower expression of HMGB1,UBE2B were correlated to longer OS in EC.In addition,a prognostic risk score based on 7 DDR gene expression(POLN,HMGB1,TOP3B,PER1,UBE2B,ATM,PALB2)was constructed for the prognosis of EC.Meanwhile,EC cancer samples were divided into 3 subtypes based on 132 DDR genes expressions.Clinical profile analysis showed cluster C1 and C2 showed a similar frequency of T2,which was remarked higher than that in cluster 3.Moreover,we found the immune cell inflation levels were significantly changed in different subtypes of EC.The infiltration levels of T cell CD8+,B cell and NK cells were greatly higher in cluster 2 than that in cluster 1 and cluster 3.The results showed T cell CD4+infiltration levels were dramatically higher in cluster 1 than that in cluster 2 and cluster 3.Finally,we perform bioinformatics analysis of DEGs among 3 subtypes of EC and found DDR genes may be related to multiple signaling,such as Base excision repair,Cell cycle,Hedgehog signaling pathway,and Glycolysis/Gluconeogenesis.These results showed DDR genes may serve as new target for the prognosis of EC and prediction of the potential response of immune therapy in EC.

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families

Objective:Approximately 5%–10%of breast cancer(BC)patients display familial traits that are genetically inherited among the members of a family.The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families.Methods:Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.Results:Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8%(96/116)of the cases.Among these,80.8%of the mutated genes were related to DNA damage repair.Fourteen possible disease-causing variants were identified in 13 of 27 BC families.Only 25.9%(7/27)of the BC families exhibited hereditary deficiency in BRCA1/2 genes,while 22.2%of the BC families exhibited defects in non-BRCA genes.In all,41.7%(40/96)of the mutation carriers had BRCA mutations,88.5%(85/96)had non-BRCA mutations,and 30.2%(29/96)had both BRCA and non-BRCA mutations.The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations(P<0.05).However,the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations(P<0.05).Conclusions:In addition to BRCA1/2,genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC.Therefore,profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.