scholarly journals Patient-Level DNA Damage Repair Pathway Profiles and Anti-Tumor Immunity for Gastric Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Shenghan Lou ◽  
Yufei Wang ◽  
Jian Zhang ◽  
Xin Yin ◽  
Yao Zhang ◽  
...  

DNA damage repair (DDR) comprises the detection and correction of alterations in the chemical structure of DNA. The dysfunction of the DDR process has been determined to have important implications for tumor carcinogenesis, malignancy progression, treatment resistance, and prognosis assessment. However, the role of the DDR process in gastric cancer (GC) remains to be fully understood. Thus, a total of 2,019 GC samples from our hospital (Harbin Medical University Cancer Hospital in china) and 12 public data sets were included in our study. In this study, single-sample gene set enrichment analysis (ssGSEA) was used to generate the DDR pathway activity profiles of 8 DDR sub-pathways and identify a DDR pathway signature by combining the DDR sub-pathway gene sets. The DDR pathway profiling’s impacts on the clinical outcomes, biological functions, genetic variants, immune heterogeneity, and treatment responses were analyzed through multidimensional genomics and clinical data. The results demonstrate that the DDR pathway profiling was clearly distinguished between tumor and normal tissues. The DDR pathway profiling reveals patient-level variations, which may contribute to explaining the high heterogeneity of human GC for the biological features and treatment outcomes. Thus, tumors with low DDR signature scores were independently correlated with shorter overall survival time and significantly associated with mesenchymal, invasion, and metastasis phenotypes. The statistical model integrating this DDR pathway signature with other clinical predictors outperforms each predictor alone for predicting overall survival in discrimination, calibration, and net clinical benefit. Moreover, low DDR signature scores were tightly associated with genome stability, characterized by low tumor mutational burden (TMB) and low fractions of genome alteration. Furthermore, this study confirms that patients with low DDR pathway signature scores might not benefit from adjuvant chemotherapy and a monoclonal antibody directed against programmed cell death-1 ligand 1 (anti-PD1) therapy. These findings highlighted that the DDR pathway profiling confers important implications for patients with GC and provides insights into the specific clinical and molecular features underlying the DDR process, which may help to facilitate clinical management.

2017 ◽  
Vol 140 (11) ◽  
pp. 2587-2595 ◽  
Author(s):  
Livia Ronchetti ◽  
Elisa Melucci ◽  
Francesca De Nicola ◽  
Frauke Goeman ◽  
Beatrice Casini ◽  
...  

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Wenjie Huang ◽  
Huijuan Tang ◽  
Fang Wen ◽  
Xiaona Lu ◽  
Qingpei Li ◽  
...  

APOPTOSIS ◽  
2012 ◽  
Vol 18 (3) ◽  
pp. 347-360 ◽  
Author(s):  
A. Gutiérrez-González ◽  
C. Belda-Iniesta ◽  
J. Bargiela-Iparraguirre ◽  
G. Dominguez ◽  
P. García Alfonso ◽  
...  

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4022-4022
Author(s):  
Kai Zimmer ◽  
Florian Kocher ◽  
Gerold Untergasser ◽  
Alberto Puccini ◽  
Joanne Xiu ◽  
...  

4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p < 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p < 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p < 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p < 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p < 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p < 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.


2021 ◽  
Author(s):  
Miaoqin Chen ◽  
Weikai Wang ◽  
Shiman Hu ◽  
Yifan Tong ◽  
Yiling Li ◽  
...  

Abstract BackgroundHepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify novel druggable candidate genes for patients with HCC.MethodsThe role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, nude mice assay, WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, Western blotting, comet assay, and Immunofluorescence.ResultsHigh expression of WIP1 is associated with poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation in vitro and in vivo via inducing DNA damage. WIP1 knockout retarded DEN (Diethylnitrosamine) induced mice hepato-carcinogenesis. In addition, suppression of WIP1 together with PARP inhibition induced synthetic lethality in HCC cells by disrupting DNA damage repair.ConclusionWIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair might be a novel strategy for HCC management.


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