A 15-DNA Repair Gene Prognostic Signature for Immunotherapy in Gastric Cancer

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responds to immunotherapy. The relationships between tumor DNA damage response, the immune system and immunotherapy have recently attracted attention. Accumulating evidence indicate that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsible to immunotherapy, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of gastric adenocarcinoma. The results showed that DRGS high score patients showed significantly better therapeutic outcomes compared to DRGS low score patients (P < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival and may benefit more from ICB therapy, as compared to the low-score patients. Therefore, the DRGS and its scoring system may have implications in tailoring immunotherapy in gastric cancers.

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Association of DNA repair gene XRCC1 and XPD polymorphisms with genetic susceptibility to gastric cancer in a Chinese population

Cancer Epidemiology ◽

10.1016/j.canep.2010.08.008 ◽

2011 ◽

Vol 35 (2) ◽

pp. 170-174 ◽

Cited By ~ 23

Author(s):

Tao Yuan ◽

Shaoli Deng ◽

Ming Chen ◽

Wei Chen ◽

Weiping Lu ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Repair ◽

Genetic Susceptibility ◽

Chinese Population ◽

Repair Gene ◽

Dna Repair Gene

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Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.5035 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 5035-5035 ◽

Cited By ~ 14

Author(s):

Karim Boudadi ◽

Daniel L. Suzman ◽

Brandon Luber ◽

Hao Wang ◽

John Silberstein ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Response Rate ◽

Objective Response ◽

Gene Mutations ◽

Immune Checkpoint Blockade ◽

Phase 2 ◽

Repair Gene ◽

Dna Repair Gene ◽

Castrate Resistant

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

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The DNA Repair Gene ERCC6 rs1917799 Polymorphism is Associated with Gastric Cancer Risk in Chinese

Asian Pacific Journal of Cancer Prevention ◽

10.7314/apjcp.2013.14.10.6103 ◽

2013 ◽

Vol 14 (10) ◽

pp. 6103-6108 ◽

Cited By ~ 10

Author(s):

Jing-Wei Liu ◽

Cai-Yun He ◽

Li-Ping Sun ◽

Qian Xu ◽

Cheng-Zhong Xing ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Repair ◽

Cancer Risk ◽

Gastric Cancer Risk ◽

Repair Gene ◽

Dna Repair Gene

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Detection and clinical significance of DNA repair gene ERCC8 tag SNPs in gastric cancer

The Turkish Journal of Gastroenterology ◽

10.5152/tjg.2018.17662 ◽

2018 ◽

Vol 29 (4) ◽

pp. 392-396 ◽

Cited By ~ 1

Author(s):

Xingre Lu ◽

◽

Fengyu Chen ◽

Xiaowen Liu ◽

Diao Yuan ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Repair ◽

Clinical Significance ◽

Repair Gene ◽

Tag Snps ◽

Dna Repair Gene

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Development and validation of a DNA repair gene signature for prognosis prediction in Colon Cancer

Journal of Cancer ◽

10.7150/jca.46328 ◽

2020 ◽

Vol 11 (20) ◽

pp. 5918-5928

Author(s):

Xin Wang ◽

Cong Tan ◽

Min Ye ◽

Xu Wang ◽

Weiwei Weng ◽

...

Keyword(s):

Colon Cancer ◽

Dna Repair ◽

Gene Signature ◽

Repair Gene ◽

Prognosis Prediction ◽

Dna Repair Gene ◽

Development And Validation

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Prognostic value of DNA repair gene based on stratification of gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.12 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 12-12

Author(s):

Jinjia Chang ◽

Midie Xu ◽

Hui Sun ◽

Wenhua Li ◽

Min Ye ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Repair ◽

Clustering Analysis ◽

Molecular Subtypes ◽

Expression Profiles ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Key Genes ◽

Repair Genes

12 Background: DNA repair genes can be used as prognostic biomarkers in many types of cancer. We aimed to identify prognostic DNA repair genes in patients with gastric cancer (GC) by systematically bioinformatic approaches using web-based database. Methods: Global gene expression profiles from altogether 1,325 GC patients’ samples from six independent datasets were included in the study. Clustering analysis was performed to screen potentially abnormal DNA repair genes related to the prognosis of GC, followed by unsupervised clustering analysis to identify molecular subtypes of GC. Characteristics and prognosis differences were analyzed among these molecular subtypes, and modular key genes in molecular subtypes were identified based on changes in expression correlation. Multivariate Cox proportional hazard analysis was used to find the independent prognostic gene. Kaplan-Meier method and log-rank test was used to estimate correlations of key DNA repair genes with GC patients’overall survival. Results: There were 57 key genes significantly associated to GC patients’ prognosis, and patients were stratified into three molecular clusters based on their expression profiles, in which patients in Cluster 3 showed the best survival (P < 0.05). After a three-phase training, test and validation process, the expression profile of 13 independent key DNA repair genes were identified can classify the prognostic risk of patients. Compared with patients with low-risk score, patients with high risk score in the training set had shorter overall survival (P < 0.0001). Furthermore, we verified equivalent findings by these key DNA repair genes in the test set (P < 0.0001) and the independent validation set (P = 0.0024). Conclusions: Our results suggest a great potential for the use of DNA repair gene profiling as a powerful marker in prognostication and inform treatment decisions for GC patients.

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