Peer Review #3 of "A signature of tumor DNA repair genes associated with the prognosis of surgically-resected lung adenocarcinoma (v0.1)"

Abstract Reactive Oxygen Species (ROS) are present in high amount in patients with tumors, and these ROS can kill and destroy tumor cells. Thus, tumor cells upregulate ROS-related genes to protect themselves and reduce their destruction. Cancer cells already damaged by ROS can be repaired by expressing DNA repair genes consequently promoting their proliferation. In this work, lung adenocarcinoma (LUAD) transcriptome data in the TCGA database was analyzed and samples were clustered into 5 ROS-related categories and 6 DNA repair categories. Survival analysis revealed a significant difference in patient survival between the two classification methods. In addition, the samples corresponding to the two categories overlap, thus, the gene expression profile of the same sample with different categories and survival prognosis was further explored, and the connection between ROS-related genes and DNA repair genes was investigated. The interactive sample recombination classification was used, revealing that the patient's prognosis was worse when the ROS-related genes and DNA repair genes were expressed at the same time. The further research on the potential regulatory network of the two categories of genes and the correlation analysis revealed that ROS-related genes and DNA repair genes have a mutual regulatory relationship. The ROS-related genes NQO1, TXNRD1, and PRDX4 could establish links with other DNA repair genes through the DNA repair gene NEIL3, thereby increasing the growth of tumor cells and balancing the level of ROS, leading to tumor cell death and constant damage to the tumor cell repair system, thus prolonging patient survival. Thus, targeting ROS-related genes and DNA repair genes might be a promising strategy in the treatment of LUAD. Finally, a survival prognostic model of ROS-related genes and DNA repair genes was established (TERT, PRKDC, PTTG1, SMUG1, TXNRD1, CAT, H2AFX and PFKP), the risk score might be used as an independent prognostic factor in LUAD patients.

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DNA repair genes are associated with tumor tissue differentiation and immune environment in lung adenocarcinoma: a bioinformatics analysis based on big data

Journal of Thoracic Disease ◽

10.21037/jtd-21-949 ◽

2021 ◽

Vol 13 (7) ◽

pp. 4464-4475

Author(s):

Jiayin Li ◽

Jingxu Zhou ◽

Jing Zhang ◽

Zhiwei Xiao ◽

Wenping Wang ◽

...

Keyword(s):

Dna Repair ◽

Big Data ◽

Lung Adenocarcinoma ◽

Tumor Tissue ◽

Bioinformatics Analysis ◽

Tissue Differentiation ◽

Dna Repair Genes ◽

Repair Genes

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Germline DNA repair mutations in metastatic castration-resistant prostate cancer: Therapy response and applicability of circulating tumor DNA.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.140 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 140-140 ◽

Cited By ~ 2

Author(s):

Werner J. Struss ◽

Matti Annala ◽

Evan W Warner ◽

Kevin Beja ◽

Gillian Vandekerkhove ◽

...

Keyword(s):

Dna Repair ◽

Targeted Therapy ◽

Gene Loss ◽

Germline Mutations ◽

Circulating Tumor Dna ◽

Dna Repair Genes ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Repair Genes ◽

Tumor Dna

140 Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to Androgen Receptor (AR) targeted therapy. The aim of this study was to determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies, and secondly to establish whether biallelic DNA-repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Methods: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In affected patients, matched plasma ctDNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Results: 24/319 (7.5%) patients had deleterious germline mutations, with BRCA2 (n = 16), PALB2 (n = 2) and CDK12 (n = 2) being the most frequent. Patients (n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but after starting ADT progressed to mCRPC with a median time of 12.3 months (95% CI 5.1-18.4). The median time to progression on first and second line AR-targeted therapy in the mCRPC setting was 3.2 months (95% CI 1.9-4.4) and 1.0 month (95% CI 0.8-1.1), respectively. For patients receiving chemotherapy as their initial therapy for mCRPC (n = 8) the median PFS was 7.5 months (95% CI 6.5-8.2). 10/11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. Conclusions: mCRPC patients with germline DNA repair defects exhibit transient responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

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