Association between DNA damage repair gene somatic mutations and immune‐related gene expression in ovarian cancer

Abstract

Background Defects in DNA damage repair (DDR) system may lead to genomic instability and manifest as increased immunogenicity. DDR deficiency is prevalent in ovarian cancer (OvCa); however, the association of DDR mutation with immune profiles in OvCa remains largely unknown. This knowledge will provide an essential basis to the rational design of biomarker‐guided immune combination therapy of OvCa in the future. Methods Whole‐exome sequencing data of 587 OvCa from The Cancer Genome Atlas (TCGA) were used to determine the expression profiles of 47 immune‐related genes and the abundance of tumor‐infiltrating immune cells. A Chinese OvCa cohort (n = 220) tested by next‐generation sequencing (NGS) was used to validate the association between DDR status and tumor mutation burden (TMB). Results A total of 19.3% in TCGA cohort and 25.9% in Chinese cohort harbored at least one DDR somatic mutation. DDR deficiency exhibited a distinct immune profile with significant higher expression levels of PTPRCAP, CCL5, IFI16, LAG3, IL15RA, and GBP1 in OvCa in the TCGA cohort. Different DDR pathway deficiency displayed various immune profiles. Increased levels of Th1 cells, TMB, and neoantigen were also observed in DDR‐deficient tumors. Conclusions DDR deficiency was associated with specific immune signatures in OvCa. Our findings emphasize the urgent need for biomarker‐guided rational immune combination therapy to maximize the OvCa patients who could benefit from immunotherapy.

Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers

“…Finally, we observed considerable differences in the deregulation of transcriptome for the same mutation when comparing breast and ovarian cancers. Consistent with previous reports BRCA mutations in breast cancer were mostly associated with regulation of cell cycle, DNA damage, and cell proliferation in breast cancer [71], and with immune system-related processes in ovarian cancer [61], which may be an indicator of differential role of BRCA1 and BRCA2 in the pathogenesis of these diseases. Previous studies have already suggested mechanisms of how DNA damage may trigger immune response [72,73]; however, the question of why its intensity is higher in ovarian rather than in breast cancer remains open.…”

Cytokine-Induced Guanylate Binding Protein 1 (GBP1) Release from Human Ovarian Cancer Cells

“…It is tempting to speculate that the correlation of high GBP1 mRNA expression and better survival, could reflect an underlying anti-tumor T cell response. Indeed, a very recent study reported an association between somatic mutations of DNA damage repair genes and a specific immune signature, which included the GBP1 gene in EOC [43]. It is well established that defects in the DNA repair system are associated with increased mutational load and generation of tumor-associated neo-antigens, which enhance tumor immunogenicity and the potential responsiveness to immunotherapy [44].…”

A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer

“…In melanoma, gene up-regulation in DDR pathways is associated with tumor metastasis (40). DDR gene mutations were linked to immune-related gene expression in ovarian cancer and muscle invasive bladder cancer (41,42). DDR was also reported to be involved in cancer metabolism.…”