Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

Abstract

Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PD-L1) expression.A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma.A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC.Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.

BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA‐like breast cancers treated with neoadjuvant chemotherapy

“…Forty-one genes, including two principal DDR genes (BRCA1 and BRCA2), 37 additional DDR genes (FANCD2, BAP1, ATR, RAD17, XRCC4, RAD50, RAP80, FANCE, MLL3/XRCC2/PTIP, WRN, NBS1, PTEN, FANCF, MRE11A, ATM, CHEK1, FANCM, RAD51B, XRCC3, RAD51, TP53BP1, MRG15/BLM, ERCC4, PALB2, PAGR1, FANCA, RAD51D, CDK12, RAD51C, BRIP1, MLL4, ERCC1/2, and CHEK2), two oncogenes (MYC and CCNE1), and one checkpoint and apoptosis gene (TP53) were selected to analyze genomic aberrations (gains, amplifications, losses, and UPDs) because previous studies reported the involvement of these genes in the DDR pathway or genomic instabilities. 1,3,8,9,[19][20][21][22][23][24][25][26] The numbers of the four chromosome aberrations (gains, losses, amplifications, and UPDs) were examined in each tumor. Gains and amplifications in two oncogenes (MYC and CCNE1) were individually analyzed; however, they were combined and referred to as amplifications in subsequent sections.…”

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

“…41 It is possible that RAD51B deficiency increases the mutational burden of tumors through HRD, potentially making these patients good candidates for immunotherapy due to their increased likelihood of harboring neoantigens. 53 Taken together, these findings suggest that genetic ancestry may play an important role in mutational development and cancer progression. This highlights the need to accumulate more genetic data from diverse populations in order to better understand the heightened aggressive breast cancer risk observed in individuals of African ancestry.…”

“…It has been shown that loss‐of‐function mutations in homologous recombination genes other than BRCA1/2 can facilitate HRD signature activity . It is possible that RAD51B deficiency increases the mutational burden of tumors through HRD, potentially making these patients good candidates for immunotherapy due to their increased likelihood of harboring neoantigens . Taken together, these findings suggest that genetic ancestry may play an important role in mutational development and cancer progression.…”

RAD51Bme Levels as a Potential Predictive Biomarker for PD-1 Blockade Response in Non-Small Cell Lung Cancer

“…Homologous recombination repair (HRR) is the leading DNA repair mechanism of double-strand DNA breaks (DSB) that uses the homologous region of the sister chromatid as the replicative template in order to reliably repair DSB [16]. RAD51 protein has an important activity in HRR, promoting the insertion of the broken ends of the DSB into the sister chromatid [17,18]. Its action is dependent on RAD51-like proteins: RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 [17][18][19].…”

“…RAD51 protein has an important activity in HRR, promoting the insertion of the broken ends of the DSB into the sister chromatid [17,18]. Its action is dependent on RAD51-like proteins: RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 [17][18][19]. Defects in the HRR pathway entail cell proliferation despite DNA damage, promoting cancer development [20].…”