The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Abstract

Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single-nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510-0.899, p = 0.007; OR = 0.565, 95% CI: 0.368-0.869, p = 0.009; OR = 0.628, 95% CI: 0.439-0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities.

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“…Variations in toxicity and response to therapy and/ or in survival were seen in patients with lung [8][9][10][11], pancreatic [12], breast [13,14], laryngeal [15], cervical [16], and ovarian [17] cancer treated with CDDPbased schemes and/or RT, which were attributed to abnormalities in production or function of proteins encoded by single nucleotide polymorphisms (SNPs) in genes of MMR pathway. In fact, variant "A", "G", "A", and "A" alleles of MLH1 c.-93G>A (rs1800734) [18], MSH2 c.211+9C>G (rs2303426) [19], MSH3 c.3133G>A (rs26279) [20], and EXO1 c.1765G>A (rs1047840) [21], reduce levels of expressed protein compared with respective wild-type alleles, and have reduced DNA repair as consequence.…”

REV3L gene variants rs1002481, rs462779, and rs465646 lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir.

“…Additionally, these variants have also been found associated with severe toxicities in NSCLC patients undergoing platinum-based chemotherapy [23] REV3L interact with many genes as visualized in String tool software v 10.5 [32] (Supplementary gure S2) and by using SNIPA Insilco tool [33], we found rs1002481 and rs465646 playing a direct regulatory role in Gene Expression and rs462779 having a direct effect on the transcript and it is a missense variant that cause the alteration in amino acid sequence causing protein misfolding. All the three SNPs were found to be in linkage disequilibrium and the plot symbol of each variant indicates its functional annotation (Figure 2).…”

“…The present study conducted an association study of rs1002481 (T>A), rs462779 (G>A), rs465646 (G>A), and rs11153292(G>A) single nucleotide variants (SNVs) in the REV3L (Protein reversion less 3-like) gene located on chromosome 6q21 (Chr 6: 111,299,028-111,483,71) with NSCLC in the population of Jammu and Kashmir. These variants were selected based on literature survey as they play an important role in carcinogenesis [18][19][20][21][22][23]. SNV rs1002481 is an intronic variant located on Intron 7, rs462779 is an exonic variant located on exon 15, rs465646 is located on 3' UTR region of REV3L and rs11153292 is an intronic variant located on Intron 6.…”

Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment

“…Associations with neutropenia have been identified but the results have been contradictory [96][97][98][99][100]. Moreover, SNPs associated with hematological toxicity in DNA repair pathways have been extensively studied in several platinum-based chemotherapy combinations [100][101][102][103][104][105]. These genes are mainly located in the nucleotide excision repair pathway responsible for repairing intra-strand crosslinks.…”

“…These genes are mainly located in the nucleotide excision repair pathway responsible for repairing intra-strand crosslinks. SNPs in ERCC2, IL16, MMS19L, RAD18, XPC, XPD, and XRCC1 have for instance been associated with either hematological toxicity or leukopenia [101,103,[105][106][107][108].…”