Genetic variants in nucleotide excision repair pathway predict survival of esophageal squamous cell cancer patients receiving platinum‐based chemotherapy

Abstract

The benefits of platinum-based chemotherapy (PBC) on survival of esophageal squamous cell carcinoma (ESCC) patients are inexplicit due to the varied therapeutic effects. Nucleotide excision repair (NER) pathway plays a vital role in removing platinum-DNA adducts in tumor cells and hence may modulate the therapeutic effect and survival outcome. The present study assessed the associations of 26 potentially functional regulatory single nucleotide polymorphisms (rSNPs) in nine core NER genes with disease-free survival (DFS) and overall survival (OS) in 339 ESCC patients. We found that ERCC2 rs2097215 T and rs3916788 A, ERCC5 rs3759497 A and XPC rs3731054 C alleles were associated with unfavorable DFS. Patients carrying high-risk allele group (HRG, 5-8 risk alleles) had a significantly shorter DFS, compared with those carrying low-risk alleles (LRG, 0-4 risk alleles) [adjusted hazards ratio (HR ) = 1.64, 95%CI = 1.23-2.19, P < 0.001]. Three of these SNPs (ie, ERCC2 rs2097215 T and rs3916788 A and ERCC5 rs3759497 A) were also significantly associated with a poorer OS (HRG vs LRG: HR = 1.75, 95%CI = 1.23-2.47, P = 0.002). The expression quantitative trait loci (eQTL) analysis revealed significant genotype-expression correlations for ERCC5 rs3759497 and ERCC2 2097215 and rs3916788, which suggest regulatory roles of these SNPs. It appears that these NER variants may independently or jointly exert an impact on survival outcome of Chinese ESCC patients undergoing adjuvant platinum-based therapy. Large studies are warranted to validate these findings.

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

“…Moreover, targeting altered DDR pathways could be an effective way for cancer treatment (4,5). Gene polymorphisms in BER, NER and NHEJ pathway genes have been reported to be related to higher risk of ESCC (12)(13)(14)(15)(16). However, the alterations in DDR pathways, including gene mutations, CNVs, and abnormal expression, are still largely unknown in ESCC, and how alterations in DDR pathways contribute to ESCC needs to be further explored.…”

“…Genetic variants in NER genes were linked to exert an impact on survival outcomes of Chinese ESCC patients (14,15). Moreover, genetic polymorphisms of XRCC6 and XRCC5, two genes in NHEJ pathway, were related to higher risk of ESCC (16).…”

“…In ESCC, polymorphisms of BER genes were reported to be probably associated with the susceptibility to ESCC ( 12 , 13 ). Genetic variants in NER genes were linked to exert an impact on survival outcomes of Chinese ESCC patients ( 14 , 15 ). Moreover, genetic polymorphisms of XRCC6 and XRCC5 , two genes in NHEJ pathway, were related to higher risk of ESCC ( 16 ).…”

Polymorphisms in ERCC5 rs17655 and ERCC1 rs735482 Genes Associated with the Survival of Male Patients with Postoperative Oral Squamous Cell Carcinoma Treated with Adjuvant Concurrent Chemoradiotherapy

“…SNPs in the NER pathway were selected from studies that indicated that SNPs were associated with the risk or prognosis of malignancies in ethnic Chinese [16,18,19,20]. A total of 13 potentially functional SNPs in ERCC5 (rs2094258, rs1047768, rs17655, and rs873601), ERCC2 (rs13181 and rs1799793), ERCC1 (rs735482, rs3212986, and rs11615), XPC (rs2228001 and rs2228000), and XPA (rs1800975 and rs10817938) genes were genotyped using the Sequenom iPLEX MassARRAY system (Sequenom, Inc., San Diego, CA, USA).…”

“…Thus, we conducted a retrospective cohort study to test whether SNPs in genes involved in the NER pathway are associated with prognosis in male patients with OSCC treated with adjuvant CCRT. A total of 13 SNPs in ERCC5 , ERCC2 , ERCC1 , XPC , and XPA genes, which have been found to affect the risk and/or survival of cancers, were selected in the present study [13,14,16,17,18,19,20]. Their associations with clinical outcomes were evaluated using alternative genetic models, including additive, dominant, and recessive models.…”