Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

Abstract

DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.

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

“…The corresponding protein plays an important function in damage sensing and DNA binding [27]. SNPs in this gene have been found to affect clinical outcomes in various cancer types [18,28,29]. Li and colleagues observed that the XPC rs2228000 TT genotypes were associated with shorter OS than the CC+CT genotype individuals in a study of Japanese gastric cancer patients [30].…”

Associations of mRNA expression of DNA repair genes and genetic polymorphisms with cancer risk: a bioinformatics analysis and meta-analysis

“…The SNPs XPA rs10817938, XPA rs2808668 and XPF rs3136038 are all the polymorphisms in the site of the gene promoter. The SNP rs10817938 is located in the 5'-untranslated region (UTR), which is a T to C substitution distant from the transcriptional start site (TSS) about -2718bp, meanwhile, rs2808668 is a T to C substitution located -514bp from the TSS within XPA gene, which have been reported novel promoter SNPs in the XPA loci associated with cancer risk and development including hepatic cancer (HCC) 26, breast cancer 19, gastric cancer 24, oral squamous cell carcinoma (OSCC) 25. Furthermore the SNP rs3136038 is near the 5' end of XPF gene (also known as ERCC4, excision repair cross-complementation group 4 gene) exhibits remarkably associated with the susceptibility of variety of cancer such as breast cancer 55, 63, lung cancer 56, ESCC 61, gastric cancer 39, etc.…”

Somatic pharmacogenomics of gastrointestinal stromal tumor

“…Therefore, it is conceivable that polymorphisms or gene expression regulation through methylation/miRNA mechanisms could represent key players in affecting the final clinical outcome. By virtue of this consideration, possible pharmacogenetic [57][58][59][60][61][62] and epigenetic [63][64][65][66] mechanisms of imatinib and sunitinib resistance have been broadly investigated in GISTs [67][68][69][70][71] . Despite the extensive research, data are controversial and to date none of them supports the use of pharmacogenetic or pharmacoepigenetic tests to optimize treatment outcome in GIST patients.…”