Polymorphisms in DNA repair pathway genes and&nbsp;<em>ABCG2</em>&nbsp;gene in advanced colorectal cancer: correlation with tumor characteristics and clinical outcome in oxaliplatin-based chemotherapy

Abstract

ObjectiveMultiple factors are involved in oxaliplatin-resistant process in colorectal cancer (CRC) patients including decreased drug accumulation and enhanced capacity to repair and tolerate DNA damage. In the present study, we aimed to assess the impact of six single-nucleotide polymorphisms (SNPs) in DNA repair genes and ABCG2 gene on prognosis in advanced CRC patients treated with oxaliplatin-based chemotherapy.MethodsIn this study, 580 advanced CRC patients were recruited. Six SNPs of DNA repair genes (XPA rs10817938, XPA rs2808668, XPC rs2607775, and WRN rs1346044) and ABCG2 gene (rs2231142 and rs2622621) were genotyped by using the TaqMan assay.ResultsRegarding interaction with environmental factors, ABCG2 rs2231142 and the first-degree family history of cancer and XPC rs2607775 or ABCG2 rs2622621 and lymph node metastases status demonstrated significant interactions. Of these six SNPs, XPA rs10817938 CT/ TT genotypes retained its significant association with longer overall survival (OS) (P=0.008) in CRC patients receiving oxaliplatin-based chemotherapy (n=580). Furthermore, a significantly better impact on the disease-free survival (DFS) (P=0.001) and OS (P<0.0001) was found in ABCG2 rs2231142CA/AA carriers. Furthermore, ABCG2 rs2622621 CG/GG genotype was verified to be an independent poor prognostic factor in DFS (P=0.010) and OS (P=0.030). In the stratification analysis, XPA rs10817938 CT/CC, rs2231142 CA/AA, and rs2622621 CC genotypes of ABCG2 were predictive of significantly better prognosis in the patients with tumor differentiation grade 3 (n=523), clinical stage IV (n=73), or lymph node-positive status (n=557). Additionally, multivariate logistic regression and multiple dimension reduction analysis consistently revealed that the combination of selected SNPs and five known risk factors showed a better prediction prognosis and represented the best model to predict CRC prognosis.ConclusionThe current data indicated that the XPA gene and ABCG2 gene had significant interaction with environmental factors and prognosis, which could provide a comprehensive understanding of the implications of those SNPs in the prediction of prognosis in advanced CRC patients receiving oxaliplatin-based chemotherapy.

FBXW4 Acts as a Protector of FOLFOX-Based Chemotherapy in Metastatic Colorectal Cancer Identified by Co-Expression Network Analysis

“…The previous study reported that FBXW4 regulates the ubiquitination and cell cycle (Lockwood et al, 2013). In the present study, we found that FBXW4 was not only related to the cell cycle signaling pathway, but was also related to the DNA replication signaling pathway, which is associated with oxaliplatin resistance (Martinez-Balibrea et al, 2015;Hu et al, 2019). However, the underlying mechanism by which FBXW4 increases FOLFOX regimen sensitivity in mCRC patients is still unclear.…”

Genetic Variants in DNA Repair Pathways as Potential Biomarkers in Predicting Treatment Outcome of Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: A Systematic Review

“…In Table S3 ( Supplementary Material ), three SNPs in the XPC gene that are potentially predictive of treatment response to oxaliplatin-based therapy in CRC patients are reported ( Liu et al., 2012 ; Kap et al., 2015 ; Hu et al., 2019 ). Only one SNP was significantly associated with survival.…”

“…Following our selection criteria, for XPA in the NER pathway ( Stoehlmacher et al., 2004 ; Monzo et al., 2007 ; Hu et al., 2019 ), SRBC in the HR pathway ( Moutinho et al., 2014 ) and MGMT in the DNA synthesis pathway ( Park et al., 2010 ) results remain inconclusive because the observed associations have not yet been replicated and the studies itself were relatively small (<300 patients).…”

XPA: DNA Repair Protein of Significant Clinical Importance

“…In contrast to A23G SNP, the G709A SNP has virtually no impact on the repair of UV-and benzo(a)pyrene diol epoxide-induced DNA damage compared to wild-type XPA [186,187], and appears to have a protective effect for LC patients [166][167][168]. [154,155,159,[166][167][168][169][170][171][172][173][174][175][176][177][178][179][180]185,[191][192][193] Three further SNPs reside in intron sequences of XPA: rs3176658, which causes C to T transition, rs3176721, a C to A transversion, and rs2808667, a T to C transition (www.ncbi.nlm.nih.gov/snp). rs3176658 and rs3176721 are associated with efficacy of platinum-based chemotherapy in LC [188], while rs3176658 alone has been shown to be significantly associated with LC risk [189] and with response to neoadjuvant radiochemotherapy treatment of locally advanced rectal cancer (RC) [190].…”

“…These SNPs are located at transcription factor binding sites, impacting XPA mRNA level, which may influence the cellular response to platinum-based chemotherapies. Indeed, rs10817938 heterozygous CT and homozygous TT genotypes have been associated with longer overall survival (OS) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy [155]. In addition, these SNPs have been shown to be associated with the risk and development of numerous cancers and display significant gene-environment interactions (see below).…”