Genetic variants in RPA1 associated with the response to oxaliplatin-based chemotherapy in colorectal cancer.

Abstract

Oxaliplatin (L-OHP) is a commonly used first-line chemotherapy for colorectal cancer. Genetic variants in nucleotide excision repair (NER) pathway genes may alter genomic integrity and the efficacy of oxaliplatin-based chemotherapy in colorectal cancer. We investigated the association between genetic variants in 19 NER pathway genes and the disease control rate (DCR) and progression-free survival (PFS) among 166 colorectal cancer patients who received oxaliplatin-based chemotherapy. Expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression (GTEx) portal. Gene harboring significant SNP was overexpressed or knocked down to demonstrate the effect on cell phenotypes with or without oxaliplatin treatment. We found that rs5030740, located in the 3'-untranslated region (3'-UTR) of RPA1, was associated with DCR [OR = 2.99 (1.33-5.69), P = 4.00 × 10-3] and PFS [HR = 1.86 (1.30-2.68), P = 7.39 × 10-4]. The C allele was significantly associated with higher RPA1 mRNA expression levels according to eQTL analysis (P = 0.010 for sigmoid colonand P = 0.004 for transversecolon). The C allele of rs5030740 disrupted let-7e-5p binding to enhance RPA1 expression. Functionally, RPA1 knockdown inhibited cell proliferation and promoted cell apoptosis, whereas RPA1 overexpression promoted proliferation and suppressed apoptosis. Furthermore, low RPA1 expression increased sensitivity to oxaliplatin in colon cancer cells and inhibited proliferation after oxaliplatin treatment. Our findings demonstrate an association between rs5030740 and the DCR and PFS of colorectal cancer patients. RPA1 functions as a putative oncogene in tumorigenesis by reducing sensitivity to oxaliplatin and could serve as a potential prognostic biomarker in colorectal cancer.