Genetic variants in RPA1 associated with the response to oxaliplatin-based chemotherapy in colorectal cancer
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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 colon and P = 0.004 for transverse colon). 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.
KeywordsColorectal cancer Oxaliplatin Nucleotide excision repair Genetic variants Survival
Nucleotide excision repair
Disease control rate
Expression quantitative trait loci
The Genotype-Tissue Expression
Response evaluation criteria in solid tumors
Kyoto Encyclopedia of Genes and Genomes
Minor allele frequency
The Cancer Genome Atlas
This study was partly supported by National Natural Science Foundation of China (81822039, 81872697, 81803926 and 81773516), the National Key R&D Program of China (2017YFC0908200), the Qinlan Project of Jiangsu (Meilin Wang), Six Talent Peaks Project of Jiangsu Province (YY-020), the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine), and the Science and Technology Development Founding of Nanjing Medical University (2017NJMUZD140).
MW, MN, and YW conceived and designed the experiments. SL, KX and DG wrote the paper. LH, LX and ZC contributed reagents/materials/analysis tools. LZ, MD, HC and ZZ recruited samples. All authors reviewed the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
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