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

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

L-OHP:

Oxaliplatin

NER:

Nucleotide excision repair

3′-UTR:

3′-Untranslated region

DCR:

Disease control rate

PFS:

Progression-free survival

eQTL:

Expression quantitative trait loci

GTEx:

The Genotype-Tissue Expression

SNPs:

Single-nucleotide polymorphisms

CT:

Computed tomography

RECIST:

Response evaluation criteria in solid tumors

CR:

Complete response

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MAF:

Minor allele frequency

LD:

Linkage disequilibrium

TCGA:

The Cancer Genome Atlas

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Acknowledgements

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).

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Author notes

  1. Shuwei Li, Kaili Xu and Dongying Gu contributed equally to the writing of this article.

Authors and Affiliations

  1. Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China

    Shuwei Li, Kaili Xu, Lisheng Xie, Mulong Du, Haiyan Chu, Zhengdong Zhang & Meilin Wang

  2. Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center of Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China

    Shuwei Li, Kaili Xu, Lisheng Xie, Haiyan Chu, Zhengdong Zhang & Meilin Wang

  3. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    Dongying Gu

  4. Department of Colorectal Surgery, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China

    Lei He, Zhimin Fan & Min Ni

  5. First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Zhengxin Chen

  6. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Lingjun Zhu

  7. Department of Biostatistics, Nanjing Medical University, Nanjing, China

    Mulong Du

  8. Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China

    Yuan Wu

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  1. Shuwei Li
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Contributions

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.

Corresponding authors

Correspondence to Yuan Wu, Min Ni or Meilin Wang.

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The authors declare no conflicts of interest.

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Li, S., Xu, K., Gu, D. et al. Genetic variants in RPA1 associated with the response to oxaliplatin-based chemotherapy in colorectal cancer. J Gastroenterol 54, 939–949 (2019). https://doi.org/10.1007/s00535-019-01571-z

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  • DOI: https://doi.org/10.1007/s00535-019-01571-z

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