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

  • Shuwei Li
  • Kaili Xu
  • Dongying Gu
  • Lei He
  • Lisheng Xie
  • Zhengxin Chen
  • Zhimin Fan
  • Lingjun Zhu
  • Mulong Du
  • Haiyan Chu
  • Zhengdong Zhang
  • Yuan WuEmail author
  • Min NiEmail author
  • Meilin WangEmail author
Original Article—Alimentary Tract
  • 119 Downloads

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.

Keywords

Colorectal cancer Oxaliplatin Nucleotide excision repair Genetic variants Survival 

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

Notes

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).

Author 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.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

535_2019_1571_MOESM1_ESM.docx (1.5 mb)
Supplementary material 1 (DOCX 1569 kb)

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Copyright information

© Japanese Society of Gastroenterology 2019

Authors and Affiliations

  • Shuwei Li
    • 1
    • 2
  • Kaili Xu
    • 1
    • 2
  • Dongying Gu
    • 3
  • Lei He
    • 4
  • Lisheng Xie
    • 1
    • 2
  • Zhengxin Chen
    • 5
  • Zhimin Fan
    • 4
  • Lingjun Zhu
    • 6
  • Mulong Du
    • 1
    • 7
  • Haiyan Chu
    • 1
    • 2
  • Zhengdong Zhang
    • 1
    • 2
  • Yuan Wu
    • 8
    Email author
  • Min Ni
    • 4
    Email author
  • Meilin Wang
    • 1
    • 2
    Email author
  1. 1.Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized MedicineNanjing Medical UniversityNanjingChina
  2. 2.Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center of Global Health, School of Public HealthNanjing Medical UniversityNanjingChina
  3. 3.Department of Oncology, Nanjing First HospitalNanjing Medical UniversityNanjingChina
  4. 4.Department of Colorectal SurgeryThe Third Affiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
  5. 5.First School of Clinical MedicineNanjing University of Chinese MedicineNanjingChina
  6. 6.Department of OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  7. 7.Department of BiostatisticsNanjing Medical UniversityNanjingChina
  8. 8.Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer ResearchThe Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina

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