Expression quantitative trait loci in ABC transporters are associated with survival in 5-FU treated colorectal cancer patients
Language English Country Great Britain, England Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31922572
DOI
10.1093/mutage/gez050
PII: 5699895
Knihovny.cz E-resources
- MeSH
- ATP-Binding Cassette Transporters blood genetics MeSH
- Databases, Genetic MeSH
- Fluorouracil therapeutic use MeSH
- Genotype MeSH
- Polymorphism, Single Nucleotide MeSH
- Colorectal Neoplasms drug therapy genetics metabolism mortality MeSH
- Middle Aged MeSH
- Humans MeSH
- Quantitative Trait Loci MeSH
- Follow-Up Studies MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATP-Binding Cassette Transporters MeSH
- Fluorouracil MeSH
The chemotherapeutic efficacy in colorectal cancer (CRC) is limited due to the inter-individual variability in drug response and the development of tumour resistance. ATP-binding cassette (ABC) transporters are crucial in the development of resistance by the efflux of anticancer agents from cancer cells. In this study, we identified 14 single nucleotide polymorphisms (SNPs) in 11 ABC transporter genes acting as an expression of quantitative trait loci (eQTLs), i.e. whose variation influence the expression of many downstream genes. These SNPs were genotyped in a case-control study comprising 1098 cases and 1442 healthy controls and analysed in relation to CRC development risk and patient survival. Considering a strict correction for multiple tests, we did not observe any significant association between SNPs and CRC risk. The rs3819720 polymorphism in the ABCB3/TAP2 gene was statistically significantly associated with shorter overall survival (OS) in the codominant, and dominant models [GA vs. GG, hazard ratio (HR) = 1.48; P = 0.002; AA vs. GG, HR = 1.70; P = 0.004 and GA + AA vs. GG, HR = 1.52; P = 0.0006]. Additionally, GA carriers of the same SNP displayed worse OS after receiving 5-FU based chemotherapy. The variant allele of rs3819720 polymorphism statistically significantly affected the expression of 36 downstream genes. Screening for eQTL polymorphisms in relevant genes such as ABC transporters that can regulate the expression of several other genes may help to identify the genetic background involved in the individual response to the treatment of CRC patients.
Biomedical Centre Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic
Candiolo Cancer Institute FPO IRCCS Candiolo Italy
Department of Molecular Biology of Cancer Institute of Experimental Medicine Prague Czech Republic
Division of Functional Genome Analysis German Cancer Research Centre Heidelberg Germany
Division of Molecular Genetic Epidemiology
IIGM Italian Institute for Genomic Medicine Turin Italy
Institute for Clinical and Experimental Medicine IKEM Prague Czech Republic
Toxicogenomics Unit National Institute of Public Health Prague Czech Republic
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