Pathway based analysis of SNPs with relevance to 5-FU therapy: Relation to intratumoral mRNA expression and survival
Silje H. Nordgard
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Faculty of Medicine, University of Oslo, Norway
Search for more papers by this authorGrethe I.G. Alnæs
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Search for more papers by this authorOle Christian Lingjærde
Department of Informatics, University of Oslo, Oslo, Norway
Search for more papers by this authorKnut Liestøl
Department of Informatics, University of Oslo, Oslo, Norway
Search for more papers by this authorTherese Sørlie
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Search for more papers by this authorPer Eystein Lønning
Institute of Medicine, University of Bergen, Norway
Department of Oncology, Haukeland University Hospital, Norway
Search for more papers by this authorAnne-Lise Børresen-Dale
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Faculty of Medicine, University of Oslo, Norway
Search for more papers by this authorCorresponding Author
Vessela N. Kristensen
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Faculty of Medicine, University of Oslo, Norway
Fax +47-22-93-44-40.
Department of Genetics, Institute for Cancer Research, Montebello, Oslo 0310, NorwaySearch for more papers by this authorSilje H. Nordgard
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Faculty of Medicine, University of Oslo, Norway
Search for more papers by this authorGrethe I.G. Alnæs
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Search for more papers by this authorOle Christian Lingjærde
Department of Informatics, University of Oslo, Oslo, Norway
Search for more papers by this authorKnut Liestøl
Department of Informatics, University of Oslo, Oslo, Norway
Search for more papers by this authorTherese Sørlie
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Search for more papers by this authorPer Eystein Lønning
Institute of Medicine, University of Bergen, Norway
Department of Oncology, Haukeland University Hospital, Norway
Search for more papers by this authorAnne-Lise Børresen-Dale
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Faculty of Medicine, University of Oslo, Norway
Search for more papers by this authorCorresponding Author
Vessela N. Kristensen
Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
Faculty of Medicine, University of Oslo, Norway
Fax +47-22-93-44-40.
Department of Genetics, Institute for Cancer Research, Montebello, Oslo 0310, NorwaySearch for more papers by this authorAbstract
Genetic factors are thought to play a role in resistance towards chemotherapeutic agents such as 5-fluorouracil (5-FU). Approximately 30 genes are directly or indirectly involved in 5-FU metabolism, and genetic variation in any of these may contribute to anti-tumor response. Polymorphisms in these genes were analyzed in relation to tumoral mRNA levels of 5-FU metabolizing genes, response to chemotherapy and survival. A total of 21 genetic variants were studied in 35 breast cancer patients treated with 5-FluoroUracil, mitomycin (FUMI) and in a similar cohort of 90 doxorubicin treated breast cancer patients. Genotype distributions were compared using 109 healthy controls. No significant association was found between any polymorphisms and response to chemotherapy as measured by shrinkage of tumor. However, carriers of 3 copies of the TYMS 5′UTR repeat had shorter survival than noncarriers (p = .048) in the FUMI treatment group, but not in the doxorubicin treated group. Carriers of 3 copies of the repeat were also more frequently observed in both patients groups than in healthy controls (p = .034). Several highly significant associations were observed between genotypes and expression levels of 5-FU metabolizing genes. A SNP in codon 72 of TP53 was revealed to be a key regulator of 5-FU metabolizing genes such as DHFR and MTHFR, constituting 50% of all significant associations observed after FUMI therapy. These data suggest that 3 copies of the TYMS 5′UTR repeat may give a treatment specific reduced survival in breast cancer patients, and that TP53 may have a direct, allele specific, role in 5-FU mediated response. © 2008 Wiley-Liss, Inc.
Supporting Information
This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/0020-7136/suppmat .
| Filename | Description |
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| ijc23541-IJC-07-2447SupFig1Nanogen.tif3.6 MB | Supporting Information file ijc23541-IJC-07-2447SupFig1Nanogen.tif |
| ijc23541-IJC-07-2447SupFig2LDHaplotypes.tif6.1 MB | Supporting Information file ijc23541-IJC-07-2447SupFig2LDHaplotypes.tif |
| ijc23541-IJC-07-2447SupplementaryTableI.doc389.5 KB | Supporting Information file ijc23541-IJC-07-2447SupplementaryTableI.doc |
| ijc23541-IJC-07-2447SupplementaryTableII.doc233.5 KB | Supporting Information file ijc23541-IJC-07-2447SupplementaryTableII.doc |
| ijc23541-IJC-07-2447SupplementaryTableIII.doc144 KB | Supporting Information file ijc23541-IJC-07-2447SupplementaryTableIII.doc |
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