Journal Article

DKFZ-2018-00754

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients.

Kap, E. J. (First author)DKFZ* ; Seibold, P.DKFZ* ; Scherer, D. ; Habermann, N. ; Balavarca, Y.DKFZ* ; Jansen, L.DKFZ* ; Zucknick, M. ; Becker, N.DKFZ* ; Hoffmeister, M.DKFZ* ; Ulrich, A. ; Benner, A.DKFZ* ; Ulrich, C. M. ; Burwinkel, B.DKFZ* ; Brenner, H.DKFZ* ; Chang-Claude, J. (Last author)DKFZ*

2016
Wiley-Liss Bognor Regis

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Please use a persistent id in citations: doi:10.1002/ijc.30026

Abstract: Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.

Keyword(s): ATP-Binding Cassette Transporters ; Biomarkers, Tumor ; Organoplatinum Compounds ; oxaliplatin ; Alcohol Oxidoreductases ; glyoxylate reductase ; Adenosine Triphosphatases ; Leucovorin ; Fluorouracil

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Contributing Institute(s):

1. Epidemiologie von Krebserkrankungen (C020)
2. Biostatistik (C060)
3. Klinische Epidemiologie und Alternsforschung (C070)
4. Molekulare Epidemiologie (C080)
5. Präventive Onkologie (G110)
6. DKTK Heidelberg (L101)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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