SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients

TY - JOUR

T1 - SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients

AU - Kap, Elisabeth J

AU - Seibold, Petra

AU - Scherer, Dominique

AU - Habermann, Nina

AU - Balavarca, Yesilda

AU - Jansen, Lina

AU - Zucknick, Manuela

AU - Becker, Natalia

AU - Hoffmeister, Michael

AU - Ulrich, Alexis

AU - Benner, Axel

AU - Ulrich, Cornelia M

AU - Burwinkel, Barbara

AU - Brenner, Hermann

AU - Chang-Claude, Jenny

N1 - © 2016 UICC.

PY - 2016/6/15

Y1 - 2016/6/15

N2 - 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 employed a 2-step procedure to comprehensively investigate 1444 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. Firstly, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Secondly, 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-value < 0.05) were selected. Model selection resulted in the inclusion of fourteen 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 that are more likely to benefit from treatment with oxaliplatin. This article is protected by copyright. All rights reserved.

AB - 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 employed a 2-step procedure to comprehensively investigate 1444 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. Firstly, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Secondly, 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-value < 0.05) were selected. Model selection resulted in the inclusion of fourteen 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 that are more likely to benefit from treatment with oxaliplatin. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ijc.30026

DO - 10.1002/ijc.30026

M3 - SCORING: Journal article

C2 - 26835885

VL - 138

SP - 2993

EP - 3001

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 12

ER -