Excision Repair Cross-Complementation group 1 (ERCC1) C118T SNP does not affect cellular response to oxaliplatin.
OBJECTIVE
ERCC1 is involved in the repair of oxaliplatin-induced DNA damage. Studies for the association of the C118T SNP with clinical response to treatment with platinum drugs have rendered inconsistent results. We investigated the ERCC1 C118T SNP with respect to overall and progression-free survival in patients with advanced colorectal cancer (ACC) treated with oxaliplatin and in vitro DNA repair capacity after oxaliplatin exposure. In addition we discuss discrepancies from other studies concerning ERCC1 C118T.


METHODS
Progression-free survival was determined in 145 ACC patients treated with oxaliplatin-based chemotherapy in a phase 3 trial. For the in vitro studies regarding ERCC1 functionality, we transfected an ERCC1 negative cell line with 118C or 118T ERCC1. Cellular sensitivity and DNA repair capacity after exposure to oxaliplatin was examined by Sulphorodamine B growth inhibition assay, COMET assay and Rad51 foci staining.


RESULTS
We found no association between ERCC1 C118T and progression-free or overall survival. In addition, transfection of either 118C or 118T restores DNA-repair capacity of UV20 cells to the same level and chemosensitivity to oxaliplatin was similar in ERCC1 118C and 118T transfected cells.


CONCLUSIONS
This study shows that the ERCC1 C118T variants are not associated with survival in ACC patients treated with oxaliplatin or the in vitro sensitivity and DNA-repair capacity in 118C and 118T transfected cell lines. Therefore, ERCC1 C118T genotyping seems of no value in individualizing oxaliplatin based chemotherapy in ACC.
Department of Clinical Oncology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: l.h.tanja@lumc.nl.
Lieke H
LH
van Huis-Tanja
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: d.m.kweekel@lumc.nl.
Dina M
DM
Kweekel
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Xiaobo
X
Lu
Department of Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: c.l.m.c.franken@lumc.nl.
Kees
K
Franken
Department of Medical Oncology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Electronic address: mkoopman-6@umcutrecht.nl.
Miriam
M
Koopman
Department of Clinical Oncology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: a.j.gelderblom@lumc.nl.
Hans
H
Gelderblom
Department of Biometrics, Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: nfantonini@gmail.com.
Ninja F
NF
Antonini
Department of Medical Oncology, Academic Medical Center, University of Amsterdam, PO BOX 22660, 1100 DD Amsterdam, The Netherlands. Electronic address: c.j.a.punt@amc.uva.nl.
Cornelis J A
CJ
Punt
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: h.j.guchelaar@lumc.nl.
Henk-Jan
HJ
Guchelaar
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Electronic address: r.j.h.m.van_der_straaten@lumc.nl.
Tahar
T
van der Straaten
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003412:Cricetulus; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C071447:ERCC1 protein, human; D004720:Endonucleases
Colorectal cancer; DNA repair; ERCC1; Oxaliplatin; Pharmacogenomics