Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients.
Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64-14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30-25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.
Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid 28029, Spain.
D
D
Caronia
A
A
Patiño-García
R L
RL
Milne
M
M
Zalacain-Díez
G
G
Pita
M R
MR
Alonso
L T
LT
Moreno
L
L
Sierrasesumaga-Ariznabarreta
J
J
Benítez
A
A
González-Neira
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018579:Patient Selection; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*; D055815:Young Adult
D000970:Antineoplastic Agents; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002945:Cisplatin