Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer.
OBJECTIVE
Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival.


METHODS
Data were collected on survival and BLMH genotype of 304 patients with TC treated with bleomycin-containing chemotherapy at the University Medical Center Groningen, the Netherlands, between 1977 and 2003. Survival according to genotype was analyzed using Kaplan-Meier curves with log-rank testing and Cox regression analysis with adjustment for confounders.


RESULTS
BLMH gene SNP A1450G has a significant effect on TC-related survival (log-rank P = .001). The homozygous variant (G/G) genotype (n = 31) is associated with decreased TC related survival compared with the heterozygous variant (A/G; n = 133) and the wild-type (A/A; n = 140). With Cox regression the G/G genotype proves to be an unfavorable prognostic factor, in addition to the commonly used International Germ Cell Consensus Classification prognosis group, with a hazard ratio of 4.97 (95% CI, 2.17 to 11.39) for TC-related death. Furthermore, the G/G genotype shows a higher prevalence of early relapses.


CONCLUSIONS
The homozygous variant G/G of BLMH gene SNP A1450G is associated with reduced survival and higher prevalence of early relapses in TC patients treated with bleomycin-containing chemotherapy. This association is hypothesis generating and may eventually be of value for risk classification and selection for alternative treatment strategies in patients with disseminated TC.
de Haas
Esther C
EC
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
Zwart
Nynke
N
Meijer
Coby
C
Nuver
Janine
J
Boezen
H Marike
HM
Suurmeijer
Albert J H
AJ
Hoekstra
Harald J
HJ
van der Steege
Gerrit
G
Sleijfer
Dirk Th
DT
Gietema
Jourik A
JA
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001761:Bleomycin / Q000008:administration & dosage* / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D003546:Cysteine Endopeptidases / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011658:Pulmonary Fibrosis / Q000139:chemically induced; D012044:Regression Analysis; D015996:Survival Rate; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000401:mortality
D001761:Bleomycin; D005047:Etoposide; D003546:Cysteine Endopeptidases; C031262:bleomycin hydrolase; D002945:Cisplatin