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Variation in Bleomycin Hydrolase Gene Is Associated With Reduced Survival After Chemotherapy for Testicular Germ Cell Cancer

Esther C. de Haas, Nynke Zwart, Coby Meijer, Janine Nuver, H. Marike Boezen, Albert J.H. Suurmeijer, Harald J. Hoekstra, Gerrit van der Steege, Dirk Th. Sleijfer, Jourik A. Gietema

From the Departments of Medical Oncology, Epidemiology, Pathology, Surgical Oncology, Medical Biology, Medical Genetics; and the Genotyping Facility, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Corresponding author: Jourik A. Gietema, MD, PhD, Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands; e-mail: j.a.gietema{at}int.umcg.nl

Purpose 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.

Patients and 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.

Conclusion 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.

Supported by Grants No. CVZ 01-211 from the Health Care Insurance Board/Dutch Association of University Medical Centers, the Netherlands, and RUG2000-2177 from the Dutch Cancer Society, the Netherlands.

Presented in part as an oral presentation at the 43rd Annual Meeting of the American Association of Clinical Oncology, Chicago, IL, June 1-5, 2007.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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