title: Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients.
abstract: Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy.
  
  
  
  In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival.
  
  
  
  BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant.
  
  
  
  We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Gabriela G F
authors.initials: GGF
authors.lastname: van der Schoot
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Nico-Derk L
authors.initials: NL
authors.lastname: Westerink
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Sjoukje
authors.initials: S
authors.lastname: Lubberts
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Janine
authors.initials: J
authors.lastname: Nuver
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Zwart
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Annemiek M E
authors.initials: AME
authors.lastname: Walenkamp
authors.affiliation: Department of Pulmonary Medicine, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Johan B
authors.initials: JB
authors.lastname: Wempe
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Coby
authors.initials: C
authors.lastname: Meijer
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands. Electronic address: j.a.gietema@umcg.nl.
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D014644:Genetic Variation; D000071020:Hemochromatosis Protein / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019190:Iron Overload / Q000235:genetics; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000401:mortality; D008171:Lung Diseases / Q000139:chemically induced* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000401:mortality; D055815:Young Adult
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D001761:Bleomycin; D002945:Cisplatin
keywords: Antineoplastic agents; Bleomycin; Cisplatin; HFE; Survivors; Testicular neoplasms; Toxicity; Variation