title: Genetic variations associated with the effect of testicular cancer treatment on gonadal hormones.
abstract: OBJECTIVE
  Do genetic variations in the testosterone pathway genes modify the effect of treatment on the levels of testosterone and LH in long-term testicular cancer (TC) survivors (TCSs)?
  
  
  CONCLUSIONS
  Variations in LH receptor (LHR) and in 5α-reductase II (SRD5A2) genes may modify the effect of TC treatment on testosterone levels, whereas genetic variations in the androgen receptor (AR) may modify the effect on LH levels.
  
  
  BACKGROUND
  TCSs experience variable degrees of long-term reduction in gonadal function after treatment. This variability can in part be explained by treatment intensity, but may also be due to individual variations in genes involved in the function and metabolism of reproductive hormones.
  
  
  METHODS
  Cross-sectional study on testosterone and LH levels in 637 Norwegian TCSs in relation to genetic variants and TC treatment.
  
  
  METHODS
  The single nucleotide polymorphisms LHR Asn291Ser (rs12470652) and Ser312Asn (rs2293275), as well as SRD5A2 Ala49Thr (rs9282858) and Val89Leu (rs523349) were analyzed by allele-specific PCR. The insertion polymorphism LHR InsLQ (rs4539842) was analyzed by sequencing. The numbers of AR CAG and GGN repeats were determined by capillary electrophoresis. Blood samples were collected 5-21 years after diagnosis (median 11 years) and serum total testosterone and LH were analyzed by commercial immunoassays. The TCSs were divided into four groups according to their treatment; surgery only, radiotherapy and chemotherapy with ≤850 or >850 mg of cisplatin. Polymorphisms presenting P < 0.1 for the interaction term with treatment in an initial two-way analysis of covariance (ANCOVA) were investigated further in two consecutive one-way ANCOVA analyses to elucidate the interaction between treatment and genotype.
  
  
  RESULTS
  For the whole group of TCSs, there were no significant differences between the hormone levels in homozygotes for the wild type and carriers of at least one polymorphic allele for the investigated polymorphisms. Three of the polymorphisms showed signs of interaction with treatment, i.e. LHR InsLQ, SRD5A2 A49T and the AR CAG repeat. Follow-up analyses revealed three situations where only one of the genotypes of the polymorphism where associated with significantly different hormone levels after surgery compared with after additional cytotoxic treatment: For LHR InsLQ, only the wild-type allele was associated with lower testosterone levels after cisplatin > 850 mg compared with after surgery (24% lower, P < 0.001). For SRD5A2 A49T, testosterone levels were lower after radiotherapy compared with after surgery, but only for the heterozygotes for the polymorphism (39% lower, P = 0.001). In comparison, the testosterone levels were just slightly lower after radiotherapy (6% lower, P = 0.039) or cisplatin ≤ 850 mg (7% lower, P = 0.041), compared with surgery, independent of genotypes. For AR CAG, only the reference length of CAG = 21-22 had significantly higher LH levels after cisplatin ≤ 850 mg compared with after surgery (70% higher, P < 0.001). Independent of genotypes, however, LH levels after cisplatin ≤ 850 mg were only 26% higher than after surgery (P = 0.005).
  
  
  CONCLUSIONS
  Unadjusted P-values are presented. For analysis involving genotypes, the level of statistical significance was adjusted for the total number of polymorphisms tested, n = 7, i.e. to P < 0.007 (0.5/7). The rather weak associations indicate that additional polymorphisms are involved in the modulation.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study supporting the notion that polymorphisms may explain at least some of the inter-individual differences in endocrine response to TC treatment. Our findings suggest that individuals with certain genotypes may be more vulnerable to certain treatments. Knowledge on genetic predisposition concerning treatment-related endocrine gonadotoxicity to different treatment regimens may help tailoring TC therapy when possible.
  
  
  BACKGROUND
  This study was supported by the Research Council of Norway (Grant No. 160619). There were no competing interests.
authors.affiliation: Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, P.O. Box 4, St. Olavs plass, Oslo NO-0130, Norway.
authors.forename: E L
authors.initials: EL
authors.lastname: Aschim
authors.affiliation: Department of Clinical Cancer Research, Oslo University Hospital, Oslo NO-0424, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, P.O. Box 4, St. Olavs plass, Oslo NO-0130, Norway.
authors.forename: W
authors.initials: W
authors.lastname: Kristiansen
authors.affiliation: Molecular Reproduction Research, Department of Clinical Sciences Malmö, Lund University, Malmö SE-205 02, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Giwercman
authors.affiliation: Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, P.O. Box 4, St. Olavs plass, Oslo NO-0130, Norway.
authors.forename: O
authors.initials: O
authors.lastname: Witczak
authors.affiliation: Department of Clinical Cancer Research, Oslo University Hospital, Oslo NO-0424, Norway.
authors.forename: S D
authors.initials: SD
authors.lastname: Fosså
authors.affiliation: Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, P.O. Box 4, St. Olavs plass, Oslo NO-0130, Norway trine.b.haugen@hioa.no.
authors.forename: T B
authors.initials: TB
authors.lastname: Haugen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003430:Cross-Sectional Studies; D005838:Genotype; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood*; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011974:Receptors, LH / Q000235:genetics; D017741:Survivors; D013736:Testicular Neoplasms / Q000235:genetics*; D013739:Testosterone / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; D011974:Receptors, LH; D013739:Testosterone; D007986:Luteinizing Hormone
keywords: long-term; polymorphism; sex hormones; testicular cancer; treatment