Functional glutathione S-transferase genotypes among testicular germ cell tumor survivors: associations with primary and post-chemotherapy tumor histology.
OBJECTIVE
The pathogenesis of testicular germ cell tumor (TGCT) remains unknown. The aim of this study was to evaluate the pathogenic role of functional polymorphisms in detoxification enzymes among TGCT patients, through association studies of constitutive genotypes and medical parameters before and after chemotherapy.


METHODS
Germline deletion polymorphisms in the glutathione S-transferase mu 1 (GSTM1) and the GST theta 1 (GSTT1), and a functional single nucleotide polymorphism in GST pi 1 (GSTP1, Ile105Val), were analyzed in TGCT survivors (TCSs) (n = 675) and controls (n = 189). Statistical analyses were performed for the genotype distributions between the TCSs and control populations, and between the genotypes and clinicopathological parameters of the TCSs.


RESULTS
The GST genotypes showed comparable distributions among the TCSs and the control population. However, the genotype combination GSTT1positive/GSTP1-GG or GSTP1-AG/GSTM1positive was more frequent among the TCSs [P = 0.050, odds ratio (OR): 1.47, 95% confidence interval (CI): 0.998-2.165]. The combined genotype GSTT1positive/GSTP1AA/GSTM1positive was associated with decreased risk of development of pure embryonal carcinoma (P = 0.009, OR: 0.309, 95% CI: 0.122-0.784) and the GSTP1-A-allele (i.e. genotypes GSTP-AA or GSTP-AG) was also associated with decreased risk for development of pure teratoma (P = 0.032, OR: 0.326, 95% CI: 0.122-0.873). Furthermore, the GSTP1-A-allele was overrepresented within the 'good prognosis group' (P = 0.032, OR: 2.407, 95% CI: 1.060-5.469), whereas the GSTM1nulltype was associated with the extent of TC qualifying as 'poor prognosis group' (P = 0.025, OR: 2.839, 95% CI: 1.104-7.301). The GSTP1-AG genotype was associated with necrosis in the tumor's post-chemotherapy histology (P = 0.001, OR: 16.087, 95% CI: 1.930-134.087). Failure, after platinum-based chemotherapy, was associated with the GSTT1positive/GSTP-AA or GSTP-GG/GSTM1-positive genotype (P = 0.019, OR: 2.168, 95% CI: 1.130-4.160).


CONCLUSIONS
This study confirms an association between the GSTP1-G-allele and TGCT. Combinations of GST genotypes were associated with primary and post-chemotherapy tumor histology, and prognostic group presentation.
Kraggerud
Sigrid M
SM
Department of Cancer Prevention, Centre for Cancer Biomedicine, The Norwegian Radium Hospital, Drammen, Norway.
Oldenburg
Jan
J
Alnaes
Grethe I
GI
Berg
Marianne
M
Kristensen
Vessela N
VN
Fossa
Sophie D
SD
Lothe
Ragnhild A
RA
D000293:Adolescent; D000328:Adult; D000368:Aged; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018237:Germinoma / Q000235:genetics* / Q000473:pathology; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C495790:glutathione transferase T1-1, human