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CAG repeat polymorphism in the DNA polymerase γ gene in a Polish population: an association with testicular cancer risk

2005; Elsevier BV; Volume: 16; Issue: 7 Linguagem: Inglês

10.1093/annonc/mdi205

1569-8041

Rachael Nowak, Renata Zub, Iwona Skoneczna, K. M. Sikora, Marcin Ligaj,

Sperm and Testicular Function

A growth of testicular cancer incidence rates has been reported, but the incidence varies between countries and in Poland is lower than in most European countries. The aetiology of testicular malignancies remains unknown. However, one-third of all testicular cancer patients are considered to be genetically predisposed to the disease [1.Nicholson P.W. Harland S.J. Inheritance and testicular cancer.Br J Cancer. 1995; 71: 421-426Crossref PubMed Scopus (83) Google Scholar]. Testicular dysgenesis, involving probably both environmental and genetic factors, is associated with subfertility as well as with an increased risk of testicular cancer [2.Lutke Holzik M.F. Rapley E.A. Hoekstra H.J. et al.Genetic predisposition to testicular germ-cell tumours.Lancet Oncol. 2004; 5: 363-371Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. Mutations or deletions in the mitochondrial genome have frequently been implicated in sperm dysfunction. Mitochondrial DNA is replicated and repaired by DNA polymerase γ. Its catalytic subunit is encoded by the POLG gene. The coding region of this gene contains 10 consecutive glutamine-encoding CAG codons. A polymorphism of the CAG microsatellite repeat in the POLG gene has recently been shown to be associated with unexplained male subfertility. The absence of one or both common alleles was more frequent in subfertile patients than in fertile controls [3.Rovio A.T. Marchington D.R. Donat S. et al.Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.Nat Genet. 2001; 29: 261-262Crossref PubMed Scopus (165) Google Scholar, 4.Jensen M. Leffers H. Petersen J.H. et al.Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility.Hum Rep. 2004; 19: 65-70Crossref PubMed Scopus (82) Google Scholar]. As disorders of the reproductive tract are risk factors for testicular neoplasia, we have studied CAG repeat length variation at the POLG gene locus in a group of patients with testicular tumours compared with an equivalent healthy Polish male population. Tumour samples from 49 consecutive testicular cancer patients treated in the Cancer Centre and Institute of Oncology, Warsaw, Poland, and control blood samples from 55 healthy men provided by the local blood bank were examined. To analyse the number of CAG repeats in the POLG gene, the second exon of this gene was amplified by PCR and sequenced directly using primers designed by Rovio et al. [3.Rovio A.T. Marchington D.R. Donat S. et al.Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.Nat Genet. 2001; 29: 261-262Crossref PubMed Scopus (165) Google Scholar]. Each PCR product was sequenced twice. Of the 55 healthy Polish men, 49 (89%) were homozygotes in the POLG gene with common 10 repeats in both alleles (wild-type), and six (11%) were 10/11, 10/12 and 10/9 heterozygotes in three, two and one individual, respectively. The frequency of wild-type homozygotes in the Polish healthy men population proved to be significantly different (P = 0.02 by the χ2 test) from that of other European populations (75%) [3.Rovio A.T. Marchington D.R. Donat S. et al.Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.Nat Genet. 2001; 29: 261-262Crossref PubMed Scopus (165) Google Scholar]. This is in accordance with a recent report that different populations were characterised by different numbers of CAG repeats [5.Erasmuson T. Sin I.L. Sin F.Y. Absence of association of androgen receptor trinucleotide expansion and poor semen quality.Int J Androl. 2003; 26: 46-51Crossref PubMed Scopus (19) Google Scholar]. Of 49 testicular tumour patients, 36 (74%) were wild-type homozygotes in CAG repeats in POLG gene and 13 (26%) lacked one or both wild-type alleles, with the 10/11 variant in 10 patients and the 10/12, 10/6 and 11/11 variants in one patient each. In the Polish population-specific number of CAG repeats, the polymorphic DNA polymerase γ gene was significantly more frequent in testicular cancer patients than in healthy men (26% versus 11%, P = 0.035 by the Fisher exact test). No significant differences in the pathological and clinical features of the tumours, in the course of the disease or in the response to treatment were found between carriers and non-carriers of polymorphic variants. Our data support the role of susceptibility genes in testicular cancer and indicate the polymorphic mitochondrial DNA polymerase γ gene as a likely candidate.