Abstract
Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15–40 in Western European populations1. The incidence of TGCT has risen dramatically over the last century2,3,4,5. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility6, previously diagnosed TGCT (ref. 7) and a family history of the disease8,9,10. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.
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References
Oliver, R.T. Atrophy, hormones, genes and viruses in aetiology germ cell tumours. Cancer Surv. 9, 263–286 (1990).
Zheng, T. et al. Continuing increase in incidence of germ-cell testis cancer in young adults: experience from Connecticut, USA, 1935–1992. Int. J. Cancer 65, 723–729 (1996).
Adami, H.O. et al. Testicular cancer in nine northern European countries. Int. J. Cancer 59, 33–38 (1994).
Bergstrom, R. et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon J. Natl Cancer Inst. 88, 727–733 (1996).
Wanderas, H.E., Tretli, S. & Fossa, S.D. Trends in incidence of testicular cancer in Norway 1955–1992. Eur. J. Cancer 31A, 2044–2048 (1995).
United Kingdom Testicular Cancer Study Group. Aetiology of testicular cancer, association with congenital abnormalities, age at puberty, infertility and exercise. BMJ 308, 1393–1339 (1994).
Bokemeyer, C. et al. Bilateral testicular tumours prevalence and clinical implications. Eur. J. Cancer 29A, 874–876 (1993).
Heimdal, K. et al. Familial testicular cancer in Norway and southern Sweden. Br. J. Cancer 73, 964–969 (1996).
Forman, D. et al. Familial testicular cancer: a report of the UK family register estimation of risk and HLA class I sib-pair analysis. Br. J. Cancer 65, 255–262 (1992).
Tollerud, D.J. et al. Familial testicular cancer and urogenital developmental anomalies. Cancer 55, 1849–1854 (1985).
The International Testicular Cancer Linkage Consortium. Candidate regions for testicular cancer susceptibility genes. APMIS 106, 64–70 (1998).
Leahy, M.G. et al. Candidate regions for a testicular cancer susceptibility gene. Hum. Mol. Genet. 4, 1551–1555 (1995).
Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).
Phelan, M.C., Stevenson, R.E., Collins, J.L. & Trent, H.E. Fragile X syndrome and neoplasia. Am. J. Med. Genet. 30, 77–82 (1988).
Hasle, H., Mellemgaard, A., Nielsen, J. & Hansen, J. Cancer incidence in men with Klinefelter syndrome. Br. J. Cancer 71, 416–420 (1995).
Hasle, H., Jacobsen, B.B., Asschenfeldt, P. & Andersen, K. Mediastinal germ cell tumour associated with Klinefelter syndrome. A report of case and review of the literature. Eur. J. Pediatr. 151, 735–739 (1992).
Okada, H. et al. Klinefelter's syndrome in the male infertility clinic. Hum. Reprod. 14, 946–952 (1999).
Reddy, S.R., Svec, F. & Richardson, P. Seminoma of the testis in a patient with 48,XXYY variant of Klinefelter's syndrome. South Med. J. 84, 773–775 (1991).
Carroll, P.R., Morse, M.J., Koduru, P.P. & Chaganti, R.S. Testicular germ cell tumor in patient with Klinefelter syndrome. Urology 31, 72–74 (1988).
Muller, J., Skakkebaek, N.E. & Ratcliffe, S.G. Quantified testicular histology in boys with sex chromosome Int. J. Androl. 18, 57–62 (1995).
Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996).
Xu, J. et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nature Genet. 20, 175–179 (1998).
Wooster, R. et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nature Genet. 2, 132–134 (1992).
Heimdal, K. et al. A segregation analysis of testicular cancer based on Norwegian and Swedish families. Br. J. Cancer 75, 1084–1087 (1997).
Nicholson, P.W. & Harland, S.J. Inheritance and testicular cancer. Br. J. Cancer 71, 421–426 (1995).
Broman, K.W., Murray, J.C., Sheffield, V.C., White, R.L. & Weber, J.L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–869 (1998).
Morton, N.E., Collins, A., Lawrence, S. & Shields, D.C. Algorithms for a location database. Ann. Hum. Genet. 56, 223–232 (1992).
Gyapay, G. et al. The 1993–94 Genethon human genetic linkage map. Nature Genet. 7, 246–339 (1994).
Acknowledgements
We thank the families and the clinicians, including T. Sandeman and K. Cox, for participation; J. Nicholls for collecting many of the ICR families; and E. Peacock for help in preparing the manuscript. We acknowledge the support of the Cancer Research Campaign, the New South Wales Cancer Council and the Imperial Cancer Research Fund.
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Rapley, E., Crockford, G., Teare, D. et al. Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours. Nat Genet 24, 197–200 (2000). https://doi.org/10.1038/72877
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DOI: https://doi.org/10.1038/72877
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