GENETIC RISK FACTORS FOR SPORADIC GERM CELL TESTICULAR TUMORS


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Abstract

Introduction.. Approximately 95% of all testicular cancers are testicular germ cell tumors (GCTTs), represented by seminoma and nonseminoma germ cell testicular cancer. There is a hypothesis that the formation of GCTTs begins in early embryogenesis being a part of testicular dysgenesis syndrome (TDS). Aim. To determine the role of genetic factors in the development of GCTTs. Materials and methods. We studied the frequency of alleles and genotypes KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876) and BAK1 (rs210138) in 97 fertile men (control), and 73 patients with GCTTs (34 seminoma and 39 nonseminoma). Results. GCTTs were statistically significantly associated with KITLG rs1508595 gene (p=0.0003 for allele G, p=0.0014 for genotype GG), and with rs995030 gene (p=0.0031 for genotype GG). When comparing patients with seminoma and control group, statistically significant differences were found for SPRY4 rs4624820 (p=0.0226 for the A and p=0.04 for the AA), for KITLG rs995030 (p=0.0375 for the G and p=0.0282 for GG), rs1508595 (p=0.0306 for G), for BAK1 rs210138 (p=0.0329 for the G and p=0.0219 for the GG). When comparing patients with nonseminoma and fertile men, statistically significant differences were found only for KITLG rs1508595 (p=0.0005 for the G and p=0.0021 for the GG). There was no statistically significant difference between the allele and genotype frequencies of the investigated genes from seminoma and nonseminoma GCTTs patients. However, these groups differed statistically significantly when genotype combinations of the three genes were investigated (p=0,029; OR 3,709 [1.147-11.99]). The combination of genotypes of the three genes was found to increase the risk of GCTTs by 6.5 times (p=0.0005; OR 6.526 [2.078-20.5], and the risk for seminoma was over 12-fold (p<0.0001; OR 12,68 [3,731-43,11]. Conclusion. A comprehensive study of genotypes associated with GCTTs in patients with manifested TDS can be used for risk stratification to identify and follow-up high-risk patients, develop approaches to family counseling and treatment, which is the basis for predictive medicine.

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About the authors

M. V Nemtsova

Russian Medical Academy of Postgraduate Education; I.M. Sechenov First Moscow State Medical University

Chief Researcher; Dr.Biol.Sci., Head of Laboratory of Medical Genetics Moscow, Russia

E. V Ivkin

Russian Medical Academy of Postgraduate Education; S.P Botkin City Clinical Hospital

Email: e.ivkin@hotmail.com
Junior Researcher at the Sector of Clinical Medicine; Urologist Moscow, Russia

A. A Tryakin

N.N. Blokhin Russian Cancer Research Center

PhD, Senior Researcher at the Department of Clinical Pharmacology and Chemotherapy; Member of the Working Group on the Development of RUSSCO Guidelines Moscow, Russia

V. V Rudenko

Research Centre of Medical Genetics

PhD, Senior Researcher Moscow, Russia

I. S Dantsev

Russian Medical Academy of Postgraduate Education

PhD Student at the Department of Medical Genetics with a Course of Prenatal Diagnosis Moscow, Russia

S. A Tyulyandin

N.N. Blokhin Russian Cancer Research Center

Dr.Med.Sci., Prof., Deputy Director; Head of the Department of Clinical Pharmacology Moscow, Russia

O. B Loran

Russian Medical Academy of Postgraduate Education

Academician of the RAS, Dr.Med.Sci., Prof., Head of the Department of Urology and Surgical Andrology Moscow, Russia

References

  1. Shanmugalingam T., Soultati A., Chowdhury S., Rudman S., Van Hemelrijck M. Global incidence and outcome of testicular cancer. Clin Epidemiol. 2013;5:417-427.
  2. Gilbert D., Raple E., Shipley J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nature Revies/ Cancer. 2011;11:278-288.
  3. Alanee S.R., Feldman D.R., Russo P., Konety B. Longterm mortality in patients with germ cell tumors: effect of primary cancer site on cause of death. Urol Oncol. 2014;32:26.e9-15.
  4. Oosterhuis J.W., Stoop H., Dohle G., Boellaard W., van Casteren N., Wolffenbuttel K., Looijenga L.H. A pathologist’s view on the testis biopsy. Int J Androl. 2011;34:e14-19.
  5. Skakkebaek N.E., Rajpert De Meyts E., Main K.M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001;16: 972-978.
  6. Honecker F., Stoop H., de Krijger R.R., Chris Lau Y.F., Bokemeyer C., Looijenga L.H. Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. J Pathol. 2004;203:849-857.
  7. Elzinga-Tinke J.E., Dohle G.R., Looijenga L.H.J. Etiology and early pathogenesis of malignant testicular germ cell tumors: towards possibilities for preinvasive diagnosis. Asian Journal of Andrology. 2015;17:381-393.
  8. Greene M.H., Kratz C.P., Mai P.L., Mueller C., Peters J.A., Bratslavsky G., Ling A., Choyke P.M., Premkumar A., Bracci J., Watkins R.J., McMaster M.L., Korde L.A. Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype. Endocrine-Related Cancer. 2010;17:09-121.
  9. Rapley E.A., Turnbull C., Al Olama A.A., Dermitzakis E.T., Linger R., Huddart R.A., Renwick A., Hughes D., Hines S., Seal S., Morrison J., Nsengimana J., Deloukas P.; UK Testicular Cancer Collaboration, Rahman N., Bishop D.T., Easton D.F., Stratton M.R. A genome-wide association study of testicular germ cell tumor. Nat Genet. 2009;41:807-810.
  10. Немцова М.В., Ивкин Е.В., Симонова О.А., Руденко В.В., Черных В.Б., Михайленко Д.С., Лоран О.Б. Полиморфизмы генов KITLG , SPRY4 и BAK1 у пациентов с герминогенными опухолями яичка и пациентов с бесплодием, обусловленным AZF-c делецией Y-хромосомы. Молекулярная биология. 2016;50(5)
  11. Chung C.C., Kanetsky P.A., Wang Z., Hildebrandt M.A., Koster R., Skotheim R.I., Kratz C.P., Turnbull C., Cortessis V.K., Bakken A.C., Bishop D.T., Cook M.B., Erickson R.L., Fossa S.D., Jacobs K.B., Korde L.A., Kraggerud S.M., Lothe R.A., Loud J.T., Rahman N., Skinner E.C., Thomas D.C., Wu X., Yeager M., Schumacher F.R., Greene M.H., Schwartz S.M., McGlynn K.A., Chanock S.J., Nathanson K.L. Meta analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet. 2013;45:680-685.
  12. Kanetsky P.A., Mitra N., Vardhanabhuti S., Li M., Vaughn D.J., Letrero R., Ciosek S.L., Doody D.R., Smith L.M., Weaver J., Albano A., Chen C., Starr J.R., Rader D.J., GodwinA.K., Reilly M.P., Hakonarson H., Schwartz S.M., Nathanson K.L. Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet. 2009;41:811-815.
  13. Turnbull C., Rapley E.A., Seal S., Pernet D., Renwick A., Hughes D., Ricketts M., Linger R., Nsengimana J., Deloukas P., Huddart R.A., Bishop D.T., Easton D.F., Stratton M.R., Rahman N.; UK Testicular Cancer Collaboration. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet. 2010;42:604-607.
  14. Turek P.J., Firpo M.T., Reijo Pera R.A. Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. Stem Cells. 2004;22:169-179
  15. Немцова М.В., Андреева Ю.Ю. Молекулярно-генетические и клинико-морфологические аспекты герминогенных опухолей яичка. Онкоурология. 2015;1:12-19.
  16. Ferli A., Pengo M., Pizzol D., Carraro U., Frigo A.C., Foresta C. Variants in KITLG predispose to testiculargerm cell cancer independently from spermatogenic function. Endocrine-Related Cancer. 2012;19:101-108.

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