Genetic and Epigenetic Alterations in Testicular Tumors

Chapter
First Online:

Abstract

Molecular alterations in cancer are gaining increasing importance as indicators of therapeutic response and prognosis. Abnormality in multiple loci in the genetic architecture and epigenetic factors could play a role in development of testicular germ cell tumors. The only recurrent cytogenetic alteration detected in testicular germ cell tumors is the gain of the short arm of chromosome 12. However, no single high-susceptibility gene has yet been found to play a major role. Genetic alterations involving chromosomes and genes, and epigenetic alterations including methylation, chromatin remodeling, and microRNA regulation are discussed.

Keywords

Testis Germ cell tumors Genetic alterations Epigenetic Methylation Chromatin remodeling MicroRNA 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    McCluggage WG, Shanks JH, Arthur K, Banerjee SS. Cellular proliferation and nuclear ploidy assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell tumours. Histopathology. 1998;33(4):361–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Mosharafa AA, Foster RS, Bihrle R, Koch MO, Ulbright TM, Einhorn LH, et al. Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors? Cancer. 2003;98(4):753–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Sonne SB, Almstrup K, Dalgaard M, Juncker AS, Edsgard D, Ruban L, et al. Analysis of gene expression profiles of microdissected cell populations indicates that testicular carcinoma in situ is an arrested gonocyte. Cancer Res. 2009;69(12):5241–50.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Hemminki K, Li X. Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer. 2004;90(9):1765–70.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Lutke Holzik MF, Rapley EA, Hoekstra HJ, Sleijfer DT, Nolte IM, Sijmons RH. Genetic predisposition to testicular germ-cell tumours. Lancet Oncol. 2004;5(6):363–71.CrossRefPubMedGoogle Scholar
  6. 6.
    Kratzer SS, Ulbright TM, Talerman A, Srigley JR, Roth LM, Wahle GR, et al. Large cell calcifying Sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. Am J Surg Pathol. 1997;21(11):1271–80.CrossRefPubMedGoogle Scholar
  7. 7.
    von Eyben FE. Chromosomes, genes, and development of testicular germ cell tumors. Cancer Genet Cytogenet. 2004;151(2):93–138.CrossRefPubMedGoogle Scholar
  8. 8.
    Houldsworth J, Korkola JE, Bosl GJ, Chaganti RS. Biology and genetics of adult male germ cell tumors. J Clin Oncol. 2006;24(35):5512–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Mohamed GH, Gelfond JA, Nicolas MM, Brand TC, Sarvis JA, Leach RJ, et al. Genomic characterization of testis cancer: association of alterations with outcome of clinical stage 1 mixed germ cell nonseminomatous germ cell tumor of the testis. Urology. 2012;80(2):485 e1–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Ottesen AM, Skakkebaek NE, Lundsteen C, Leffers H, Larsen J, Rajpert-De Meyts E. High-resolution comparative genomic hybridization detects extra chromosome arm 12p material in most cases of carcinoma in situ adjacent to overt germ cell tumors, but not before the invasive tumor development. Genes Chromosomes Cancer. 2003;38(2):117–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Sheikine Y, Genega E, Melamed J, Lee P, Reuter VE, Ye H. Molecular genetics of testicular germ cell tumors. Am J Cancer Res. 2012;2(2):153–67.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Forbes S, Clements J, Dawson E, Bamford S, Webb T, Dogan A, et al. Cosmic 2005. Br J Cancer. 2006;94(2):318–22.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003;423(6942):825–37.CrossRefPubMedGoogle Scholar
  14. 14.
    Nathanson KL, Kanetsky PA, Hawes R, Vaughn DJ, Letrero R, Tucker K, et al. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet. 2005;77(6):1034–43.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Greene MH, Kratz CP, Mai PL, Mueller C, Peters JA, Bratslavsky G, et al. Familial testicular germ cell tumors in adults: 2010 summary of genetic risk factors and clinical phenotype. Endocr Relat Cancer. 2010;17(2):R109–21.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Rapley EA, Turnbull C, Al Olama AA, Dermitzakis ET, Linger R, Huddart RA, et al. A genome-wide association study of testicular germ cell tumor. Nat Genet. 2009;41(7):807–10.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, et al. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet. 2010;42(7):604–7.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Turnbull C, Rahman N. Genome-wide association studies provide new insights into the genetic basis of testicular germ-cell tumour. Int J Androl. 2011;34(4 Pt 2):e86–96; discussion e-7.CrossRefPubMedGoogle Scholar
  19. 19.
    Kanetsky PA, Mitra N, Vardhanabhuti S, Li M, Vaughn DJ, Letrero R, et al. Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet. 2009;41(7):811–5.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Boldajipour B, Raz E. What is left behind—quality control in germ cell migration. Sci STKE. 2007;2007(383):pe16.CrossRefPubMedGoogle Scholar
  21. 21.
    Yan W, Samson M, Jegou B, Toppari J. Bcl-w forms complexes with Bax and Bak, and elevated ratios of Bax/Bcl-w and Bak/Bcl-w correspond to spermatogonial and spermatocyte apoptosis in the testis. Mol Endocrinol. 2000;14(5):682–99.CrossRefPubMedGoogle Scholar
  22. 22.
    International HapMap C, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449(7164):851–61.CrossRefPubMedGoogle Scholar
  23. 23.
    Del-Mazo J, Brieno-Enriquez MA, Garcia-Lopez J, Lopez-Fernandez LA, De-Felici M. Endocrine disruptors, gene deregulation and male germ cell tumors. Int J Dev Biol. 2013;57(2–4):225–39.CrossRefPubMedGoogle Scholar
  24. 24.
    Okamoto K. Epigenetics: a way to understand the origin and biology of testicular germ cell tumors. Int J Urol. 2012;19(6):504–11.CrossRefPubMedGoogle Scholar
  25. 25.
    Wood L, Kollmannsberger C, Jewett M, Chung P, Hotte S, O’Malley M, et al. Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J. 2010;4(2):e19–38.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Ushida H, Kawakami T, Minami K, Chano T, Okabe H, Okada Y, et al. Methylation profile of DNA repetitive elements in human testicular germ cell tumor. Mol Carcinog. 2012;51(9):711–22.CrossRefPubMedGoogle Scholar
  27. 27.
    Okamoto K, Kawakami T. Epigenetic profile of testicular germ cell tumours. Int J Androl. 2007;30(4):385–92; discussion 92.CrossRefPubMedGoogle Scholar
  28. 28.
    Rosen A, Jayram G, Drazer M, Eggener SE. Global trends in testicular cancer incidence and mortality. Eur Urol. 2011;60(2):374–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Honorio S, Agathanggelou A, Wernert N, Rothe M, Maher ER, Latif F. Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. Oncogene. 2003;22(3):461–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Kempkensteffen C, Christoph F, Weikert S, Krause H, Kollermann J, Schostak M, et al. Epigenetic silencing of the putative tumor suppressor gene testisin in testicular germ cell tumors. J Cancer Res Clin Oncol. 2006;132(12):765–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Kawakami T, Okamoto K, Sugihara H, Hattori T, Reeve AE, Ogawa O, et al. The roles of supernumerical X chromosomes and XIST expression in testicular germ cell tumors. J Urol. 2003;169(4):1546–52.CrossRefPubMedGoogle Scholar
  32. 32.
    Kerjean A, Dupont JM, Vasseur C, Le Tessier D, Cuisset L, Paldi A, et al. Establishment of the paternal methylation imprint of the human H19 and MEST/PEG1 genes during spermatogenesis. Hum Mol Genet. 2000;9(14):2183–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Ancelin K, Lange UC, Hajkova P, Schneider R, Bannister AJ, Kouzarides T, et al. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat Cell Biol. 2006;8(6): 623–30.CrossRefPubMedGoogle Scholar
  34. 34.
    Eckert D, Biermann K, Nettersheim D, Gillis AJ, Steger K, Jack HM, et al. Expression of BLIMP1/PRMT5 and concurrent histone H2A/H4 arginine 3 dimethylation in fetal germ cells, CIS/IGCNU and germ cell tumors. BMC Dev Biol. 2008;8:106.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Hayashi K, Chuva de Sousa Lopes SM, Kaneda M, Tang F, Hajkova P, Lao K, et al. MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS One. 2008;3(3):e1738.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006;124(6): 1169–81.CrossRefPubMedGoogle Scholar
  37. 37.
    Novotny GW, Nielsen JE, Sonne SB, Skakkebaek NE, Rajpert-De Meyts E, Leffers H. Analysis of gene expression in normal and neoplastic human testis: new roles of RNA. Int J Androl. 2007;30(4):316–26; discussion 26–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Palmer RD, Murray MJ, Saini HK, van Dongen S, Abreu-Goodger C, Muralidhar B, et al. Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets. Cancer Res. 2010;70(7):2911–23.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Gillis AJ, Stoop HJ, Hersmus R, Oosterhuis JW, Sun Y, Chen C, et al. High-throughput microRNAome analysis in human germ cell tumours. J Pathol. 2007;213(3):319–28.CrossRefPubMedGoogle Scholar
  40. 40.
    Juliano C, Wang J, Lin H. Uniting germline and stem cells: the function of Piwi proteins and the piRNA pathway in diverse organisms. Annu Rev Genet. 2011;45:447–69.CrossRefPubMedGoogle Scholar
  41. 41.
    Ferreira HJ, Heyn H, Garcia Del Muro X, Vidal A, Larriba S, Munoz C, et al. Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis. Epigenetics. 2013;9(1):113–8.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of PathologyCleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine InstituteClevelandUSA

Personalised recommendations