Molecular Genetics of Testicular Germ Cell Tumor

Chapter
Part of the Cancer Genetics book series (CANGENETICS)

Abstract

The term “germ cell tumor” encompasses both male and female tumors that arise from germ cells with subtypes differentiated based on chromosomal changes and imprinting status. While five subtypes of germ cell tumors are described (Oosterhuis and Looijenga 2005) only three arise in the male testis – pediatric germ cell tumors (generally yolk sac), adolescent and adult testicular germ cell tumors, and spermatocytic seminoma. Of those, the most frequent are testicular germ cell tumors (TGCT), which are the most common cancer in men aged 20–40 (Ries et al. 2007). The incidence of TGCT in the United States has steadily risen from 3.2 in 100,000 in 1973 to 5.3 per 100,000 in 2004 (54%) (Ries et al. 2007), mainly limited to the white population. However, TGCT is still relatively rare, accounting for only 2% of male malignancies. In 2007, it is estimated that 7,920 men will be diagnosed with TGCT in the United States (Ries et al. 2007). TGCT has been described as “a model for a curable neoplasm,” since most patients will be cured and become long-term survivors.

Currently, the prognosis and treatment of patients with TGCT is based upon the histology of the tumor and stage at presentation. There are two major histologic subtypes of TGCT: seminomas and nonseminomas (also known as nonseminomatous germ cell tumor); each subtype constitutes ∼50% of TGCT diagnoses. Standard pathological analysis is used mainly to discriminate between seminoma and nonseminoma. However, immunohistochemical markers are a very useful adjunct to characterize the different subtypes of nonseminoma, embryonal carcinoma, teratoma, yolk sac tumor and choriocarcinoma, and seminoma. A panel of PLAP (placental-like alkaline phosphatase), Oct3/4, CD30, cytokeratin, AFP (alpha-fetoprotein), and HCG (human chorionic gonadotropin) can be used to identify the different types of TGCT. Seminomas are positive for PLAP and Oct3/4, embryonal carcinoma PLAP, Oct3/4, CD30 and cytokeratin, yolk sac tumor cytokeratin and AFP, and choriocarcinoma HCG.

Keywords

Migration Codon Imatinib Infertility Cytosine 

References

  1. Almstrup K, Hoei-Hansen CE, Wirkner U, Blake J, Schwager C, Ansorge W, Nielsen JE, Skakkebaek NE, Rajpert-De Meyts E, Leffers H (2004) Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling. Cancer Res 64:4736–4743PubMedGoogle Scholar
  2. Almstrup K, Hoei-Hansen CE, Nielsen JE, Wirkner U, Ansorge W, Skakkebaek NE, Rajpert-De Meyts E, Leffers H (2005) Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours. Br J Cancer 92:1934–1941PubMedGoogle Scholar
  3. Almstrup K, Leffers H, Lothe RA, Skakkebaek NE, Sonne SB, Nielsen JE, Rajpert-De Meyts E, Skotheim RI (2007) Improved gene expression signature of testicular carcinoma in situ. Int J Androl 30:292–302 discussion 303PubMedGoogle Scholar
  4. Beumer TL, Roepers-Gajadien HL, Gademan IS, Kal HB, De Rooij DG (2000) Involvement of the D-type cyclins in germ cell proliferation and differentiation in the mouse. Biol Reprod 63:1893–1898PubMedGoogle Scholar
  5. Biermann K, Goke F, Nettersheim D, Eckert D, Zhou H, Kahl P, Gashaw I, Schorle H, Buttner R (2007) c-KIT is frequently mutated in bilateral germ cell tumours and down-regulated during progression from intratubular germ cell neoplasia to seminoma. J Pathol 213:311–318PubMedGoogle Scholar
  6. Bignell G, Smith R, Hunter C, Stephens P, Davies H, Greenman C, Teague J, Butler A, Edkins S, Stevens C, O’Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Gillis AJ, Stoop HJ, van Gurp RJ, Oosterhuis JW, Looijenga LH, Futreal PA, Wooster R, Stratton MR (2006) Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer 45:42–46PubMedGoogle Scholar
  7. Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P (2006) Retinoid signaling determines germ cell fate in mice. Science 312:596–600PubMedGoogle Scholar
  8. Castrillon DH, Quade BJ, Wang TY, Quigley C, Crum CP (2000) The human VASA gene is specifically expressed in the germ cell lineage. Proc Natl Acad Sci U S A 97:9585–9590PubMedGoogle Scholar
  9. Choueiri TK, Stephenson AJ, Gilligan T, Klein EA (2007) Management of clinical stage I nonseminomatous germ cell testicular cancer. Urol Clin N Am 34:137–148 abstract viiiGoogle Scholar
  10. Clark AT, Rodriguez RT, Bodnar MS, Abeyta MJ, Cedars MI, Turek PJ, Firpo MT, Reijo Pera RA (2004) Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. Stem Cells 22:169–179PubMedGoogle Scholar
  11. Coffey J, Linger R, Pugh J, Dudakia D, Sokal M, Easton DF, Timothy Bishop D, Stratton M, Huddart R, Rapley EA (2008) Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes Chromosomes Cancer 47:34–42PubMedGoogle Scholar
  12. Cools M, van Aerde K, Kersemaekers AM, Boter M, Drop SL, Wolffenbuttel KP, Steyerberg EW, Oosterhuis JW, Looijenga LH (2005) Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab 90:5295–5303PubMedGoogle Scholar
  13. Cools M, Honecker F, Stoop H, Veltman JD, de Krijger RR, Steyerberg E, Wolffenbuttel KP, Bokemeyer C, Lau YF, Drop SL, Looijenga LH (2006) Maturation delay of germ cells in fetuses with trisomy 21 results in increased risk for the development of testicular germ cell tumors. Hum Pathol 37:101–111PubMedGoogle Scholar
  14. de Wit R, Fizazi K (2006) Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24:5482–5492PubMedGoogle Scholar
  15. Devouassoux-Shisheboran M, Mauduit C, Bouvier R, Berger F, Bouras M, Droz JP, Benahmed M (2001) Expression of hMLH1 and hMSH2 and assessment of microsatellite instability in testicular and mediastinal germ cell tumours. Mol Hum Reprod 7:1099–1105PubMedGoogle Scholar
  16. Di Vizio D, Cito L, Boccia A, Chieffi P, Insabato L, Pettinato G, Motti ML, Schepis F, D’Amico W, Fabiani F, Tavernise B, Venuta S, Fusco A, Viglietto G (2005) Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene 24:1882–1894PubMedGoogle Scholar
  17. Ezeh UI, Turek PJ, Reijo RA, Clark AT (2005) Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104:2255–2265PubMedGoogle Scholar
  18. Faulkner SW, Friedlander ML (2000) Microsatellite instability in germ cell tumors of the testis and ovary. Gynecol Oncol 79:38–43PubMedGoogle Scholar
  19. Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ (2008) Medical treatment of advanced testicular cancer. JAMA 299:672–684PubMedGoogle Scholar
  20. Forbes S, Clements J, Dawson E, Bamford S, Webb T, Dogan A, Flanagan A, Teague J, Wooster R, Futreal PA, Stratton MR (2006) COSMIC 2005. Br J Cancer 94:318–322PubMedGoogle Scholar
  21. Gillis AJ, Stoop HJ, Hersmus R, Oosterhuis JW, Sun Y, Chen C, Guenther S, Sherlock J, Veltman I, Baeten J, van der Spek PJ, de Alarcon P, Looijenga LH (2007) High-throughput microRNAome analysis in human germ cell tumours. J Pathol 213:319–328PubMedGoogle Scholar
  22. Goddard NC, McIntyre A, Summersgill B, Gilbert D, Kitazawa S, Shipley J (2007) KIT and RAS signaling pathways in testicular germ cell tumours: new data and a review of the literature. Int J Androl 30:337–348 discussion 349PubMedGoogle Scholar
  23. Hatakeyama S, Ohyama C, Minagawa S, Inoue T, Kakinuma H, Kyan A, Arai Y, Suga T, Nakayama J, Kato T, Habuchi T, Fukuda MN (2004) Functional correlation of trophinin expression with the malignancy of testicular germ cell tumor. Cancer Res 64:4257–4262PubMedGoogle Scholar
  24. Heimdal K, Lothe RA, Lystad S, Holm R, Fossa SD, Borresen AL (1993) No germline TP53 mutations detected in familial and bilateral testicular cancer. Genes Chromosomes Cancer 6:92–97PubMedGoogle Scholar
  25. Hoei-Hansen CE, Nielsen JE, Almstrup K, Hansen MA, Skakkebaek NE, Rajpert-Demeyts E, Leffers H (2004) Identification of genes differentially expressed in testes containing carcinoma in situ. Mol Hum Reprod 10:423–431PubMedGoogle Scholar
  26. Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E (2005) Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology 47:48–56PubMedGoogle Scholar
  27. Hoei-Hansen CE, Sehested A, Juhler M, Lau YF, Skakkebaek NE, Laursen H, Rajpert-De Meyts E (2006) New evidence for the origin of intracranial germ cell tumours from primordial germ cells: expression of pluripotency and cell differentiation markers. J Pathol 209:25–33PubMedGoogle Scholar
  28. Hofer MD, Browne TJ, He L, Skotheim RI, Lothe RA, Rubin MA (2005) Identification of two molecular groups of seminomas by using expression and tissue microarrays. Clin Cancer Res 11:5722–5729PubMedGoogle Scholar
  29. Honorio S, Agathanggelou A, Wernert N, Rothe M, Maher ER, Latif F (2003) 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 22:461–466PubMedGoogle Scholar
  30. Houldsworth J, Xiao H, Murty VV, Chen W, Ray B, Reuter VE, Bosl GJ, Chaganti RS (1998) Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. Oncogene 16:2345–2349PubMedGoogle Scholar
  31. Houldsworth J, Korkola JE, Bosl GJ, Chaganti RS (2006) Biology and genetics of adult male germ cell tumors. J Clin Oncol 24:5512–5518PubMedGoogle Scholar
  32. Huddart RA, Wooster R, Horwich A, Cooper CS (1995) Microsatellite instability in human testicular germ cell tumours. Br J Cancer 72:642–645PubMedGoogle Scholar
  33. International Germ Cell Cancer Collaborative Group (1997) International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594–603Google Scholar
  34. Jaruzelska J, Kotecki M, Kusz K, Spik A, Firpo M, Reijo Pera RA (2003) Conservation of a Pumilio–Nanos complex from Drosophila germ plasm to human germ cells. Dev Genes Evol 213:120–126Google Scholar
  35. Juric D, Sale S, Hromas RA, Yu R, Wang Y, Duran GE, Tibshirani R, Einhorn LH, Sikic BI (2005) Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures. Proc Natl Acad Sci U S A 102:17763–17768PubMedGoogle Scholar
  36. Kanetsky PA, Mitra N, Vardhanabhuti S, Li M, Vaughn DJ, Letrero R, Ciosek SL, Doody DR, Smith LM, Weaver J, Albano A, Chen C, Starr JR, Rader DJ, Godwin AK, Reilly MP, Hakonarson H, Schwartz SM, Nathanson KL (2009) Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet 41 (7): 811–5 Google Scholar
  37. Kemmer K, Corless CL, Fletcher JA, Mcgreevey L, Haley A, Griffith D, Cummings OW, Wait C, Town A, Heinrich MC (2004) KIT mutations are common in testicular seminomas. Am J Pathol 164:305–313PubMedGoogle Scholar
  38. Kerley-Hamilton JS, Pike AM, Li N, Direnzo J, Spinella MJ (2005) A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. Oncogene 24:6090–6100PubMedGoogle Scholar
  39. Kersemaekers AM, Mayer F, Molier M, van Weeren PC, Oosterhuis JW, Bokemeyer C, Looijenga LH (2002) Role of P53 and MDM2 in treatment response of human germ cell tumors [see comment]. J Clin Oncol 20:1551–1561PubMedGoogle Scholar
  40. Kitazono M, Sumizawa T, Takebayashi Y, Chen ZS, Furukawa T, Nagayama S, Tani A, Takao S, Aikou T, Akiyama S (1999) Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells [see comment]. J Natl Cancer Inst 91:1647–1653PubMedGoogle Scholar
  41. Kollmannsberger C, Mayer F, Pressler H, Koch S, Kanz L, Oosterhuis JW, Looijenga LH, Bokemeyer C (2002) Absence of c-KIT and members of the epidermal growth factor receptor family in refractory germ cell cancer [see comment]. Cancer 95:301–308PubMedGoogle Scholar
  42. Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE, Bosl GJ, Chaganti RS (2006) Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res 66:820–827PubMedGoogle Scholar
  43. Korkola JE, Heck S, Olshen AB, Reuter VE, Bosl GJ, Houldsworth J, Chaganti RS (2008) In vivo differentiation and genomic evolution in adult male germ cell tumors. Genes Chromosomes Cancer 47:43–55PubMedGoogle Scholar
  44. Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC (2006) Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A 103:2474–2479PubMedGoogle Scholar
  45. Koul S, Mckiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, Assaad AM, Mansukhani M, Reuter VE, Bosl GJ, Chaganti RS, Murty VV (2004) Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. Mol Cancer 3:16PubMedGoogle Scholar
  46. Kraggerud SM, Skotheim RI, Szymanska J, Eknaes M, Fossa SD, Stenwig AE, Peltomaki P, Lothe RA (2002) Genome profiles of familial/bilateral and sporadic testicular germ cell tumors. Genes Chromosomes Cancer 34:168–174PubMedGoogle Scholar
  47. Lind GE, Skotheim RI, Fraga MF, Abeler VM, Esteller M, Lothe RA (2006) Novel epigenetically deregulated genes in testicular cancer include homeobox genes and SCGB3A1 (HIN-1). J Pathol 210:441–449PubMedGoogle Scholar
  48. Lind GE, Skotheim RI, Lothe RA (2007) The epigenome of testicular germ cell tumors. APMIS 115:1147–1160PubMedGoogle Scholar
  49. Liu B, Nicolaides NC, Markowitz S, Willson JK, Parsons RE, Jen J, Papadopolous N, Peltomaki P, de la Chapelle A, Hamilton SR, Kinzler KW, Vogelstein B (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9:48–55PubMedGoogle Scholar
  50. Looijenga LH, de Leeuw H, van Oorschot M, van Gurp RJ, Stoop H, Gillis AJ, de Gouveia Brazao CA, Weber RF, Kirkels WJ, van Dijk T, von Lindern M, Valk P, Lajos G, Olah E, Nesland JM, Fossa SD, Oosterhuis JW (2003) Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors. Cancer Res 63:7674–7678PubMedGoogle Scholar
  51. Looijenga LH, Gillis AJ, Stoop H, Hersmus R, Oosterhuis JW (2007) Relevance of microRNAs in normal and malignant development, including human testicular germ cell tumours. Int J Androl 30:304–314 discussion 314–315PubMedGoogle Scholar
  52. Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, Pylkkanen L, Heimdal K, Andersen TI, Moller P, Rognum TO, Fossa SD, Haldorsen T, Langmark F, Brogger A, de la Chapelle A, Borresen A-L (1993) Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53:5849–5852PubMedGoogle Scholar
  53. Madani A, Kemmer K, Sweeney C, Corless C, Ulbright T, Heinrich M, Einhorn L (2003) Expression of KIT and epidermal growth factor receptor in chemotherapy refractory non-seminomatous germ-cell tumors. Ann Oncol 14:873–880PubMedGoogle Scholar
  54. Mandoky L, Geczi L, Bodrogi I, Toth J, Bak M (2003) Expression of HER-2/neu in testicular tumors. Anticancer Res 23:3447–3451PubMedGoogle Scholar
  55. Mandoky L, Geczi L, Bodrogi I, Toth J, Csuka O, Kasler M, Bak M (2004a) Clinical relevance of HER-2/neu expression in germ-cell testicular tumors. Anticancer Res 24:2219–2224PubMedGoogle Scholar
  56. Mandoky L, Geczi L, Doleschall Z, Bodrogi I, Csuka O, Kasler M, Bak M (2004b) Expression and prognostic value of the lung resistance-related protein (LRP) in germ cell testicular tumors. Anticancer Res 24:1097–1104PubMedGoogle Scholar
  57. Masters JR, Koberle B (2003) Curing metastatic cancer: lessons from testicular germ-cell tumours. Nat Rev Cancer 3:517–525PubMedGoogle Scholar
  58. Mauduit C, Hamamah S, Benahmed M (1999) Stem cell factor/c-kit system in spermatogenesis. Hum Reprod Update 5:535–545PubMedGoogle Scholar
  59. Mayer F, Gillis AJ, Dinjens W, Oosterhuis JW, Bokemeyer C, Looijenga LH (2002) Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment. Cancer Res 62:2758–2760PubMedGoogle Scholar
  60. Mayer F, Honecker F, Looijenga LH, Bokemeyer C (2003a) Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors. Ann Oncol 14:825–832PubMedGoogle Scholar
  61. Mayer F, Stoop H, Scheffer GL, Scheper R, Oosterhuis JW, Looijenga LH, Bokemeyer C (2003b) Molecular determinants of treatment response in human germ cell tumors. Clin Cancer Res 9:767–773PubMedGoogle Scholar
  62. Mazumdar M, Bacik J, Tickoo SK, Dobrzynski D, Donadio A, Bajorin D, Motzer R, Reuter V, Bosl GJ (2003) Cluster analysis of p53 and Ki67 expression, apoptosis, alpha-fetoprotein, and human chorionic gonadotrophin indicates a favorable prognostic subgroup within the embryonal carcinoma germ cell tumor. J Clin Oncol 21:2679–2688PubMedGoogle Scholar
  63. McIntyre A, Summersgill B, Grygalewicz B, Gillis AJ, Stoop J, van Gurp RJ, Dennis N, Fisher C, Huddart R, Cooper C, Clark J, Oosterhuis JW, Looijenga LH, Shipley J (2005a) Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Res 65:8085–8089PubMedGoogle Scholar
  64. Mcintyre A, Summersgill B, Spendlove HE, Huddart R, Houlston R, Shipley J (2005b) Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors. Neoplasia 7:1047–1052PubMedGoogle Scholar
  65. Moul JW, Theune SM, Chang EH (1992) Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization. Genes Chromosomes Cancer 5:109–118PubMedGoogle Scholar
  66. Murty VV, Chaganti RS (1998) A genetic perspective of male germ cell tumors. Semin Oncol 25:133–144PubMedGoogle Scholar
  67. Murty VV, Li RG, Mathew S, Reuter VE, Bronson DL, Bosl GJ, Chaganti RS (1994) Replication error-type genetic instability at 1q42–43 in human male germ cell tumors. Cancer Res 54:3983–3985PubMedGoogle Scholar
  68. Neill M, Warde P, Fleshner N (2007) Management of low-stage testicular seminoma. Urol Clin N Am 34:127–136 abstract vii–viiiGoogle Scholar
  69. Noce T, Okamoto-Ito S, Tsunekawa N (2001) Vasa homolog genes in mammalian germ cell development. Cell Struct Funct 26:131–136PubMedGoogle Scholar
  70. Nystrom-Lahti M, Parsons R, Sistonen P, Pylkkanen L, Aaltonen LA, Leach FS, Hamilton SR, Watson P, Bronson E, Fusaro R, Cavalieri J, Lynch J, Lanspa SJ, Smyrk T, Lynch P, Drouhard T, Kinzler KW, Vogelstein B, Lynch HT, de la Chapelle A, Peltomaki P (1994) Mismatch repair genes on chromosomes 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. Am J Hum Genet 55:659–665PubMedGoogle Scholar
  71. Olasz J, Mandoky L, Geczi L, Bodrogi I, Csuka O, Bak M (2005) Influence of hMLH1 methylation, mismatch repair deficiency and microsatellite instability on chemoresistance of testicular germ-cell tumors. Anticancer Res 25:4319–4324PubMedGoogle Scholar
  72. Olie RA, Looijenga LH, Boerrigter L, Top B, Rodenhuis S, Langeveld A, Mulder MP, Oosterhuis JW (1995) N- and KRAS mutations in primary testicular germ cell tumors: incidence and possible biological implications. Genes Chromosomes Cancer 12:110–116PubMedGoogle Scholar
  73. Oosterhuis JW, Looijenga LH (2005) Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer 5:210–222PubMedGoogle Scholar
  74. Palumbo C, van Roozendaal K, Gillis AJ, van Gurp RH, de Munnik H, Oosterhuis JW, van Zoelen EJ, Looijenga LH (2002) Expression of the PDGF alpha-receptor 1.5 kb transcript, OCT-4, and c-KIT in human normal and malignant tissues. Implications for the early diagnosis of testicular germ cell tumours and for our understanding of regulatory mechanisms. J Pathol 196:467–477PubMedGoogle Scholar
  75. Pectasides D, Nikolaou M, Pectasides E, Koumarianou A, Valavanis C, Economopoulos T (2008) Complete response after imatinib mesylate administration in a patient with chemoresistant stage IV seminoma. Anticancer Res 28 (4C):2317–20Google Scholar
  76. Pedersini R, Vattemi E, Mazzoleni G, Graiff C (2007) Complete response after treatment with imatinib in pretreated disseminated testicular seminoma with overexpression of c-KIT. Lancet Oncol 8 (11):1039–40Google Scholar
  77. Peltomaki P, Aaltonen L, Sistonen P, Pylkkanen L, Mecklin J-P, Jarvinen H, Green JS, Jass JR, Weber JL, Leach FS, Petersen GM, Hamilton SR, de la Chapelle A, Vogelstein B (1993a) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812PubMedGoogle Scholar
  78. Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, David L, Holm R, Ryberg D, Haugen A, Et AL (1993b) Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855PubMedGoogle Scholar
  79. Peng HQ, Hogg D, Malkin D, Bailey D, Gallie BL, Bulbul M, Jewett M, Buchanan J, Goss PE (1993) Mutations of the p53 gene do not occur in testis cancer. Cancer Res 53:3574–3578PubMedGoogle Scholar
  80. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28:622–629PubMedGoogle Scholar
  81. Port M, Schmelz HU, Stockinger M, Sparwasser C, Albers P, Pottek T, Abend M (2005) Gene expression profiling in seminoma and nonseminoma. J Clin Oncol 23:58–69PubMedGoogle Scholar
  82. Przygodzki RM, Hubbs AE, Zhao FQ, O’Leary TJ (2002) Primary mediastinal seminomas: evidence of single and multiple KIT mutations. Lab Invest 82:1369–1375PubMedGoogle Scholar
  83. Rajpert-De Meyts E, Jorgensen N, Brondum-Nielsen K, Muller J, Skakkebaek NE (1998) Developmental arrest of germ cells in the pathogenesis of germ cell neoplasia. APMIS 106:198–204 discussion 204–206PubMedGoogle Scholar
  84. Rajpert-De Meyts E, Bartkova J, Samson M, Hoei-Hansen CE, Frydelund-Larsen L, Bartek J, Skakkebaek NE (2003) The emerging phenotype of the testicular carcinoma in situ germ cell. APMIS 111:267–278 discussion 278–279PubMedGoogle Scholar
  85. Rao PH, Houldsworth J, Palanisamy N, Murty VV, Reuter VE, Motzer RJ, Bosl GJ, Chaganti RS (1998) Chromosomal amplification is associated with cisplatin resistance of human male germ cell tumors. Cancer Res 58:4260–4263PubMedGoogle Scholar
  86. Rapley EA, Hockley S, Warren W, Johnson L, Huddart R, Crockford G, Forman D, Leahy MG, Oliver DT, Tucker K, Friedlander M, Phillips KA, Hogg D, Jewett MA, Lohynska R, Daugaard G, Richard S, Heidenreich A, Geczi L, Bodrogi I, Olah E, Ormiston WJ, Daly PA, Looijenga LH, Guilford P, Aass N, Fossa SD, Heimdal K, Tjulandin SA, Liubchenko L, Stoll H, Weber W, Einhorn L, Weber BL, McMaster M, Greene MH, Bishop DT, Easton D, Stratton MR (2004) Somatic mutations of KIT in familial testicular germ cell tumours. Br J Cancer 90:2397–2401PubMedGoogle Scholar
  87. Rapley EA, Turnbull C, Al Olama AA, Dermitzakis ET, Linger R, Huddart RA, Renwick A, Hughes D, Hines S, Seal S, Morrison J, Nsengimana J, Deloukas P, Rahman N, Bishop DT, Easton DF, Stratton MR (2009) A genome-wide association study of testicular germ cell tumor. Nat Genet 41 (7):807–10Google Scholar
  88. Reijo RA, Dorfman DM, Slee R, Renshaw AA, Loughlin KR, Cooke H, Page DC (2000) DAZ family proteins exist throughout male germ cell development and transit from nucleus to cytoplasm at meiosis in humans and mice. Biol Reprod 63:1490–1496PubMedGoogle Scholar
  89. Ries LAG, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Horner MJ, Howlader N, Eisner MP, Reichman M, Edwards BK (2007) SEER cancer statistics review, 1975–2004. National Cancer Institute, Bethesda, MDGoogle Scholar
  90. Rodriguez E, Mathew S, Reuter V, Ilson DH, Bosl GJ, Chaganti RS (1992) Cytogenetic analysis of 124 prospectively ascertained male germ cell tumors. Cancer Res 52:2285–2291PubMedGoogle Scholar
  91. Rodriguez S, Jafer O, Goker H, Summersgill BM, Zafarana G, Gillis AJ, van Gurp RJ, Oosterhuis JW, Lu YJ, Huddart R, Cooper CS, Clark J, Looijenga LH, Shipley JM (2003) Expression profile of genes from 12p in testicular germ cell tumors of adolescents and adults associated with i(12p) and amplification at 12p11.2-p12.1. Oncogene 22:1880–1891PubMedGoogle Scholar
  92. Rosenberg C, van Gurp RJ, Geelen E, Oosterhuis JW, Looijenga LH (2000) Overrepresentation of the short arm of chromosome 12 is related to invasive growth of human testicular seminomas and nonseminomas. Oncogene 19:5858–5862PubMedGoogle Scholar
  93. Sakuma Y, Sakurai S, Oguni S, Hironaka M, Saito K (2003) Alterations of the c-kit gene in testicular germ cell tumors. Cancer Sci 94:486–491PubMedGoogle Scholar
  94. Satge D, Sasco AJ, Cure H, Leduc B, Sommelet D, Vekemans MJ (1997) An excess of testicular germ cell tumors in Down’s syndrome: three case reports and a review of the literature. Cancer 80:929–935PubMedGoogle Scholar
  95. Scheffer GL, Wijngaard PL, Flens MJ, Izquierdo MA, Slovak ML, Pinedo HM, Meijer CJ, Clevers HC, Scheper RJ (1995) The drug resistance-related protein LRP is the human major vault protein [see comment]. Nat Med 1:578–582PubMedGoogle Scholar
  96. Schenkman NS, Sesterhenn IA, Washington L, Tong YA, Weghorst CM, Buzard GS, Srivastava S, Moul JW (1995) Increased p53 protein does not correlate to p53 gene mutations in microdissected human testicular germ cell tumors. J Urol 154:617–621PubMedGoogle Scholar
  97. Schmoll HJ, Souchon R, Krege S, Albers P, Beyer J, Kollmannsberger C, Fossa SD, Skakkebaek NE, de Wit R, Fizazi K, Droz JP, Pizzocaro G, Daugaard G, de Mulder PH, Horwich A, Oliver T, Huddart R, Rosti G, Paz Ares L, Pont O, Hartmann JT, Aass N, Algaba F, Bamberg M, Bodrogi I, Bokemeyer C, Classen J, Clemm S, Culine S, de Wit M, Derigs HG, Dieckmann KP, Flasshove M, Garcia del Muro X, Gerl A, Germa-Lluch JR, Hartmann M, Heidenreich A, Hoeltl W, Joffe J, Jones W, Kaiser G, Klepp O, Kliesch S, Kisbenedek L, Koehrmann KU, Kuczyk M, Laguna MP, Leiva O, Loy V, Mason MD, Mead GM, Mueller RP, Nicolai N, Oosterhof GO, Pottek T, Rick O, Schmidberger H, Sedlmayer F, Siegert W, Studer U, Tjulandin S, von der Maase H, Walz P, Weinknecht S, Weissbach L, Winter E, Wittekind C (2004) European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 15:1377–1399PubMedGoogle Scholar
  98. Schweyer S, Soruri A, Meschter O, Heintze A, Zschunke F, Miosge N, Thelen P, Schlott T, Radzun HJ, Fayyazi A (2004) Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation. Br J Cancer 91:589–598PubMedGoogle Scholar
  99. Shuin T, Misaki H, Kubota Y, Yao M, Hosaka M (1994) Differential expression of protooncogenes in human germ cell tumors of the testis. Cancer 73:1721–1727PubMedGoogle Scholar
  100. Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, Mcginnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA (1996) Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384:470–474PubMedGoogle Scholar
  101. Skotheim RI, Monni O, Mousses S, Fossa SD, Kallioniemi OP, Lothe RA, Kallioniemi A (2002) New insights into testicular germ cell tumorigenesis from gene expression profiling. Cancer Res 62:2359–2364PubMedGoogle Scholar
  102. Skotheim RI, Lind GE, Monni O, Nesland JM, Abeler VM, Fossa SD, Duale N, Brunborg G, Kallioniemi O, Andrews PW, Lothe RA (2005) Differentiation of human embryonal carcinomas in vitro and in vivo reveals expression profiles relevant to normal development. Cancer Res 65:5588–5598PubMedGoogle Scholar
  103. Skotheim RI, Autio R, Lind GE, Kraggerud SM, Andrews PW, Monni O, Kallioniemi O, Lothe RA (2006) Novel genomic aberrations in testicular germ cell tumors by array-CGH, and associated gene expression changes. Cell Oncol 28:315–326PubMedGoogle Scholar
  104. Smiraglia DJ, Szymanska J, Kraggerud SM, Lothe RA, Peltomaki P, Plass C (2002) Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors. Oncogene 21:3909–3916PubMedGoogle Scholar
  105. Smith-Sorensen B, Lind GE, Skotheim RI, Fossa SD, Fodstad O, Stenwig AE, Jakobsen KS, Lothe RA (2002) Frequent promoter hypermethylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene in testicular cancer. Oncogene 21:8878–8884PubMedGoogle Scholar
  106. Sommerer F, Hengge UR, Markwarth A, Vomschloss S, Stolzenburg JU, Wittekind C, Tannapfel A (2005) Mutations of BRAF and RAS are rare events in germ cell tumours. Int J Cancer 113:329–335PubMedGoogle Scholar
  107. Tsuda M, Sasaoka Y, Kiso M, Abe K, Haraguchi S, Kobayashi S, Saga Y (2003) Conserved role of nanos proteins in germ cell development. Science 301:1239–1241PubMedGoogle Scholar
  108. van Gurp RJ, Oosterhuis JW, Kalscheuer V, Mariman EC, Looijenga LH (1994) Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors. J Natl Cancer Inst 86:1070–1075PubMedGoogle Scholar
  109. Velasco A, Riquelme E, Schultz M, Wistuba II, Villarroel L, Koh MS, Leach FS (2004) Microsatellite instability and loss of heterozygosity have distinct prognostic value for testicular germ cell tumor recurrence. Cancer Biol Ther 3:1152–1158 discussion 1159–1161PubMedGoogle Scholar
  110. von Eyben FE (2004) Chromosomes, genes, and development of testicular germ cell tumors. Cancer Genet Cytogenet 151:93–138PubMedGoogle Scholar
  111. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu Y-P, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, Nojima H, Looijenga LH, Agami R (2006) A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124:1169–1181PubMedGoogle Scholar
  112. Yabuta N, Okada N, Ito A, Hosomi T, Nishihara S, Sasayama Y, Fujimori A, Okuzaki D, Zhao H, Ikawa M, Okabe M, Nojima H (2007) Lats2 is an essential mitotic regulator required for the coordination of cell division. J Biol Chem 282:19259–19271PubMedGoogle Scholar
  113. Youngren KK, Coveney D, Peng X, Bhattacharya C, Schmidt LS, Nickerson ML, Lamb BT, Deng JM, Behringer RR, Capel B, Rubin EM, Nadeau JH, Matin A (2005) The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435:360–364PubMedGoogle Scholar
  114. Zafarana G, Grygalewicz B, Gillis AJ, Vissers LE, van de Vliet W, van Gurp RJ, Stoop H, Debiec-Rychter M, Oosterhuis JW, van Kessel AG, Schoenmakers EF, Looijenga LH, Veltman JA (2003) 12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH. Oncogene 22:7695–7701PubMedGoogle Scholar
  115. Zeeman AM, Stoop H, Boter M, Gillis AJ, Castrillon DH, Oosterhuis JW, Looijenga LH (2002) VASA is a specific marker for both normal and malignant human germ cells. Lab Invest 82:159–166PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Medicine, Division of Medical GeneticsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations