Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development

Seminars in Cell and Developmental Biology

Volumn 45, Issue , 2015, Pages 124-137

  Jørgensen, Anne ^a   Lindhardt Johansen, Marie ^a   Juul, Anders ^a   Skakkebaek, Niels E ^a   Main, Katharina M ^a   Rajpert De Meyts, Ewa ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

Carcinoma in situ germ cell neoplasia in situ; DSD; Germ cell neoplasms; Gonadal development; Sex differentiation; Testicular dysgenesis syndrome

Indexed keywords

CANCER RISK; CELL MATURATION; DISEASE ASSOCIATION; DISORDER OF SEX DEVELOPMENT; DNA POLYMORPHISM; ENVIRONMENTAL FACTOR; GERM CELL; GERM CELL TUMOR; GONAD DEVELOPMENT; GONADAL DYSGENESIS; GONADOBLASTOMA; HISTOPATHOLOGY; HUMAN; MEIOSIS; OVARY DEVELOPMENT; PATHOGENESIS; PHENOTYPE; REVIEW; RISK ASSESSMENT; SEX; SEX DIFFERENCE; SEX DIFFERENTIATION; TESTIS DEVELOPMENT; Y CHROMOSOME; ANIMAL; CARCINOGENESIS; GENETICS; GROWTH, DEVELOPMENT AND AGING; MALE; NEOPLASM; PATHOLOGY; PHYSIOLOGY; TESTIS; TESTIS TUMOR;

ANIMALS; CARCINOGENESIS; GERM CELLS; GONADAL DYSGENESIS; HUMANS; MALE; NEOPLASMS, GERM CELL AND EMBRYONAL; TESTICULAR NEOPLASMS; TESTIS;

EID: 84949220465     PISSN: 10849521     EISSN: 10963634     Source Type: Journal    
DOI: 10.1016/j.semcdb.2015.09.013     Document Type: Review

References (155)

1. Hughes I.A., Houk C., Ahmed S.F., Lee P.A. Consensus statement on management of intersex disorders. Arch. Dis. Child. 2006, 91(7):554-563. LWPES Consensus Group; ESPE Consensus Group.
2. Hoei-Hansen C.E., Nielsen J.E., Almstrup K., Sonne S.B., Graem N., Skakkebaek N.E., Leffers H., Rajpert-De Meyts E. Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors. Clin. Cancer Res. 2004, 10(24):8521-8530.
3. Skakkebaek N.E., Rajpert-de M.E., Main KM: Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod. 2001, 16:972-978.
4. Juul A., Almstrup K., Andersson A.M., Jensen T.K., Jørgensen N., Main K.M., Rajpert-De Meyts E., Toppari J., Skakkebæk N.E. Possible fetal determinants of male infertility. Nat. Rev. Endocrinol. 2014, 10(9):553-562.
5. Bashamboo A., McElreavey K. Gene mutations associated with anomalies of human gonad formation. Sex Dev. 2013, 7:126-146.
6. Mendonca B.B., Arnhold I.J.P., Domenice S., Costa E.M.F. 46,XY disorders of sexual development. Endotext [Internet] January 2013, MDText.com, Inc. 2000-2013, South Dartmouth, MA, Available from: http://www.ncbi.nlm.nih.gov/books/NBK279170/. L.J. De Groot, P. Beck-Peccoz, G. Chrousos, K. Dungan, A. Grossman, J.M. Hershman, C. Koch, R. McLachlan, M. New, R. Rebar, F. Singer, A. Vinik, M.O. Weickert (Eds.).
7. Ono M., Harley V.R. Disorders of sex development: new genes, new concepts. Nat. Rev. Endocrinol. 2013, 9(2):79-91.
8. Arboleda V.A., Sandberg D.E., Vilain E. DSDs: genetics, underlying pathologies and psychosexual differentiation. Nat. Rev. Endocrinol. 2014, 10(10):603-615.
9. Skakkebaek N.E., Holm M., Hoei-Hansen C., Jørgensen N., Rajpert-De Meyts E. Association between testicular dysgenesis syndrome (TDS) and testicular neoplasia: evidence from 20 adult patients with signs of maldevelopment of the testis. APMIS 2003, 111(1):1-9.
10. Guminska A., Oszukowska E., Kuzanski W., Sosnowski M., Wolski J.K., Walczak-Jedrzejowska R., Marchlewska K., Niedzielski J., Kula K., Slowikowska-Hilczer J. Less advanced testicular dysgenesis is associated by a higher prevalence of germ cell neoplasia. Int. J. Androl. 2010, 33(1):e153-e162.
11. Znaor A., Lortet-Tieulent J., Jemal A., Bray F. International variations and trends in testicular cancer incidence and mortality. Eur. Urol. 2014, 65:1095-1106.
12. Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum. Reprod. Update 2006, 12(3):303-323.
13. Looijenga L.H., Van Agthoven T., Biermann K. Development of malignant germ cells - the genvironmental hypothesis. Int. J. Dev. Biol. 2013, 57(2-4):241-253.
14. Gkountela S., Li Z., Vincent J.J., Zhang K.X., Chen A., Pellegrini M., Clark A.T. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat. Cell. Biol. 2013, 15(1):113-122.
15. Barrios F., Irie N., Surani M.A. Perceiving signals, building networks, reprogramming germ cell fate. Int. J. Dev. Biol. 2013, 57(2-4):123-132.
16. Tang W.W., Dietmann S., Irie N., Leitch H.G., Floros V.I., Bradshaw C.R., Hackett J.A., Chinnery P.F., Surani M.A. A unique gene regulatory network resets the human germline epigenome for development. Cell 2015, 161(6):1453-1467.
17. Møllgård K., Jespersen A., Lutterodt M.C., Yding Andersen C., Høyer P.E., Byskov A.G. Human primordial germ cells migrate along nerve fibers and Schwann cells from the dorsal hind gut mesentery to the gonadal ridge. Mol. Hum. Reprod. 2010, 16(9):621-631.
18. Mamsen L.S., Brøchner C.B., Byskov A.G., Møllgard K. The migration and loss of human primordial germ stem cells from the hind gut epithelium towards the gonadal ridge. Int. J. Dev. Biol. 2012, 56(10-12):771-778.
19. Sinclair A.H., Berta P., Palmer M.S., Hawkins J.R., Griffiths B.L., Smith M.J., Foster J.W., Frischauf A.M., Lovell-Badge R., Goodfellow P.N. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990, 346(6281):240-244.
20. Berta P., Hawkins J.R., Sinclair A.H., Taylor A., Griffiths B.L., Goodfellow P.N., Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature 1990, 348(6300):448-450.
21. Hanley N.A., Hagan D.M., Clement-Jones M., Ball S.G., Strachan T., Salas-Cortés L., McElreavey K., Lindsay S., Robson S., Bullen P., Ostrer H., Wilson D.I. SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech. Dev. 2000, 91(1-2):403-407.
22. Harley V.R., Jackson D.I., Hextall P.J., Hawkins J.R., Berkovitz G.D., Sockanathan S., Lovell-Badge R., Goodfellow P.N. DNA binding activity of recombinant SRY from normal males and XY females. Science 1992, 255(5043):453-456.
23. Hawkins J.R., Taylor A., Berta P., Levilliers J., Van der Auwera B., Goodfellow P.N. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum. Genet. 1992, 88(4):471-474.
24. Ostrer H., Huang H.Y., Masch R.J., Shapiro E. A cellular study of human testis development. Sex Dev. 2007, 1(5):286-292.
25. Kalfa N., Fellous M., Boizet-Bonhoure B., Patte C., Duvillard P., Pienkowski C., Jaubert F., Ecochard A., Sultan C. Aberrant expression of ovary determining gene FOXL2 in the testis and juvenile granulosa cell tumor in children. J. Urol. 2008, 180(4 Suppl):1810-1813.
26. Koopman P., Gubbay J., Vivian N., Goodfellow P., Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry. Nature 1991, 351(6322):117-121.
27. Jørgensen A., Nielsen J.E., Perlman S., Lundvall L., Mitchell R.T., Juul A., Rajpert-De Meyts E. Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development. Hum. Reprod. 2015, 30:2351-2363. 10.1093/humrep/dev194.
28. O'Shaughnessy P.J., Baker P.J., Monteiro A., Cassie S., Bhattacharya S., Fowler P.A. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. J. Clin. Endocrinol. Metab. 2007, 92(12):4792-4801.
29. Rajpert-De Meyts E., Jørgensen N., Graem N., Müller J., Cate R.L., Skakkebaek N.E. Expression of anti-Müllerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. J. Clin. Endocrinol. Metab. 1999, 84(10):3836-3844.
30. Gaskell T.L., Esnal A., Robinson L.L., Anderson R.A., Saunders P.T. Immunohistochemical profiling of germ cells within the human fetal testis: identification of three subpopulations. Biol. Reprod. 2004, 71(6):2012-2021.
31. Josso N., Rey R., Picard J.Y. Testicular anti-Müllerian hormone: clinical applications in DSD. Semin Reprod. Med. 2012, 30(5):364-373.
32. Siiteri P.K., Wilson J.D. Testosterone formation and metabolism during male sexual differentiation in the human embryo. J. Clin. Endocrinol. Metab. 1974, 38(1):113-125.
33. Huhtaniemi I., Pelliniemi L.J. Fetal Leydig cells: cellular origin, morphology, life span, and special functional features. Proc. Soc. Exp. Biol. Med. 1992, 201(2):125-140.
34. O'Shaughnessy P.J., Fowler P.A. Endocrinology of the mammalian fetal testis. Reproduction 2011, 141(1):37-46.
35. Robinson L.L., Gaskell T.L., Saunders P.T., Anderson R.A. Germ cell specific expression of c-kit in the human fetal gonad. Mol. Hum. Reprod. 2001, 7(9):845-852.
36. Rajpert-De Meyts E., Hanstein R., Jørgensen N., Graem N., Vogt P.H., Skakkebaek N.E. Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads. Hum. Reprod. 2004, 19(6):1338-1344.
37. Hoei-Hansen C.E., Almstrup K., Nielsen J.E., Brask Sonne S., Graem N., Skakkebaek N.E., Leffers H., Rajpert-De Meyts E. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology 2005, 47(1):48-56.
38. Stoop H., Honecker F., Cools M., de Krijger R., Bokemeyer C., Looijenga L.H. Differentiation and development of human female germ cells during prenatal gonadogenesis: an immunohistochemical study. Hum. Reprod. 2005, 20(6):1466-1476.
39. Bendsen E., Byskov A.G., Laursen S.B., Larsen H.P., Andersen C.Y., Westergaard L.G. Number of germ cells and somatic cells in human fetal testes during the first weeks after sex differentiation. Hum. Reprod. 2003, 18(1):13-18.
40. 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(3):849-857.
41. Pauls K., Schorle H., Jeske W., Brehm R., Steger K., Wernert N., Buttner R., Zhou H. Spatial expression of germ cell markers during maturation of human fetal male gonads: an immunohistochemical study. Hum. Reprod. 2006, 21:397-404.
42. Ewen K.A., Olesen I.A., Winge S.B., Nielsen A.R., Nielsen J.E., Graem N., Juul A., Rajpert-De Meyts E. Expression of FGFR3 during human testis development and in germ cell-derived tumours of young adults. Int. J. Dev. Biol. 2013, 57:141-151.
43. Culty M. Gonocytes from the fifties to the present: is there a reason to change the name?. Biol. Reprod. 2013, 89(2):46.
44. Jørgensen N., Giwercman A., Müller J., Skakkebaek N.E. Immunohistochemical markers of carcinoma in situ of the testis also expressed in normal infantile germ cells. Histopathology 1993, 22(4):373-378.
45. Yao H.H., Matzuk M.M., Jorgez C.J., Menke D.B., Page D.C., Swain A., Capel B. Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis. Dev. Dyn. 2004, 230(2):210-215.
46. Parma P., Radi O., Vidal V., Chaboissier M.C., Dellambra E., Valentini S., Guerra L., Schedl A., Camerino G. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat. Genet. 2006, 38(11):1304-1309.
47. Chassot A.A., Ranc F., Gregoire E.P., Roepers-Gajadien H.L., Taketo M.M., Camerino G., de Rooij D.G., Schedl A., Chaboissier M.C. Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum. Mol. Genet. 2008, 17(9):1264-1277.
48. Ottolenghi C., Pelosi E., Tran J., Colombino M., Douglass E., Nedorezov T., Cao A., Forabosco A., Schlessinger D. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum. Mol. Genet. 2007, 16(23):2795-2804.
49. Bendsen E., Byskov A.G., Andersen C.Y., Westergaard L.G. Number of germ cells and somatic cells in human fetal ovaries during the first weeks after sex differentiation. Hum. Reprod. 2006, 21(1):30-35.
50. Baker T.G. A quantitative and cytological study of germ cells in human ovaries. Proc. R. Soc. Lond. B: Biol. Sci. 1963, 158:417-433.
51. Duffin K., Bayne R.A., Childs A.J., Collins C., Anderson R.A. The forkhead transcription factor FOXL2 is expressed in somatic cells of the human ovaryprior to follicle formation. Mol. Hum. Reprod. 2009, 15:771-777.
52. Eddie S.L., Childs A.J., Kinnell H.L., Brown P., Jabbour H.N., Anderson R.A. Prokineticin ligands and receptors are expressed in the human fetal ovary and regulate germ cell expression of COX2. J. Clin. Endocrinol. Metab. 2015, 100:E1197-E1205.
53. Martins da Silva S.J., Bayne R.A., Cambray N., Hartley P.S., McNeilly A.S., Anderson R.A. Expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation. Dev. Biol. 2004, 266(2):334-345.
54. Rabinovici J., Jaffe R.B. Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads. Endocr. Rev. 1990, 11(4):532-557.
55. Albamonte M.S., Willis M.A., Albamonte M.I., Jensen F., Espinosa M.B., Vitullo A.D. The developing human ovary: immunohistochemical analysis of germ-cell-specific VASA protein, BCL-2/BAX expression balance and apoptosis. Hum. Reprod. 2008, 23:1895-1901.
56. Hartshorne G.M., Lyrakou S., Hamoda H., Oloto E., Ghafari F. Oogenesis and cell death in human prenatal ovaries: what are the criteria for oocyte selection?. Mol. Hum. Reprod. 2009, 15(12):805-819.
57. Sforza C., Vizzotto L., Ferrario V.F., Forabosco A. Position of follicles in normal human ovary during definitive histogenesis. Early Hum. Dev. 2003, 74(1):27-35.
58. Fulton N., Martins da Silva S.J., Bayne R.A., Anderson R.A. Germ cell proliferation and apoptosis in the developing human ovary. J. Clin. Endocrinol. Metab. 2005, 90(8):4664-4670.
59. Abir R., Orvieto R., Dicker D., Zukerman Z., Barnett M., Fisch B. Preliminary studies on apoptosis in human fetal ovaries. Fertil. Steril. 2002, 78(2):259-264.
60. Maheshwari A., Fowler P.A. Primordial follicular assembly in humans-revisited. Zygote 2008, 16(4):285-296.
61. Modi D.N., Sane S., Bhartiya D. Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol. Hum. Reprod. 2003, 9(4):219-225.
62. Singh R.P., Carr D.H. The anatomy and histology of XO human embryos and fetuses. Anat. Rec. 1966, 155:369-383.
63. Weiss L. Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner's syndrome. J. Med. Genet. 1971, 8(4):540-544.
64. Jørgensen A., Rajpert-De Meyts E. Regulation of meiotic entry and gonadal sex differentiation in the human: normal and disrupted signaling. Biomol. Concepts 2014, 5(4):331-341.
65. Le Bouffant R., Guerquin M.J., Duquenne C., Frydman N., Coffigny H., Rouiller-Fabre V., Frydman R., Habert R., Livera G. Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. Hum. Reprod. 2010, 25(10):2579-2590.
66. Childs A.J., Cowan G., Kinnell H.L., Anderson R.A., Saunders P.T. Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. PLoS ONE 2011, 6(6):e20249.
67. Houmard B., Small C., Yang L., Naluai-Cecchini T., Cheng E., Hassold T., Griswold M. Global gene expression in the human fetal testis and ovary. Biol. Reprod. 2009, 81(2):438-443.
68. Gondos B., Westergaard L., Byskov A.G. Initiation of oogenesis in the human fetal ovary: ultrastructural and squash preparation study. Am. J. Obstet. Gynecol. 1986, 155(1):189-195.
69. Anderson R.A., Fulton N., Cowan G., Coutts S., Saunders P.T. Conserved and divergent patterns of expression of DAZL, VASA and OCT4 in the germ cells of the human fetal ovary and testis. BMC Dev. Biol. 2007, 7:136.
70. Hilscher W. The genetic control and germ cell kinetics of the female and male germ line in mammals including man. Hum. Reprod. 1991, 6(10):1416-1425.
71. Fowler P.A., Flannigan S., Mathers A., Gillanders K., Lea R.G., Wood M.J., Maheshwari A., Bhattacharya S., Collie-Duguid E.S., Baker P.J., Monteiro A., O'Shaughnessy P.J. Gene expression analysis of human fetal ovarian primordial follicle formation. J. Clin. Endocrinol. Metab. 2009, 94(4):1427-1435.
72. Kerr C.L., Hill C.M., Blumenthal P.D., Gearhart J.D. Expression of pluripotent stem cell markers in the human fetal ovary. Hum. Reprod. 2008, 23(3):589-599.
73. Byskov A.G., Høyer P.E., Yding Andersen C., Kristensen S.G., Jespersen A., Møllgård K. No evidence for the presence of oogonia in the human ovary after their final clearance during the first two years of life. Hum. Reprod. 2011, 26(8):2129-2239.
74. Jørgensen A., Nielsen J.E., Jensen M.B., Græm N., Rajpert-De Meyts E. Analysis of meiosis regulators in human gonads: a sexually dimorphic spatio-temporal expression pattern suggests involvement of DMRT1 in meiotic entry. Mol. Hum. Reprod. 2012, 18(11):523-534.
75. Lambrot R., Coffigny H., Pairault C., Donnadieu A.C., Frydman R., Habert R., Rouiller-Fabre V. Use of organ culture to study the human fetal testis development: effect of retinoic acid. J. Clin. Endocrinol. Metab. 2006, 91(7):2696-2703.
76. Suzuki A., Saga Y. Nanos2 suppresses meiosis and promotes male germ cell differentiation. Genes Dev. 2008, 22(4):430-435.
77. Matson C.K., Murphy M.W., Griswold M.D., Yoshida S., Bardwell V.J., Zarkower D. The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Dev. Cell 2010, 19:612-624.
78. Moniot B., Berta P., Scherer G., Südbeck P., Poulat F. Male specific expression suggests role of DMRT1 in human sex determination. Mech. Dev. 2000, 91(1-2):323-325.
79. Barrios F., Filipponi D., Pellegrini M., Paronetto M.P., Di Siena S., Geremia R., Rossi P., De Felici M., Jannini E.A., Dolci S. Opposing effects of retinoic acid and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells. J. Cell. Sci. 2010, 123(Pt 6):871-880.
80. Bowles J., Feng C.W., Spiller C., Davidson T.L., Jackson A., Koopman P. FGF9 suppresses meiosis and promotes male germ cell fate in mice. Dev. Cell 2010, 19(3):440-449.
81. Souquet B., Tourpin S., Messiaen S., Moison D., Habert R., Livera G. Nodal signaling regulates the entry into meiosis in fetal germ cells. Endocrinology 2012, 153(5):2466-2473.
82. Spiller C.M., Feng C.W., Jackson A., Gillis A.J., Rolland A.D., Looijenga L.H., Koopman P., Bowles J. Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. Development 2012, 139(22):4123-4132.
83. Oosterhuis J.W., Looijenga L.H. Testicular germ-cell tumours in a broader perspective. Nat. Rev. Cancer 2005, 5:210-222.
84. Atlas of Tumor Pathology. Tumors of the Testis, Adnexa, Spermatic cord, and Scrotum 1999, 1-385. Armed Forces Institute of Pathology, Washington, DC, USA. T.M. Ulbright, M.B. Amin, R.H. Young (Eds.).
85. Kraggerud S.M., Hoei-Hansen C.E., Alagaratnam S., Skotheim R.I., Abeler V.M., Rajpert-De Meyts E., Lothe R.A. Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis. Endocr. Rev. 2013, 34(3):339-376.
86. Skakkebaek N.E. Possible carcinoma-in-situ of the testis. Lancet 1972, 2:516-517.
87. Loy V., Dieckmann K.P. Carcinoma in situ of the testis: intratubular germ cell neoplasia or testicular intraepithelial neoplasia?. Hum. Pathol. 1990, 21(4):457-458.
88. Ulbright T.M., Amin M.B., Balzer B., Berney D., Epstein J.I., Guo C., Idrees M.T., Looijenga L., Paner G., Rajpert-De Meyts E., Skakkebæk N.E., Tickoo S.K., Yilmaz A., Oosterhuis J.W. Germ cell tumours. WHO Classification of Tumours of the Urinary System and Male Genital Organs, 2016, IARC Press, Lyon. 4th edition. H. Moch, P.A. Humphrey, V.E. Reuter, T.M. Ulbright (Eds.).
89. Skakkebaek N.E., Berthelsen J.G., Giwercman A., Müller J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int. J. Androl. 1987, 10(1):19-28.
90. Berthelsen J.G., Skakkebaek N.E., von der Maase H., Sørensen B.L., Mogensen P. Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. Br. Med. J. 1982, 285:1683-1686.
91. Dieckmann K.P., Loy V. Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J. Clin. Oncol. 1996, 14:3126-3132.
92. Looijenga L.H., Stoop H., de Leeuw H.P., de Gouveia Brazao C.A., Gillis A.J., van Roozendaal K.E., van Zoelen E.J., Weber R.F., Wolffenbuttel K.P., van Dekken H., Honecker F., Bokemeyer C., Perlman E.J., Schneider D.T., Kononen J., Sauter G., Oosterhuis J.W. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003, 63(9):2244-2250.
93. Almstrup K., Hoei-Hansen C.E., Wirkner U., Blake J., Schwager C., Ansorge W., Nielsen J.E., Skakkebaek N.E., Rajpert-De Meyts E., Leffers H. Embryonic stem cell-like features of testicular carcinoma in situ revealed by genome-wide gene expression profiling. Cancer Res. 2004, 64:4736-4743.
94. Sonne S.B., Almstrup K., Dalgaard M., Juncker A.S., Edsgard D., Ruban L., Harrison N.J., Schwager C., Abdollahi A., Huber P.E., Brunak S., Gjerdrum L.M., Moore H.D., Andrews P.W., Skakkebaek N.E., Rajpert-De Meyts E., Leffers H. Analysis of gene expression profiles of microdissected cell populations indicates that testicular carcinoma in situ is an arrested gonocyte. Cancer Res. 2009, 69(12):5241-5250.
95. Müller J., Skakkebaek N.E. Testicular carcinoma in situ in children with the androgen insensitivity (testicular feminisation) syndrome. Br. Med. 1984, 12(288(6428)):1419-1420.
96. Müller J., Skakkebaek N.E., Ritzén M., Plöen L., Petersen K.E. Carcinoma in situ of the testis in children with 45,X/46,XY gonadal dysgenesis. J. Pediatr. 1985, 106(3):431-436.
97. Ramani P., Yeung C.K., Habeebu S.S. Testicular intratubular germ cell neoplasia in children and adolescents with intersex. Am. J. Surg. Pathol. 1993, 17(11):1124-1133.
98. Slowikowska-Hilczer J., Nuclear D.N.A. content and proliferative potential of human gonocytes in the testes of intersex children. Folia Histochem. Cytobiol. 2001, 39:167-168.
99. Chemes H.E., Venara M., del R.G., Arcari A.J., Musse M.P., Papazian R., Forclaz V., Gottlieb S. Is a CIS phenotype apparent in children with disorders of sex development? Milder testicular dysgenesis is associated with a higher risk of malignancy. Andrology 2015, 3:59-69.
100. Cools M., van Aerde K., Kersemaekers A.M., Boter M., Drop S.L., Wolffenbuttel K.P., Steyerberg E.W., Oosterhuis J.W., Looijenga LH: Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J. Clin. Endocrinol. Metab. 2005, 90:5295-5303.
101. Scully R.E. Gonadoblastoma. A review of 74 cases. Cancer 1970, 25:1340-1356.
102. Müller J., Visfeldt J., Philip J., Skakkebaek N.E. Carcinoma in situ, gonadoblastoma, and early invasive neoplasia in a nine-year-old girl with 46,XY gonadal dysgenesis. APMIS 1992, 100(2):170-174.
103. Li Y., Vilain E., Conte F., Rajpert-De Meyts E., Lau Y.F. Testis-specific protein Y-encoded gene is expressed in early and late stages of gonadoblastoma and testicular carcinoma in situ. Urol. Oncol. 2007, 25(2):141-146.
104. Hersmus R., Kalfa N., de Leeuw B., Stoop H., Oosterhuis J.W., de Krijger R., Wolffenbuttel K.P., Drop S.L., Veitia R.A., Fellous M., Jaubert F., Looijenga L.H. FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). J. Pathol. 2008, 215(1):31-38.
105. Jørgensen N., Müller J., Jaubert F., Clausen O.P., Skakkebaek N.E. Heterogeneity of gonadoblastoma germ cells: similarities with immature germ cells, spermatogonia and testicular carcinoma in situ cells. Histopathology 1997, 30(2):177-186.
106. Rajpert-De Meyts E., Bartkova J., Samson M., Hoei-Hansen C.E., Frydelund-Larsen L., Bartek J., Skakkebaek N.E. The emerging phenotype of the testicular carcinoma in situ germ cell. APMIS 2003, 111:267-278.
107. Cools M., Stoop H., Kersemaekers A.M., Drop S.L., Wolffenbuttel K.P., Bourguignon J.P., Slowikowska-Hilczer J., Kula K., Faradz S.M., Oosterhuis J.W., Looijenga L.H. Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads. J. Clin. Endocrinol. Metab. 2006, 91:2404-2413.
108. Rajpert-De Meyts E., Kvist M., Skakkebaek N.E. Heterogeneity of expression of immunohistochemical tumour markers in testicular carcinoma in situ: pathogenetic relevance. Virchows Arch. 1996, 428:133-139.
109. Mitchell R.T., E Camacho-Moll M., Macdonald J., Anderson R.A., Kelnar C.J., O'Donnell M., Sharpe R.M., Smith L.B., Grigor K.M., Wallace W.H., Stoop H., Wolffenbuttel K.P., Donat R., Saunders P.T., Looijenga L.H. Intratubular germ cell neoplasia of the human testis: heterogeneous protein expression and relation to invasive potential. Mod. Pathol. 2014, 27:1255-1266.
110. Gueler B., Sonne S.B., Zimmer J., Hilscher B., Hilscher W., Græm N., Rajpert-De Meyts E., Vogt P.H. AZFa protein DDX3Y is differentially expressed in human male germ cells during development and in testicular tumours: new evidence for phenotypic plasticity of germ cells. Hum. Reprod. 2012, 27:1547-1555.
111. Jørgensen A., Nielsen J.E., Almstrup K., Toft B.G., Petersen B.L., Rajpert-De Meyts E. Dysregulation of the mitosis-meiosis switch in testicular carcinoma in situ. J. Pathol. 2013, 229(4):588-598.
112. Stoop H., Honecker F., van de Geijn G.J., Gillis A.J., Cools M.C., de B.M., Bokemeyer C., Wolffenbuttel K.P., Drop S.L., de Krijger R.R., Dennis N., Summersgill B., McIntyre A., Shipley J., Oosterhuis J.W., Looijenga LH: Stem cell factor as a novel diagnostic marker for early malignant germ cells. J. Pathol. 2008, 216:43-54.
113. Müller J., Ritzén E.M., Ivarsson S.-A., Rajpert-De Meyts E., Norjavaara E., Skakkebæk N.E. Management of males with 45,X/46,XY gonadal dysgenesis. Horm. Res. 1999, 52:11-14.
114. Lee P.A., Houk C.P., Ahmed S.F., Hughes I.A. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology, Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006, 118(2):e488-e500.
115. Baxter R.M., Arboleda V.A., Lee H., Barseghyan H., Adam M.P., Fechner P.Y., Bargman R., Keegan C., Travers S., Schelley S., Hudgins L., Mathew R.P., Stalker H.J., Zori R., Gordon O.K., Ramos-Platt L., Pawlikowska-Haddal A., Eskin A., Nelson S.F., Délot E., Vilain E. Exome sequencing for the diagnosis of 46,XY disorders of sex development. J. Clin. Endocrinol. Metab. 2015, 100(2):E333-E344.
116. Kalfa N., Paris F., Philibert P., Orsini M., Broussous S., Fauconnet-Servant N., Audran F., Gaspari L., Lehors H., Haddad M., Guys J.M., Reynaud R., Alessandrini P., Merrot T., Wagner K., Kurzenne J.Y., Bastiani F., Bréaud J., Valla J.S., Lacombe G.M., Dobremez E., Zahhaf A., Daures J.P., Sultan C. Is hypospadias associated with prenatal exposure to endocrine disruptors? A French collaborative controlled study of a cohort of 300 consecutive children without genetic defect. Eur. Urol. May 2015, 10.1016/j.eururo.2015.05.008.
117. Achermann J.C., Hughes I.A. Disorders of sex development. Williams Textbook of Endocrinology 2008, 783-841. Elsevier, Philadelphia. 11th ed. H.M. Kronenberg, S. Melmed, K.S. Polonsky (Eds.).
118. Ahmed S.F., Achermann J.C., Arlt W., Balen A., Conway G., Edwards Z., Elford S., Hughes I.A., Izatt L., Krone N., Miles H., O'Toole S., Perry L., Sanders C., Simmonds M., Watt A., Willis D. Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin. Endocrinol. (Oxf.) Aug 2015, (Revised 2015). 10.1111/cen.12857.
119. Cools M., Pleskacova J., Stoop H., Hoebeke P., Van L.E., Drop S.L., Lebl J., Oosterhuis J.W., Looijenga L.H., Wolffenbuttel KP: Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism. J. Clin. Endocrinol. Metab. 2011, 96:E1171-E1180.
120. Lindhardt Johansen M., Hagen C.P., Rajpert-De Meyts E., Kjaergaard S., Petersen B.L., Skakkebaek N.E., Main K.M., Juul A: 45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function - a retrospective longitudinal study. J. Clin. Endocrinol. Metab. 2012, 97:E1540-E1549.
121. Liu A.X., Shi H.Y., Cai Z.J., Liu A., Zhang D., Huang H.F., Jin H.M. Increased risk of gonadal malignancy and prophylactic gonadectomy: a study of 102 phenotypic female patients with Y chromosome or Y-derived sequences. Hum. Reprod. 2014, 29:1413-1419.
122. Slowikowska-Hilczer J., Szarras-Czapnik M., Wolski J., Oszukowska E., Hilczer M., Jakubowski L., Walczak-Jedrzejowska M., Marchlewska K., Filipiak E., Kaluzewski B., Baka-Ostrowska M., Niedzielski J., Kula K. The risk of neoplasm associated with dysgenetic testes in pre- and pubertal/adult patients. Folia Histochem. Cytobiol. 2015, (in press).
123. Hannema S.E., Scott I.S., Rajpert-De Meyts, Skakkebaek N.E., Coleman N., Hughes IA: Testicular development in the complete androgen insensitivity syndrome. J. Pathol. 2006, 208:518-527.
124. Wunsch L., Holterhus P.M., Wessel L., Hiort O. Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis. BJU Int. 2012, 110:E958-E965.
125. Beaulieu B.M., Lemieux N., Brochu P. Undifferentiated gonadal tissue, Y chromosome instability, and tumors in XY gonadal dysgenesis. Pediatr. Dev. Pathol. 2011, 14:445-459.
126. Nakhal R.S., Hall-Craggs M., Freeman A., Kirkham A., Conway G.S., Arora R., Woodhouse C.R., Wood D.N., Creighton S.M. Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013, 268:153-160.
127. Michala L., Goswami D., Creighton S.M., Conway G.S. Swyer syndrome: presentation and outcomes. BJOG 2008, 115(6):737-741.
128. Sircili M.H., Denes F.T., Costa E.M., Machado M.G., Inacio M., Silva R.B., Srougi M., Mendonca B.B., Domenice S. Long-term followup of a large cohort of patients with ovotesticular disorder of sex development. J. Urol. 2014, 191:1532-1536.
129. Cools M., Boter M., van G.R., Stoop H., Poddighe P., Lau Y.F., Drop S.L., Wolffenbuttel K.P., Looijenga L.H. Impact of the Y-containing cell line on histological differentiation patterns in dysgenetic gonads. Clin. Endocrinol. (Oxf.) 2007, 67:184-192.
130. Kaprova-Pleskacova J., Stoop H., Bruggenwirth H., Cools M., Wolffenbuttel K.P., Drop S.L., Snajderova M., Lebl J., Oosterhuis J.W., Looijenga L.H. Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology. Mod. Pathol. 2014, 27:721-730.
131. Zelaya G., Lopez Marti J.M., Marino R., Garcia de Davila M.T., Gallego M.S. Gonadoblastoma in patients with Ullrich-Turner syndrome. Pediatr. Dev. Pathol. 2015, 18:117-121.
132. Barros B.A., Moraes S.G., Coeli F.B., Assumpcao J.G., De Mello M.P., Maciel-Guerra A.T., Carvalho A.B., Viguetti-Campos N., Vieira T.A., Amstalden E.M., Andrade J.G., Esquiaveto-Aun A.M., Marques-de-Faria A.P., D'Souza-Li L.F., Lemos-Marini S.H., Guerra G. OCT4 immunohistochemistry may be necessary to identify the real risk of gonadal tumors in patients with Turner syndrome and Y chromosome sequences. Hum. Reprod. 2011, 26:3450-3455.
133. Bastian C., Muller J.B., Lortat-Jacob S., Nihoul-Fekete C., Bignon-Topalovic J., McElreavey K., Bashamboo A., Brauner R. Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis. Fertil. Steril. 2015, 103:1297-1304.
134. Juniarto A.Z., Setyawati B.A., Miranti I.P., Santosa A., Hersmus R., Stoop H., Cools M., Oosterhuis J.W., Drop S.L., Faradz S.M., Looijenga L.H. Gonadal malignancy in 13 consecutive collected patients with disorders of sex development (DSD) from Semarang (Indonesia). J. Clin. Pathol. 2013, 66:198-204.
135. Bianco B., Lipay M., Guedes A., Oliveira K., Verreschi I.T. SRY gene increases the risk of developing gonadoblastoma and/or nontumoral gonadal lesions in Turner syndrome. Int. J. Gynecol. Pathol. 2009, 28:197-202.
136. Capito C., Leclair M.D., Arnaud A., David A., Baron S., Corradini N., Heloury Y. 46,XY pure gonadal dysgenesis: clinical presentations and management of the tumor risk. J. Pediatr. Urol. 2011, 7:72-75.
137. Modi D., Bhartiya D. Y chromosome mosaicism and occurrence of gonadoblastoma in cases of Turner syndrome and amenorrhoea. Reprod. Biomed. Online 2007, 15:547-553.
138. Sallai A., Solyom J., Dobos M., Szabo J., Halasz Z., Sagodi L., Niederland T., Kozari A., Bertalan R., Ugocsai P., Fekete G. Y-chromosome markers in Turner syndrome: screening of 130 patients. J. Endocrinol. Invest. 2010, 33:222-227.
139. Zielinska D., Zajaczek S., Rzepka-Gorska I. Tumors of dysgenetic gonads in Swyer syndrome. J. Pediatr. Surg. 2007, 42:1721-1724.
140. Freriks K., Timmers H.J., Netea-Maier R.T., Beerendonk C.C., Otten B.J., van Alfen-van der Velden J.A., Traas M.A., Mieloo H., van de Zande G.W., Hoefsloot L.H., Hermus A.R., Smeets D.F. Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome. Eur. J. Med. Genet. 2013, 56:497-501.
141. Hoei-Hansen C.E., Kraggerud S.M., Abeler V.M., Kaern J., Rajpert-De Meyts E., Lothe R.A. Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol. Cancer 2007, 6:12.
142. Hersmus R., Stoop H., van de Geijn G.J., Eini R., Biermann K., Oosterhuis J.W., Dhooge C., Schneider D.T., Meijssen I.C., Dinjens W.N., Dubbink H.J., Drop S.L., Looijenga L.H. Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas. PLoS ONE 2012, 7(8):e43952.
143. Słowikowska-Hilczer J., Romer T.E., Kula K. Neoplastic potential of germ cells in relation to disturbances of gonadal organogenesis and changes in karyotype. J. Androl. 2003, 24:270-278.
144. Pleskacova J., Hersmus R., Oosterhuis J.W., Setyawati B.A., Faradz S.M., Cools M., Wolffenbuttel K.P., Lebl J., Drop S.L., Looijenga L.H. Tumor risk in disorders of sex development. Sex Dev. 2010, 4:259-269.
145. van der Zwan Y.G., Biermann K., Wolffenbuttel K.P., Cools M., Looijenga L.H. Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model. Eur. Urol. 2015, 67:692-701.
146. Burckhardt M.A., Udhane S., Marti N., Schnyder I., Tapia C., Nielsen J.E., Mullis P.E., Rajpert-De Meyts E., Flueck C. Human 3β-hydroxysteroid-dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature. Eur. J. Endocrinol. 2015, 173(5):K1-K12. 10.1530/EJE-15-0599.
147. Rajpert-De Meyts E., Skakkebæk N.E. The role of puberty for testicular cancer. The Onset of Puberty in Perspective 2000, 201-213. Elsevier Science, Amsterdam. J.P. Bourguignon, T.M. Plant (Eds.).
148. Cox K., Bryce J., Jiang J., Rodie M., Sinnott R., Alkhawari M., Arlt W., Audi L., Balsamo A., Bertelloni S., Cools M., Darendeliler F., Drop S., Ellaithi M., Guran T., Hiort O., Holterhus P.M., Hughes I., Krone N., Lisa L., Morel Y., Soder O., Wieacker P., Ahmed S.F. Novel associations in disorders of sex development: findings from the I-DSD Registry. J. Clin. Endocrinol. Metab. 2014, 99:E348-E355. 10.1210/jc.2013-2918.
149. Cools M. Germ cell cancer risk in DSD patients. Ann. Endocrinol. (Paris) 2014, 75:67-71.
150. Guercio G., Rey R.A. Fertility issues in the management of patients with disorders of sex development. Endocr. Dev. 2014, 27:87-98.
151. Litchfield K., Shipley J., Turnbull C. Common variants identified in genome-wide association studies of testicular germ cell tumour: an update, biological insights and clinical application. Andrology 2015, 3(1):34-46.
152. Uhlenhaut N.H., Jakob S., Anlag K., Eisenberger T., Sekido R., Kress J., Treier A.C., Klugmann C., Klasen C., Holter N.I., Riethmacher D., Schütz G., Cooney A.J., Lovell-Badge R., Treier M. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 2009, 139(6):1130-1142.
153. Matson C.K., Murphy M.W., Sarver A.L., Griswold M.D., Bardwell V.J., Zarkower D. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 2011, 476(7358):101-104.
154. Minkina A., Matson C.K., Lindeman R.E., Ghyselinck N.B., Bardwell V.J., Zarkower D. DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Dev. Cell 2014, 29(5):511-520.
155. Jørgensen N., Rajpert-De Meyts E., Main K.M., Skakkebaek N.E. Testicular dysgenesis syndrome comprises some but not all cases of hypospadias and impaired spermatogenesis. Int. J. Androl. 2010, 33:298-303.