Skip to main content
SpringerLink
Log in

Genomic and gene expression signature of the pre-invasive testicular carcinoma in situ

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Testicular cancer is the most common malignancy among men in the reproductive age and the incidence is increasing, probably caused by environmental factors. Most testicular cancers are testicular germ cell tumours and all originate from a carcinoma in situ (CIS) pattern. In this review, we focus on the pre-invasive CIS and its possible fetal origin by reviewing recent data originating from DNA microarrays and comparative genomic hybridisations. A comparison of gene expression and genomic aberrations reveal chromosomal “hot spots” with mutual clustering of gene expression and genomic amplification. Some of the genes found in the hot spots may be involved in creating the CIS phenotype. On the other hand, many genes that are highly expressed in CIS are not present in the hot-spot areas. The gene expression profile of CIS thus most likely reflects the combined result of genomic amplification and increased transcriptional activation and/or deficiency in the epigenetic silencing of specific loci. Amplification of chromosome 12p, appears to be a good genomic marker of the transition from the pre-malignant to malignant CIS cell; this is consistent with recent findings of propagation advantages in cultured undifferentiated embryonic stem cells after spontaneous amplification in similar regions. The gene expression profile of CIS cells has remarkable similarity to that of embryonic stem cells and supports our long-standing hypothesis of an early developmental origin of CIS and testicular germ cell cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Albrechtsen R, Nielsen MH, Skakkebaek NE, Wewer U (1982) Carcinoma in situ of the testis. Some ultrastructural characteristics of germ cells. Acta Pathol Microbiol Immunol Scand A 90:301–303

    PubMed  Google Scholar 

  • 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 64:4736–4743

    Article  PubMed  Google Scholar 

  • Atkin NB, Baker MC (1982) Specific chromosome change, i(12p), in testicular tumours? Lancet 320:1349

    Article  Google Scholar 

  • Bergstrom R, Adami HO, Mohner M, Zatonski W, Storm H, Ekbom A, Tretli S, Teppo L, Akre O, Hakulinen T (1996) Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J Natl Cancer Inst 88:727–733

    PubMed  Google Scholar 

  • Boisen KA, Kaleva M, Main KM, Virtanen HE, Haavisto AM, Schmidt IM, Chellakooty M, Damgaard IN, Mau C, Reunanen M, Skakkebaek NE, Toppari J (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet 363:1264–1269

    Article  PubMed  Google Scholar 

  • Draper JS, Smith K, Gokhale P, Moore HD, Maltby E, Johnson J, Meisner L, Zwaka TP, Thomson JA, Andrews PW (2004) Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat Biotechnol 22:53–54

    Article  PubMed  Google Scholar 

  • Fisher JS (2004) Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 127:305–315

    Article  PubMed  Google Scholar 

  • Fisher JS, Macpherson S, Marchetti N, Sharpe RM (2003) Human “testicular dysgenesis syndrome”: a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum Reprod 18:1383–1394

    Article  PubMed  Google Scholar 

  • Giwercman A, Cantell L, Marks A (1991) Placental-like alkaline phosphatase as a marker of carcinoma-in-situ of the testis. Comparison with monoclonal antibodies M2A and 43-9F. APMIS 99:586–594

    PubMed  Google Scholar 

  • Graaff WE de, Oosterhuis JW, Jong B de, Dam A, Putten WL van, Castedo SM, Sleijfer DT, Schraffordt Koops H (1992) Ploidy of testicular carcinoma in situ. Lab Invest 66:166–168

    PubMed  Google Scholar 

  • Hemminki K, Li X (2002) Cancer risks in second-generation immigrants to Sweden. Int J Cancer 99:229–237

    Article  PubMed  Google Scholar 

  • Hemminki K, Li X, Czene K (2002) Cancer risks in first-generation immigrants to Sweden. Int J Cancer 99:218–228

    Article  PubMed  Google Scholar 

  • Hoei-Hansen CE, Holm M, Rajpert-De Meyts E, Skakkebaek NE (2003) Histological evidence of testicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer. J Pathol 200:370–374

    Article  PubMed  Google Scholar 

  • Hoei-Hansen CE, Nielsen JE, Almstrup K, Hansen MA, Skakkebaek NE, Rajpert-DeMeyts E, Leffers H (2004a) Identification of genes differentially expressed in testes containing carcinoma in situ. Mol Hum Reprod 10:423–431

    Article  PubMed  Google Scholar 

  • Hoei-Hansen CE, Nielsen JE, Almstrup K, Sonne SB, Graem N, Skakkebaek NE, Leffers H, Meyts ER (2004b) Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors. Clin Cancer Res 10:8521–8530

    Article  PubMed  Google Scholar 

  • Honecker F, Stoop H, Krijger RR de, Chris Lau YF, Bokemeyer C, Looijenga LH (2004) Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. J Pathol 203:849–857

    Article  PubMed  Google Scholar 

  • Huyghe E, Matsuda T, Thonneau P (2003) Increasing incidence of testicular cancer worldwide: a review. J Urol 170:5–11

    Article  PubMed  Google Scholar 

  • Jorgensen N, Rajpert-De Meyts E, Graem N, Muller J, Giwercman A, Skakkebaek NE (1995) Expression of immunohistochemical markers for testicular carcinoma in situ by normal human fetal germ cells. Lab Invest 72:223–231

    PubMed  Google Scholar 

  • Looijenga LH, Rosenberg C, Gurp RJ van, Geelen E, van Echten-Arends J, Jong B de, Mostert M, Wolter Oosterhuis J (2000) Comparative genomic hybridization of microdissected samples from different stages in the development of a seminoma and a non-seminoma. J Pathol 191:187–192

    Article  PubMed  Google Scholar 

  • Looijenga LH, Stoop H, Leeuw HP de, Gouveia Brazao CA de, Gillis AJ, Roozendaal KE van, Zoelen EJ van, Weber RF, Wolffenbuttel KP, Dekken H van, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (2003) POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res 63:2244–2250

    PubMed  Google Scholar 

  • Moller H (1993) Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur Urol 23:8–13 (discussion 14–15)

    Google Scholar 

  • Nielsen H, Nielsen M, Skakkebaek NE (1974) The fine structure of possible carcinoma-in-situ in the seminiferous tubules in the testis of four infertile men. Acta Pathol Microbiol Scand A 82:235–248

    PubMed  Google Scholar 

  • Ottesen AM, Skakkebaek NE, Lundsteen C, Leffers H, Larsen J, Rajpert-De Meyts E (2003) 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 38:117–125

    PubMed  Google Scholar 

  • Ottesen AM, Larsen J, Gerdes T, Larsen JK, Lundsteen C, Skakkebaek NE, Rajpert-De Meyts E (2004) Cytogenetic investigation of testicular carcinoma in situ and early seminoma by high-resolution comparative genomic hybridization analysis of subpopulations flow sorted according to DNA content. Cancer Genet Cytogenet 149:89–97

    Article  PubMed  Google Scholar 

  • Pera MF (2004) Unnatural selection of cultured human ES cells? Nat Biotechnol 22:42–43

    Article  PubMed  Google Scholar 

  • Rajpert-De Meyts E, Skakkebaek NE (1994) Expression of the c-kit protein product in carcinoma-in-situ and invasive testicular germ cell tumours. Int J Androl 17:85–92

    PubMed  Google Scholar 

  • Rajpert-De Meyts E, Kvist M, Skakkebaek NE (1996) Heterogeneity of expression of immunohistochemical tumour markers in testicular carcinoma in situ: pathogenetic relevance. Virchows Arch 428:133–139

    Article  PubMed  Google Scholar 

  • 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 204–206)

    PubMed  Google Scholar 

  • 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 278–279)

    Article  PubMed  Google Scholar 

  • Rajpert-De Meyts E, Hanstein R, Jorgensen N, Graem N, Vogt PH, Skakkebaek NE (2004) Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads. Hum Reprod 19:1338–1344

    PubMed  Google Scholar 

  • Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298:597–600

    Article  PubMed  Google Scholar 

  • Rodriguez S, Jafer O, Goker H, Summersgill BM, Zafarana G, Gillis AJ, Gurp RJ van, 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 22:1880–1891

    Article  PubMed  Google Scholar 

  • Rorth M, Rajpert-De Meyts E, Andersson L, Dieckmann KP, Fossa SD, Grigor KM, Hendry WF, Herr HW, Looijenga LH, Oosterhuis JW, Skakkebaek NE (2000) Carcinoma in situ in the testis. Scand J Urol Nephrol Suppl 205:166–186

    PubMed  Google Scholar 

  • Rosenberg C, Gurp RJ van, 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 19:5858–5862

    Article  PubMed  Google Scholar 

  • Sato N, Sanjuan IM, Heke M, Uchida M, Naef F, Brivanlou AH (2003) Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev Biol 260:404–413

    Article  PubMed  Google Scholar 

  • Skakkebaek NE (1972) Possible carcinoma-in-situ of the testis. Lancet 300:516–517

    Article  Google Scholar 

  • Skakkebaek NE, Berthelsen JG, Giwercman A, Muller J (1987) Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 10:19–28

    PubMed  Google Scholar 

  • Skakkebaek NE, Rajpert-De Meyts E, Jorgensen N, Carlsen E, Petersen PM, Giwercman A, Andersen AG, Jensen TK, Andersson AM, Muller J (1998) Germ cell cancer and disorders of spermatogenesis: an environmental connection? APMIS 106:3–11 (discussion 12)

    PubMed  Google Scholar 

  • Skakkebaek NE, Rajpert-De Meyts E, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16:972–978

    Article  PubMed  Google Scholar 

  • Skotheim RI, Lothe RA (2003) The testicular germ cell tumour genome. APMIS 111:136–150 (discussion 50–51)

    Article  PubMed  Google Scholar 

  • 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 62:2359–2364

    PubMed  Google Scholar 

  • Sperger JM, Chen X, Draper JS, Antosiewicz JE, Chon CH, Jones SB, Brooks JD, Andrews PW, Brown PO, Thomson JA (2003) Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc Natl Acad Sci USA 100:13350–13355

    Article  PubMed  Google Scholar 

  • Summersgill B, Osin P, Lu YJ, Huddart R, Shipley J (2001) Chromosomal imbalances associated with carcinoma in situ and associated testicular germ cell tumours of adolescents and adults. Br J Cancer 85:213–220

    Article  PubMed  Google Scholar 

  • Ulbright TM, Amin MB, Young RH (1999) Tumors of the testis, adnexa, spermatic cord, and scrotum. Armed Forces Institute of Pathology, Washington, DC, USA

    Google Scholar 

  • Weir HK, Marrett LD, Kreiger N, Darlington GA, Sugar L (2000) Pre-natal and peri-natal exposures and risk of testicular germ-cell cancer. Int J Cancer 87:438–443

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Kristian Almstrup, Anne Marie Ottesen, Si Brask Sonne, Christina E. Hoei-Hansen, Henrik Leffers, Ewa Rajpert-De Meyts & Niels E. Skakkebaek

Authors
  1. Kristian Almstrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne Marie Ottesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Si Brask Sonne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christina E. Hoei-Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Henrik Leffers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ewa Rajpert-De Meyts
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Niels E. Skakkebaek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristian Almstrup.

Additional information

The work of the Copenhagen group cited in this review was supported by grants from the Svend Andersen Foundation, the Vissing Foundation, the Danish Medical Research Council, the Danish Cancer Society and the European Commission.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Almstrup, K., Ottesen, A.M., Sonne, S.B. et al. Genomic and gene expression signature of the pre-invasive testicular carcinoma in situ. Cell Tissue Res 322, 159–165 (2005). https://doi.org/10.1007/s00441-005-1084-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-005-1084-x

Keywords

Search

Navigation