Molecular Pathogenesis of Testicular Germ Cell Tumors
Authors:
V. Bakardjieva-Mihaylova 1; K. Škvárová Kramarzová 1; M. Slámová 1; T. Büchler 2; L. Boublíková 1,2
Authors place of work:
CLIP, Klinika dětské hematologie a onkologie 2. LF UK a FN Motol, Praha
1; Onkologická klinika 1. LF UK a Thomayerova nemocnice, Praha
2
Published in the journal:
Klin Onkol 2017; 30(6): 412-419
Category:
Review
doi:
https://doi.org/10.14735/amko2017412
Summary
Background:
Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men and their incidence has been increasing over the past decades. Several factors may combine and play a role in the TGCT etiology, including environmental factors and genetic predispositions at multiple genomic loci that affect both testicular germ cells and stromal cells, and their interactions within the testicular microenvironment. The pathogenesis of TGCT starts prenatally with primordial germ cell arrest, and further proceeds postnatally, giving rise to in situ germ cell neoplasia and, finally, to invasive TGCT with the characteristic 12p chromosome amplification. Apart from the genes localized here, further molecular mechanisms have been linked to TGCT pathogenesis, such as the activation of the KIT/KITL signaling pathway, and aberrations in genes involved in DNA reparation, regulation of cellular differentiation, proliferation, and survival. Despite the relatively good prognosis and known etiopathogenesis of these tumors, neither targeted therapy nor molecular prognostic/predictive factors have yet been implemented in the management of TGCT, because there is not enough information about the molecular pathways or molecules involved in TGCT development that could be used for patient stratification and treatment. Current high-throughput technologies, such as next generation sequencing at the exome or transcriptome level could provide this missing information on genetic predispositions and other factors influencing the clinical course of the disease and treatment response in TGCT.
Aim:
In this review, we summarize the main molecular characteristics of TGCT and the probable mechanisms participating in tumor initiation and progression.
Key words:
testicular germ cell tumors – signaling pathways – molecular aberrations – predictive factors – prognostic factors
The work was supported by the Czech Ministry of Education, Youth and Sports NPU I nr.LO 1604.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
20. 3. 2017
Accepted:
23. 7. 2017
Zdroje
1. Holmes L Jr, Escalante C, Garrison O et al. Testicular cancer incidence trends in the USA (1975–2004): plateau or shifting racial paradigm? Public Health 2008; 122 (9): 862–872. doi: 10.1016/j.puhe.2007.10.010.
2. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55 (2): 74–108.
3. Torre LA, Bray F, Siegel RL et. al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65 (2): 87–108. doi: 10.3322/caac.21262.
4. Parkin DM, Iscovich J. Risk of cancer in migrants and their descendants in Israel: II. Carcinomas and germ-cell tumours. Int J Cancer 1997; 70 (6): 654–660.
5. Ekbom A, Richiardi L, Akre O et al. Age at immigration and duration of stay in relation to risk for testicular cancer among Finnish immigrants in Sweden. J Natl Cancer Inst 2003; 95 (16): 1238–1240.
6. Montgomery SM, Granath F, Ehlin A et al. Germ-cell testicular cancer in offspring of Finnish immigrants to Sweden. Cancer Epidemiol Biomarkers Prev 2005; 14 (1): 280–282.
7. McIntyre A, Gilbert D, Goddard N et al. Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults. Genes Chromosomes Cancer 2008; 47 (7): 547–557. doi: 10.1002/gcc.20562.
8. Bahrami A, Ro JY, Ayala AG. An overview of testicular germ cell tumors. Arch Pathol Lab Med 2007; 131 (8): 1267–1280.
9. Shanmugalingam T, Soultati A, Chowdhury S et al. Global incidence and outcome of testicular cancer. Clin Epidemiol 2013; 5: 417–427. doi: 10.2147/CLEP.S34430.
10. Reuter VE. Origins and molecular biology of testicular germ cell tumors. Mod Pathol 2005; 18 (Suppl 2): 51–60.
11. Díez-Torre A, Silván U, Díaz-Núñez M et al. The role of microenvironment in testicular germ cell tumors. Cancer Biol Ther 2010; 10 (6): 529–536. doi: 10.4161/cbt.10.6.13227.
12. Diamantopoulos N, Kortsaris. A Testicular germ cell tumors. J BUON 2010; 15 (3): 421–434.
13. Heimdal K, Olsson H, Tretli S et al. A segregation analysis of testicular cancer based on Norwegian and Swedish families. Br J Cancer 1997; 75 (7): 1084–1087.
14. Rapley EA, Crockford GP, Teare D et al. Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours. Nat Genet 2000; 24 (2): 197–200.
15. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001; 16 (5): 972–978.
16. Ewa Rajpert-De Meyts. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update 2006; 12 (3): 303–323.
17. Holl K, Lundin E, Surcel HM et al. Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: a nested case-referent study. Int J Cancer 2009; 124 (12): 2923–2928. doi: 10.1002/ijc.24312.
18. Kristiansen W, Aschim EL, Andersen JM et al. Variations in testosterone pathway genes and susceptibility to testicular cancer in Norwegian men. Int J Androl 2012; 35 (6): 819–827.
19. Grassetti D, Giannandrea F, Paoli D et al. Androgen receptor polymorphisms and testicular cancer risk. Andrology 2015; 3 (1): 27–33. doi: 10.1111/j.2047-2927.2014.00252.x.
20. Klatte T, de Martino M, Arensmeier K et al. Management and outcome of bilateral testicular germ cell tumors: a 25-year single center experience. Int J Urol 2008; 15 (9): 821–826. doi: 10.1111/j.1442-2042.2008.02107.x.
21. Pamenter B, De Bono JS, Brown IL et al. Bilateral testicular cancer: a preventable problem? Experience from a large cancer centre. BJU Int 2003; 92 (1): 43–46.
22. Ondruš D, Ondrušová M, Šťastná V. Bilateral germ-cell testicular cancer – long-term experience. Klin Onkol 2013; 26 (6): 421–424. doi: 10.14735/amko2013421.
23. Hvarness T, Nielsen JE, Almstrup K. Phenotypic characterisation of immune cell infiltrates in testicular germ cell neoplasia. J Reprod Immunol 2013; 100 (2): 135–145. doi: 10.1016/j.jri.2013.10.005.
24. Fijak M, Bhushan S, Meinhardt A. Immunoprivileged sites: the testis. Methods Mol Biol 2011; 677: 459–470. doi: 10.1007/978-1-60761-869-0_29.
25. Schmelz HU, Port M, Hauck EW et al. Apoptosis: a key effector mechanism of lymphocyte action in human nonseminomatous testicular carcinoma? BJU Int 2005; 96 (1): 158–163. doi: 10.1111/j.1464-410X.2005.05587.x.
26. Parker C, Milosevic M, Panzarella T et al. The prognostic significance of the tumour infiltrating lymphocyte count in stage I testicular seminoma managed by surveillance. Eur J Cancer 2002; 38 (15): 2014–2019.
27. Grobholz R, Verbeke CS, Schleger C et al. Expression of MAGE antigens and analysis of the inflammatory T-cell infiltrate in human seminoma. Urol Res 2000; 28 (6): 398–403.
28. Bode PK, Thielken A, Brandt S et al. Cancer testis antigen expression in testicular germ cell tumorigenesis. Mod Pathol 2014; 27 (6): 899–905. doi: 10.1038/modpathol.2013.183.
29. Cierna Z, Mego M, Miskovska V et al. Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. Ann Oncol 2016; 27 (2): 300–305. doi: 10.1093/annonc/mdv574.
30. Silván U, Arlucea J, Andrade R et al. Angiogenesis and vascular network of teratocarcinoma from embryonic stem cell transplant into seminiferous tubules. Br J Cancer 2009; 101 (1): 64–70. doi: 10.1038/sj.bjc.6605125.
31. Boublíková L, Buchler T, Stary J et al. Molecular biology of testicular germ cell tumors: unique features awaiting clinical application. Crit Rev Oncol Hematol 2014; 89 (3): 366–385. doi: 10.1016/j.critrevonc.2013.10.001.
32. Brabrand S, Johannessen B, Axcrona U et al. Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages. Neoplasia 2015; 17 (2): 167–174. doi: 10.1016/j.neo.2014.12.005.
33. Looijenga LH, de Leeuw H, van Oorschot M et al. Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors. Cancer Res 2003; 63 (22): 7674–7678.
34. Skakkebaek NE, Berthelsen JG, Giwercman A et al. 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.
35. Looijenga LH, Gillis AJ, Stoop H et al. Dissecting the molecular pathways of (testicular) germ cell tumour pathogenesis; from initiation to treatment-resistance. Int J Androl 2011; 34 (4 Pt 2): 234–251. doi: 10.1111/j.1365-2605.2011.01157.x.
36. Skotheim RI, Lothe RA. The testicular germ cell tumour genome. APMIS 2003; 111 (1): 136–150. doi: 10.1034/j.1600-0463.2003.11101181.x.
37. Houldsworth J, Reuter V, Bosl GJ et al. Aberrant expression of cyclin D2 is an early event in human male germ cell tumorigenesis. Cell Growth Differ 1997; 8 (3): 293–299.
38. Korkola JE, Houldsworth J, Bosl GJ et al. Molecular events in germ cell tumours: linking chromosome-12 gain, acquisition of pluripotency and response to cisplatin. BJU Int 2009; 104 (9 Pt B): 1334–1338. doi: 10.1111/ j.1464-410X.2009.08855.x.
39. Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 1999; 31 (10): 1037–1051.
40. Runyan C, Schaible K, Molyneaux K et al. Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development 2006; 133 (24): 4861–4869. doi: 10.1242/dev.02688.
41. Rapley EA, Hockley S, Warren W et al. Somatic mutations of KIT in familial testicular germ cell tumours. Br J Cancer 2004; 90 (12): 2397–2401. doi: 10.1038/sj.bjc.6601880.
42. Coffey J, Linger R, Pugh J et al. 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 2008; 47 (1): 34–42. doi: 10.1002/gcc.20503.
43. Biermann K, Göke F, Nettersheim D et al. c-KIT is frequently mutated in bilateral germ cell tumours and down-regulated during progression from intratubular germ cell neoplasia to seminoma. J Pathol 2007; 213 (3): 311–318. doi: 10.1002/path.2225.
44. Pedersini R, Vattemi E, Mazzoleni G et al. Complete response after treatment with imatinib in pretreated disseminated testicular seminoma with overexpression of c-KIT. Lancet Oncol 2007; 8 (11): 1039–1040. doi: 10.1016/S1470-2045 (07) 70344-3.
45. Zeron-Medina J, Wang X, Repapi E et al. A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell 2013; 155 (2): 410–422. doi: 10.1016/j.cell.2013.09.017.
46. Gilbert D, Rapley E, Shipley J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nat Rev Cancer 2011; 11 (4): 278–288. doi: 10.1038/nrc3021.
47. 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–e96. doi: 10.1111/j.1365-2605.2011.01162.x.
48. Oosterhuis JW, Looijenga LH. Current views on the pathogenesis of testicular germ cell tumours and perspectives for future research: highlights of the 5th Copenhagen Workshop on Carcinoma in situ and Cancer of the Testis. APMIS 2003; 111 (1): 280–289.
49. Taylor-Weiner A, Zack T, O‘Donnell E et al. Genomic evolution and chemoresistance in germ-cell tumours. Nature 2016; 540 (7631): 114–118. doi: 10.1038/nature20596.
50. Mueller T, Mueller LP, Luetzkendorf J et al. Loss of Oct-3/4 expression in embryonal carcinoma cells is associated with induction of cisplatin resistance. Tumour Biol 2006; 27 (2): 71–83. doi: 10.1159/000092324.
51. Lutzker SG. P53 tumour suppressor gene and germ cell neoplasia. APMIS 1998; 106 (1): 85–89.
52. Houldsworth J, Xiao H, Murty VV et al. Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. Oncogene 1998; 16 (18): 2345–2349. doi: 10.1038/sj.onc.1201770.
53. Bártková J, Bártek J, Lukás J et al. p53 protein alterations in human testicular cancer including pre-invasive intratubular germ-cell neoplasia. Int J Cancer 1991; 49 (2): 196–202. doi: 10.1002/ijc.2910490209.
54. Riou G, Barrois M, Prost S et al. The p53 and mdm-2 genes in human testicular germ-cell tumors. Mol Carcinog 1995; 12 (3): 124–131.
55. Peng HQ, Hogg D, Malkin D et al. Mutations of the p53 gene do not occur in testis cancer. Cancer Res 1993; 53 (15): 3574–3578.
56. Rossi M, Colecchia D, Ilardi G et al. MAPK15 upregulation promotes cell proliferation and prevents DNA damage in male germ cell tumors. Oncotarget 2016; 7 (15): 20981–20998. doi: 10.18632/oncotarget.8044.
57. Masters JR, Köberle B. Curing metastatic cancer: lessons from testicular germ-cell tumours. Nat Rev Cancer 2003; 3 (7): 517–525. doi: 10.1038/nrc1120.
58. Tsuchiya N, Mishina M, Narita S et al. Association of XRCC1 gene polymorphisms with the susceptibility and chromosomal aberration of testicular germ cell tumors. Int J Oncol 2006; 28 (5): 1217–1223.
59. Peng HQ, Hogg D, Malkin D et al. Mutations of the p53 gene do not occur in testis cancer. Cancer Res 1993; 53 (15): 3574–3578.
60. Boublíkova L, Bakardjieva-Mihaylova V, Skvarova Kramarzova K et al. Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors. Cancer Lett 2016; 376 (2): 367–376. doi: 10.1016/j.canlet.2016.04.016.
61. Jørgensen A, Blomberg Jensen M et al. Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model. J Steroid Biochem Mol Biol 2013; 136: 238–246. doi: 10.1016/j.jsbmb.2012.10.008.
62. Gutekunst M, Mueller T, Weilbacher A et al. Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4. Cancer Res 2013; 73 (5): 1460–1469. doi: 10.1158/0008-5472.CAN-12-2876.
63. Mayer F, Stoop H, Scheffer GL et al. Molecular determinants of treatment response in human germ cell tumors. Clin Cancer Res 2003; 9 (2): 767–773.
64. Datta MW, Macri E, Signoretti S et al. Transition from in situ to invasive testicular germ cell neoplasia is associated with the loss of p21 and gain of mdm-2 expression. Mod Pathol 2001; 14 (5): 437–442. doi: 10.1038/modpathol.3880331.
65. Koster R, Timmer-Bosscha H, Bischoff R et al. Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis 2011; 2: e148. doi: 10.1038/cddis.2011.33.
66. Wermann H, Stoop H, Gillis AJ et al. Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J Pathol 2010; 221 (4): 433–442. doi: 10.1002/path.2725.
67. Honecker F, Wermann H, Mayer F et al. Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J Clin Oncol 2009; 27 (13): 2129–2136. doi: 10.1200/JCO.2008.18. 8623.
68. Feldman DR, Iyer G, Van Alstine L et al. Presence of somatic mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatin-resistant germ cell tumors. Clin Cancer Res 2014; 20 (14): 3712–3720. doi: 10.1158/1078-0432.CCR-13-2868.
69. Feldman DR, Bosl GJ, Sheinfeld J et al. Medical treatment of advanced testicular cancer. JAMA 2008; 299 (6): 672–684. doi: 10.1001/jama.299.6.672.
70. Bianco C, Strizzi L, Ebert A et al. Role of human cripto-1 in tumor angiogenesis. J Natl Cancer Inst 2005; 97 (2): 132–141. doi: 10.1093/jnci/dji011.
71. Spiller CM, Bowles J, Koopman P. Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors. Int J Dev Biol 2013; 57 (2–4): 211–219. doi: 10.1387/ijdb.130028pk.
72. Watanabe K, Hamada S, Bianco C et al. Requirement of glycosylphosphatidylinositol anchor of Cripto-1 for trans activity as a Nodal co-receptor. J Biol Chem 2007; 282 (49): 35772–35786. doi: 10.1074/jbc.M707351200.
73. Bianco C, Strizzi L, Mancino M et al. Identification of cripto-1 as a novel serologic marker for breast and colon cancer. Clin Cancer Res 2006; 12 (17): 5158–5164. doi: 10.1158/1078-0432.CCR-06-0274.
74. Pilgaard L, Mortensen JH, Henriksen M et al. Cripto-1 expression in glioblastoma multiforme. Brain Pathol 2014; 24 (4): 360–370. doi: 10.1111/bpa.12131.
75. Hoff AM, Alagaratnam S, Zhao S et al. Identification of Novel Fusion Genes in Testicular Germ Cell Tumors. Cancer Res 2016; 76 (1): 108–116. doi: 10.1158/0008-5472.CAN-15-1790.
76. Sturgeon CM, Duffy MJ, Stenman UH et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008; 54 (12): e11–e79. doi: 10.1373/clinchem.2008.105601.
77. Salem M, Gilligan T. Serum tumor markers and their utilization in the management of germ-cell tumors in adult males. Expert Rev Anticancer Ther 2011; 11 (1): 1–4. doi: 10.1586/era.10.219.
78. van Agthoven T, Looijenga LH. Accurate primary germ cell cancer diagnosis using serum based microRNA detection (ampTSmiR test). Oncotarget 2016. doi: 10.18632/oncotarget.10867.
79. Spiller CM, Gillis AJ, Burnet G et al. Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors. Mol Oncol 2016; 10 (4): 526–537. doi: 10.1016/j.molonc.2015.11.003.
80. Beaver JA, Gustin JP, Yi KH et al. PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. Clin Cancer Res 2013; 19 (19): 5413–5422. doi: 10.1158/1078-0432.CCR-13-0884.
81. Sommerer F, Hengge UR, Markwarth A et al. Mutations of BRAF and RAS are rare events in germ cell tumours. Int J Cancer 2005; 113 (2): 329–335. doi: 10.1002/ijc.20 567.
82. Goddard NC, McIntyre A, Summersgill B et al. KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature. Int J Androl 2007; 30 (4): 337–348. doi: 10.1111/j.1365-2605.2007.00769.x.
83. Pectasides D, Nikolaou M, Pectasides E et al. Complete response after imatinib mesylate administration in a patient with chemoresistant stage IV seminoma. Anticancer Res 2008; 28 (4C): 2317–2320.
84. Einhorn LH, Brames MJ, Heinrich MC et al. Phase II study of imatinib mesylate in chemotherapy refractory germ cell tumors expressing KIT. Am J Clin Oncol 2006; 29 (1): 12–13. doi: 10.1097/01.coc.0000195086.47548.ef.
85. Castillo-Avila W, Piulats JM, Garcia Del Muro X et al. Sunitinib inhibits tumor growth and synergizes with cisplatin in orthotopic models of cisplatin-sensitive and cisplatin-resistant human testicular germ cell tumors. Clin Cancer Res 2009; 15 (10): 3384–3395. doi: 10.1158/1078-0432.CCR-08-2170.
86. Mego M, Svetlovska D, Miskovska V et al. Phase II study of everolimus in refractory testicular germ cell tumors. Urol Oncol 2016; 34 (3): 122. e17–e22. doi: 10.1016/j.urolonc.2015.10.010.
87. Reckova M, Mego M, Sycova-Mila Z et al. Sunitinib in patients with cisplatin-refractory germ cell tumors. Onkologie 2012; 35 (7–8): 455–456. doi: 10.1159/000341079.
88. Feldman DR, Patil S, Trinos MJ et al. Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design. Cancer 2012; 118 (4): 981–986. doi: 10.1002/cncr.26375.
Štítky
Paediatric clinical oncology Surgery Clinical oncologyČlánok vyšiel v časopise
Clinical Oncology
2017 Číslo 6
- Spasmolytic Effect of Metamizole
- Metamizole at a Glance and in Practice – Effective Non-Opioid Analgesic for All Ages
- Metamizole in perioperative treatment in children under 14 years – results of a questionnaire survey from practice
- Current Insights into the Antispasmodic and Analgesic Effects of Metamizole on the Gastrointestinal Tract
- Obstacle Called Vasospasm: Which Solution Is Most Effective in Microsurgery and How to Pharmacologically Assist It?
Najčítanejšie v tomto čísle
- Catheter-related Bloodstream Infections: Do We Know All of It?
- Milk Thistle (Silybum Marianum) as a Supportive Phytotherapeutic Agent in Oncology
- The Inclusion of a Gemcitabine + Nab-paclitaxel Regimen as a 2nd Line Treatment for Advanced Pancreatic Cancer – First Experience
- Preoperative Axillary Lymph Node Marking in Patients with Breast Cancer