EUROPEAN UROLOGY 67 (2015) 702–703
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 692–701 of this issue
New Insight into the Aetiology of Testicular Germ Cell Tumours Robert Huddart * Department of Radiotherapy, The Institute of Cancer Reasearch and The Royal Marsden Hospital, Sutton, UK
Testicular germ cell tumours (TGCTs) have proven to be an intriguing conundrum. They have a unique epidemiology, with a peak age of presentation between the ages of 20 and 40 yr and a specific racial and geographical distribution. They also have a strong familial predisposition, with brothers having a six to ten times higher risk of developing a TGCT, which is much higher than for most common cancers. TGCTs have been characterised by their almost unique ability among solid tumours to be cured by systemic chemotherapy. Superimposed on these factors has been the substantial increase in incidence observed in Europe over the last 50 yr, even if this incidence has been stabilising or even falling according to recent data [1]. It has long been known that there is a clear link to other testicular abnormalities in general, and testicular maldescent in particular. These features that have increased in frequency in last century have been associated with a decline in average sperm counts. These features have been suggested to form a ‘testicular dysgenesis’ syndrome and their increased frequency is linked to increased foetal exposure to oestrogens [2]. Understanding the biological basis of these epidemiological and clinical features has been a puzzle. Classic investigation of gene mutations has not taken us very far. It has been known since the 1980s that germ cell tumours are significantly aneupoid and harbour a pathgnomic isochromosome 12p (i12p) in approximately 80% of tumours [3,4]. Later work with fluorescent in situ hybridisation and comparative genomic hybridisation suggested that many if not most i12p-negative GCTs contained an amplicon of a smaller section of 12p with a minimal common region of 12p 11.2–p12.1 [5,6]. A number of candidate genes were mapped to this region, with KRAS as a key candidate
[6,7]. However, subsequent testing of the precursor carcinoma in situ (CIS) found that 12p amplification was often absent, suggesting that development of this abnormality was more related to progression from CIS to invasive tumour than an initiating event [8]. Apart from 12p amplification, recurrent structural amplifications at 4q12, 17q21, 22q11, and Xq22, and loss from 5q33, 11q12, 16q22, and 22q11 [9] have been reported in a proportion of patients. KIT mutations have been reported in 10–23% of seminomas, but infrequently in nonseminomas [10–12]; apart from this, somatic mutations in protein kinases occur at low frequency. For instance, Bignell et al [13] noted apart from KIT mutations, a single point mutation in 518 kinase genes in 13 TGCT patients. In this context, the aetiological model proposed by Looloijenga and colleagues [14] in this issue of European Urology is most welcome. Based on evidence from a number of sources, they propose that GCT development is due to disturbance or blockage of normal germ cell maturation. This then makes the immature germ cell tumours susceptible to neoplastic change from puberty onwards. This model is attractive, as it provides a common mechanism for many of the pathologic, epidemiologic, and genetic features of germ cell tumours. Loolijenga and colleagues starting point for this hypothesis is that germ cell tumours morphologically, in their expression histochemically of a number of genes such as OCT3/4, KIT NANOG and in their imprinting pattern resemble primordial germ cells. In this model, risk factors for GCT development exert their impact through a common pathway by interfering with germ cell maturation. A key feature of the model is that it provides a mechanism for both environmental and genetic predisposing factors. Accumulating evidence suggests that changes in the hormonal milieu, and particularly increasing oestrogen
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.07.011. * Department of Radiotherapy, The Institute of Cancer Reasearch and The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel. +44 208 6613529. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.11.032 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 67 (2015) 702–703
exposure, are linked to the rising incidence of testicular cancer. A clear potential mechanism in this model on how this could increase TGCT risk is evident where this hormonal changes affects the delicate hormonal balance required during germ cell maturations. Likewise it links to recent data from genome-wide association studies (GWAS) with many of the implicated genes involved in germ cell migration and differentiation. The most important of these, with the strongest association, is the KITLG locus at 12q21, with an odds ration of 2.5, which is very high for GWAS studies. KIT is thought to have an important role in regulating the survival, proliferation, and migration of germ cells [15]. Two other risk loci (SPRY4 at 5q31 and BAK1 at 6p21) also reside in related pathways. Other loci implicated in genome association studies include pathways involved in sex determination (DMRT1 at 9p24) and germ cell differentiation/specification (DAZL at 3p24.3, PRDM14 at 8q13.3) [16–18]. Thus, the Loolijenga model looks as though it may be a good starting point to gain a better understanding of the aetiology of TGCT. Is this the full story? Probably not, as we still need to understand why 12p amplification is so important, what is the switch that determines whether germ cells develop as seminomas or nonseminomas, and, perhaps most importantly, why most TGCTs are so curable by chemotherapy but some are not. This model, however, is very welcome in at least providing a new insight to support our thinking on GCTs and providing a testable hypothesis.
703
fluorescence in situ hybridization. Cancer Genet Cytogenet 1992;63:8–16. [5] Suijkerbuijk RF, Sinke RJ, Meloni AM, et al. Overrepresentation of chromosome 12p sequences and karyotypic evolution in i(12p)negative testicular germ-cell tumors revealed by fluorescence in situ hybridization. Cancer Genet Cytogenet 1993;70:85–93. [6] Rodriguez S, Jafer O, Goker H, et al. 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 2003;22:1880–91. [7] McIntyre A, Summersgill B, Spendlove HE, Huddart R, Houlston R, Shipley J. Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors. Neoplasia 2005;7:1047–52. [8] Summersgill B, Osin P, Lu YJ, Huddart R, Shipley J. Chromosomal imbalances associated with carcinoma in situ and associated testicular germ cell tumours of adolescents and adults. Br J Cancer 2001;85:213–20. [9] McIntyre A, Summersgill B, Jafer O, et al. Defining minimum genomic regions of imbalance involved in testicular germ cell tumors of adolescents and adults through genome wide microarray analysis of cDNA clones. Oncogene 2004;23:9142–7. [10] Willmore Payne C, Holden JA, Chadwick BE, Layfield LJ. Mod Pathol 2006;19:1164–9. [11] McIntyre A, Summersgill B, Grygalewicz B, et al. 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 2005;65:8085–9. [12] 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 Chromososme Cancer 2008;47:34–42.
Conflicts of interest: The author has nothing to disclose.
[13] Bignell G, Smith R, Hunter C, et al. Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer 2006;45:
References
42–6.
[1] Singhera M, Huddart R. Testicular cancer: changing patterns of
[14] van der Zwan YG, Biermann K, Wolffenbuttel KP, Cools M, Looijenga
incidence in testicular germ cell tumours. Nat Rev Urol
LHJ. Gonadal maldevelopment as risk factor for germ cell cancer:
2013;10:312–4.
towards a clinical decision model. Eur Urol 2015;67:692–701.
[2] Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972–8. [3] Gibas Z, Prout GR, Pontes JE, Sandberg AA. Chromosome changes in germ
cell tumors
of
the
testis. Cancer
Genet
Cytogenet
1986;19:245–52. [4] Suijkerbuijk RF, Looijenga L, de Jong B, Oosterhuis JW, Cassiman JJ,
[15] Boldajipour B, Raz E. What is left behind—quality control in germ cell migration. Sci STKE (383):2007:pe16. [16] Rapley EA, Turnbull C, Al Olama AA, et al. A genome-wide association study of testicular germ cell tumor. Nat Genet 2009;41:807–10. [17] Ruark E, Seal S, McDonald H, et al. Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet 2013;45:686–9.
Geurts van Kessel A. Verification of isochromosome 12p and
[18] Turnbull C, Rapley EA, Seal S, et al. Variants near DMRT1, TERT and
identification of other chromosome 12 aberrations in gonadal
ATF7IP are associated with testicular germ cell cancer. Nat Genet
and extragonadal human germ cell tumors by bicolor double
2010;42:604–7.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 692–701 of this issue
New Insight into the Aetiology of Testicular Germ Cell Tumours Robert Huddart * Department of Radiotherapy, The Institute of Cancer Reasearch and The Royal Marsden Hospital, Sutton, UK
Testicular germ cell tumours (TGCTs) have proven to be an intriguing conundrum. They have a unique epidemiology, with a peak age of presentation between the ages of 20 and 40 yr and a specific racial and geographical distribution. They also have a strong familial predisposition, with brothers having a six to ten times higher risk of developing a TGCT, which is much higher than for most common cancers. TGCTs have been characterised by their almost unique ability among solid tumours to be cured by systemic chemotherapy. Superimposed on these factors has been the substantial increase in incidence observed in Europe over the last 50 yr, even if this incidence has been stabilising or even falling according to recent data [1]. It has long been known that there is a clear link to other testicular abnormalities in general, and testicular maldescent in particular. These features that have increased in frequency in last century have been associated with a decline in average sperm counts. These features have been suggested to form a ‘testicular dysgenesis’ syndrome and their increased frequency is linked to increased foetal exposure to oestrogens [2]. Understanding the biological basis of these epidemiological and clinical features has been a puzzle. Classic investigation of gene mutations has not taken us very far. It has been known since the 1980s that germ cell tumours are significantly aneupoid and harbour a pathgnomic isochromosome 12p (i12p) in approximately 80% of tumours [3,4]. Later work with fluorescent in situ hybridisation and comparative genomic hybridisation suggested that many if not most i12p-negative GCTs contained an amplicon of a smaller section of 12p with a minimal common region of 12p 11.2–p12.1 [5,6]. A number of candidate genes were mapped to this region, with KRAS as a key candidate
[6,7]. However, subsequent testing of the precursor carcinoma in situ (CIS) found that 12p amplification was often absent, suggesting that development of this abnormality was more related to progression from CIS to invasive tumour than an initiating event [8]. Apart from 12p amplification, recurrent structural amplifications at 4q12, 17q21, 22q11, and Xq22, and loss from 5q33, 11q12, 16q22, and 22q11 [9] have been reported in a proportion of patients. KIT mutations have been reported in 10–23% of seminomas, but infrequently in nonseminomas [10–12]; apart from this, somatic mutations in protein kinases occur at low frequency. For instance, Bignell et al [13] noted apart from KIT mutations, a single point mutation in 518 kinase genes in 13 TGCT patients. In this context, the aetiological model proposed by Looloijenga and colleagues [14] in this issue of European Urology is most welcome. Based on evidence from a number of sources, they propose that GCT development is due to disturbance or blockage of normal germ cell maturation. This then makes the immature germ cell tumours susceptible to neoplastic change from puberty onwards. This model is attractive, as it provides a common mechanism for many of the pathologic, epidemiologic, and genetic features of germ cell tumours. Loolijenga and colleagues starting point for this hypothesis is that germ cell tumours morphologically, in their expression histochemically of a number of genes such as OCT3/4, KIT NANOG and in their imprinting pattern resemble primordial germ cells. In this model, risk factors for GCT development exert their impact through a common pathway by interfering with germ cell maturation. A key feature of the model is that it provides a mechanism for both environmental and genetic predisposing factors. Accumulating evidence suggests that changes in the hormonal milieu, and particularly increasing oestrogen
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.07.011. * Department of Radiotherapy, The Institute of Cancer Reasearch and The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel. +44 208 6613529. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2014.11.032 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 67 (2015) 702–703
exposure, are linked to the rising incidence of testicular cancer. A clear potential mechanism in this model on how this could increase TGCT risk is evident where this hormonal changes affects the delicate hormonal balance required during germ cell maturations. Likewise it links to recent data from genome-wide association studies (GWAS) with many of the implicated genes involved in germ cell migration and differentiation. The most important of these, with the strongest association, is the KITLG locus at 12q21, with an odds ration of 2.5, which is very high for GWAS studies. KIT is thought to have an important role in regulating the survival, proliferation, and migration of germ cells [15]. Two other risk loci (SPRY4 at 5q31 and BAK1 at 6p21) also reside in related pathways. Other loci implicated in genome association studies include pathways involved in sex determination (DMRT1 at 9p24) and germ cell differentiation/specification (DAZL at 3p24.3, PRDM14 at 8q13.3) [16–18]. Thus, the Loolijenga model looks as though it may be a good starting point to gain a better understanding of the aetiology of TGCT. Is this the full story? Probably not, as we still need to understand why 12p amplification is so important, what is the switch that determines whether germ cells develop as seminomas or nonseminomas, and, perhaps most importantly, why most TGCTs are so curable by chemotherapy but some are not. This model, however, is very welcome in at least providing a new insight to support our thinking on GCTs and providing a testable hypothesis.
703
fluorescence in situ hybridization. Cancer Genet Cytogenet 1992;63:8–16. [5] Suijkerbuijk RF, Sinke RJ, Meloni AM, et al. Overrepresentation of chromosome 12p sequences and karyotypic evolution in i(12p)negative testicular germ-cell tumors revealed by fluorescence in situ hybridization. Cancer Genet Cytogenet 1993;70:85–93. [6] Rodriguez S, Jafer O, Goker H, et al. 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 2003;22:1880–91. [7] McIntyre A, Summersgill B, Spendlove HE, Huddart R, Houlston R, Shipley J. Activating mutations and/or expression levels of tyrosine kinase receptors GRB7, RAS, and BRAF in testicular germ cell tumors. Neoplasia 2005;7:1047–52. [8] Summersgill B, Osin P, Lu YJ, Huddart R, Shipley J. Chromosomal imbalances associated with carcinoma in situ and associated testicular germ cell tumours of adolescents and adults. Br J Cancer 2001;85:213–20. [9] McIntyre A, Summersgill B, Jafer O, et al. Defining minimum genomic regions of imbalance involved in testicular germ cell tumors of adolescents and adults through genome wide microarray analysis of cDNA clones. Oncogene 2004;23:9142–7. [10] Willmore Payne C, Holden JA, Chadwick BE, Layfield LJ. Mod Pathol 2006;19:1164–9. [11] McIntyre A, Summersgill B, Grygalewicz B, et al. 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 2005;65:8085–9. [12] 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 Chromososme Cancer 2008;47:34–42.
Conflicts of interest: The author has nothing to disclose.
[13] Bignell G, Smith R, Hunter C, et al. Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer 2006;45:
References
42–6.
[1] Singhera M, Huddart R. Testicular cancer: changing patterns of
[14] van der Zwan YG, Biermann K, Wolffenbuttel KP, Cools M, Looijenga
incidence in testicular germ cell tumours. Nat Rev Urol
LHJ. Gonadal maldevelopment as risk factor for germ cell cancer:
2013;10:312–4.
towards a clinical decision model. Eur Urol 2015;67:692–701.
[2] Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972–8. [3] Gibas Z, Prout GR, Pontes JE, Sandberg AA. Chromosome changes in germ
cell tumors
of
the
testis. Cancer
Genet
Cytogenet
1986;19:245–52. [4] Suijkerbuijk RF, Looijenga L, de Jong B, Oosterhuis JW, Cassiman JJ,
[15] Boldajipour B, Raz E. What is left behind—quality control in germ cell migration. Sci STKE (383):2007:pe16. [16] Rapley EA, Turnbull C, Al Olama AA, et al. A genome-wide association study of testicular germ cell tumor. Nat Genet 2009;41:807–10. [17] Ruark E, Seal S, McDonald H, et al. Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet 2013;45:686–9.
Geurts van Kessel A. Verification of isochromosome 12p and
[18] Turnbull C, Rapley EA, Seal S, et al. Variants near DMRT1, TERT and
identification of other chromosome 12 aberrations in gonadal
ATF7IP are associated with testicular germ cell cancer. Nat Genet
and extragonadal human germ cell tumors by bicolor double
2010;42:604–7.
