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Clinical and genetic aspects of testicular germ cell tumours.

Lutke Holzik MF, Sijmons RH, Hoekstra-Weebers JE, Sleijfer DT, Hoekstra HJ - Hered Cancer Clin Pract (2008)

Bottom Line: In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs).Its incidence has increased sharply in recent years.Whether highly penetrant TGCT-predisposing mutations truly exist or familial clustering of TGCT can be explained by combinations of weak predispositions, shared in utero or postnatal risks factors and coincidental somatic mutations is an intriguing puzzle, still waiting to be solved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. lutkeholzik@home.nl

ABSTRACT
In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs). TGCT is the most common type of malignant disorder in men aged 1540 years. Its incidence has increased sharply in recent years. Fortunately, survival of patients with TGCT has improved enormously, which can chiefly be attributed to the cisplatin-based polychemotherapy that was introduced in the nineteen eighties to treat patients with metastasized TGCT. In addition, new strategies have been developed in the surgical approach to metastasized/non-metastasized TGCT and alterations have been made to the radiotherapy technique and radiation dose for seminoma. Family history of TGCT is among the strongest risk factors for this tumour type. Although this fact and others suggest the existence of genetic predisposition to develop TGCT, no germline mutations conferring high risk of developing TGCT have been identified so far. A small deletion, referred to as gr/gr, identified on the Y chromosome is probably associated with only a modest increase in TGCT risk, and linkage of familial TGCT to the Xq27 region has not been confirmed yet. Whether highly penetrant TGCT-predisposing mutations truly exist or familial clustering of TGCT can be explained by combinations of weak predispositions, shared in utero or postnatal risks factors and coincidental somatic mutations is an intriguing puzzle, still waiting to be solved.

No MeSH data available.


Related in: MedlinePlus

The testicular dysgenesis syndrome.
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Figure 1: The testicular dysgenesis syndrome.

Mentions: Carcinoma in situ (CIS) (or intratubular germ cell neoplasia) is the precursor of TGCT and is found in nearly all TGCT together with an invasive component. CIS cells originate from primordial germ cells that "escaped" normal differentiation in utero. It is assumed that over the course of time, CIS "develops" into an invasive TGCT, but the precise transformation of premalignant CIS into a TGCT is not yet clear. It is suggested that the default pathway follows the development of CIS into seminoma and that non-seminoma requires activation of pluripotency (reprogramming) of a CIS or seminoma cell [10,11]. A theoretical model of TGCT development as part of testicular dysgenesis, taking into account a range of reported TGCT risk factors, has been developed by Skaekebaek et al. [12] and is referred to as the testicular dysgenesis syndrome (TDS) (Figure 1). In recent years several studies have looked into chromosomal abnormalities and more recently at gene mutations and gene activity in TGCT to unravel the molecular pathways underlying these tumours. A detailed overview of (non-inherited) genomic aberrations in TGCT was recently published by von Eyben [13]. Aneuploidy has been found in nearly all cases and triploidy is a common finding. Seminomas have a mean hypertriploid DNA index and non-seminomas have a mean hypotriploid DNA index (due to loss of chromosomal material during cancer progression) [11]. When looking at individual chromosomal regions, an isochromosome of the short arm of chromosome 12, i(12p), (resulting in a duplication of the short arm of chromosome 12) is found in about 80% of TGCT. The remainder have excess 12p genetic material in derivative chromosomes [14]. The exact relation between these changes and TGCT is unclear but the absence of amplification of a section of 12p in intratubular germ cell neoplasia suggests that this amplification may be related to progression of the disease rather than initiation [15]. A recent gene expression profile study on TGCT material identified differentiated expressed genes on 12p. Seventy-three genes on 12p were significantly overexpressed, indicating that the p arm of chromosome 12 may play an important role in TGCT tumorigenesis [16]. In addition to the genes located on 12p, a growing list of genes is implicated in the various stages of TGCT development. In particular, TGCT has been shown to be associated with a characteristic series of abnormalities in the retinoblastoma pathway including upregulation of cyclin D2 and p27 and downregulation of RB1 and the cyclin-dependent kinase inhibitors of p16, p18, p19 and p21 [13]. A gain of activity of the KIT gene, a member of the tyrosine kinase family, appears to play a role in the progression of CIS towards seminomas [17]. Recently, the scope of genetic study of TGCT has been extended to include the role of naturally occurring micro RNAs (miRNAs). Indeed, some of these miRNAs (miRNA-372 and 373) were shown to allow tumorigenic growth. As they have also been observed to be expressed in human seminomas and non- seminomas, but not in normal testicular tissue, it has been suggested that these miRNAs may represent a new class of oncogenes involved in TGCT [18].


Clinical and genetic aspects of testicular germ cell tumours.

Lutke Holzik MF, Sijmons RH, Hoekstra-Weebers JE, Sleijfer DT, Hoekstra HJ - Hered Cancer Clin Pract (2008)

The testicular dysgenesis syndrome.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2735737&req=5

Figure 1: The testicular dysgenesis syndrome.
Mentions: Carcinoma in situ (CIS) (or intratubular germ cell neoplasia) is the precursor of TGCT and is found in nearly all TGCT together with an invasive component. CIS cells originate from primordial germ cells that "escaped" normal differentiation in utero. It is assumed that over the course of time, CIS "develops" into an invasive TGCT, but the precise transformation of premalignant CIS into a TGCT is not yet clear. It is suggested that the default pathway follows the development of CIS into seminoma and that non-seminoma requires activation of pluripotency (reprogramming) of a CIS or seminoma cell [10,11]. A theoretical model of TGCT development as part of testicular dysgenesis, taking into account a range of reported TGCT risk factors, has been developed by Skaekebaek et al. [12] and is referred to as the testicular dysgenesis syndrome (TDS) (Figure 1). In recent years several studies have looked into chromosomal abnormalities and more recently at gene mutations and gene activity in TGCT to unravel the molecular pathways underlying these tumours. A detailed overview of (non-inherited) genomic aberrations in TGCT was recently published by von Eyben [13]. Aneuploidy has been found in nearly all cases and triploidy is a common finding. Seminomas have a mean hypertriploid DNA index and non-seminomas have a mean hypotriploid DNA index (due to loss of chromosomal material during cancer progression) [11]. When looking at individual chromosomal regions, an isochromosome of the short arm of chromosome 12, i(12p), (resulting in a duplication of the short arm of chromosome 12) is found in about 80% of TGCT. The remainder have excess 12p genetic material in derivative chromosomes [14]. The exact relation between these changes and TGCT is unclear but the absence of amplification of a section of 12p in intratubular germ cell neoplasia suggests that this amplification may be related to progression of the disease rather than initiation [15]. A recent gene expression profile study on TGCT material identified differentiated expressed genes on 12p. Seventy-three genes on 12p were significantly overexpressed, indicating that the p arm of chromosome 12 may play an important role in TGCT tumorigenesis [16]. In addition to the genes located on 12p, a growing list of genes is implicated in the various stages of TGCT development. In particular, TGCT has been shown to be associated with a characteristic series of abnormalities in the retinoblastoma pathway including upregulation of cyclin D2 and p27 and downregulation of RB1 and the cyclin-dependent kinase inhibitors of p16, p18, p19 and p21 [13]. A gain of activity of the KIT gene, a member of the tyrosine kinase family, appears to play a role in the progression of CIS towards seminomas [17]. Recently, the scope of genetic study of TGCT has been extended to include the role of naturally occurring micro RNAs (miRNAs). Indeed, some of these miRNAs (miRNA-372 and 373) were shown to allow tumorigenic growth. As they have also been observed to be expressed in human seminomas and non- seminomas, but not in normal testicular tissue, it has been suggested that these miRNAs may represent a new class of oncogenes involved in TGCT [18].

Bottom Line: In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs).Its incidence has increased sharply in recent years.Whether highly penetrant TGCT-predisposing mutations truly exist or familial clustering of TGCT can be explained by combinations of weak predispositions, shared in utero or postnatal risks factors and coincidental somatic mutations is an intriguing puzzle, still waiting to be solved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. lutkeholzik@home.nl

ABSTRACT
In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs). TGCT is the most common type of malignant disorder in men aged 1540 years. Its incidence has increased sharply in recent years. Fortunately, survival of patients with TGCT has improved enormously, which can chiefly be attributed to the cisplatin-based polychemotherapy that was introduced in the nineteen eighties to treat patients with metastasized TGCT. In addition, new strategies have been developed in the surgical approach to metastasized/non-metastasized TGCT and alterations have been made to the radiotherapy technique and radiation dose for seminoma. Family history of TGCT is among the strongest risk factors for this tumour type. Although this fact and others suggest the existence of genetic predisposition to develop TGCT, no germline mutations conferring high risk of developing TGCT have been identified so far. A small deletion, referred to as gr/gr, identified on the Y chromosome is probably associated with only a modest increase in TGCT risk, and linkage of familial TGCT to the Xq27 region has not been confirmed yet. Whether highly penetrant TGCT-predisposing mutations truly exist or familial clustering of TGCT can be explained by combinations of weak predispositions, shared in utero or postnatal risks factors and coincidental somatic mutations is an intriguing puzzle, still waiting to be solved.

No MeSH data available.


Related in: MedlinePlus