Chromosomal imbalances associated with carcinoma in situ and associated testicular germ cell tumours of adolescents and adults

Abstract

Carcinoma in situ (CIS) or intratubular germ cell neoplasia is generally considered the precursor lesion of adult testicular germ cell tumours (TGCT). The chromosomal imbalances associated with CIS and the corresponding seminoma (SE) or nonseminoma (NS) have been determined by comparative genomic hybridization (CGH) analysis of microdissected material from seven cases. Significantly, the CIS showed no gain of 12p material whereas in the invasive components of all cases gain of 12p was found, in 2 cases associated with amplification of the 12p11.2–12.1 region. Interphase fluorescence in situ analysis was consistent with this and provided evidence for the i(12p) or 12p11.2–12.1 amplification in the SE and NS but not in the corresponding CIS. This suggests a role for these changes in progression of CIS to invasive testicular cancer or progression of the invasive disease. Other imbalances such as gain of material from chromosomes 1, 5, 7, 8, 12q and X and loss of material from chromosome 18 were frequently identified (> 40% of cases) in the CIS associated with both SE and NS as well as in the invasive components. Loss of material from chromosome 4 and 13 and gain of 2p were more frequently found in the invasive components. The results shed light on the genetic relationship between the non-invasive and invasive components of testicular cancer and the stage at which particular chromosomal changes may be important. © 2001 Cancer Research Campaign http://www.bjcancer.com

Origin of pluripotent germ cell tumours: The role of microenvironment during embryonic development

“…Although polyploidization seems to appear prior to the establishment of extra 12p material (Geurts van Kessel et al, 1989;Oosterhuis et al, 1989;Ottesen et al, 2004b), the specific stage at which tumour development is initiated and genomic instability introduced remains unresolved. Due to technical problems only a small number of cases of CIS have been examined for chromosomal aberrations, however a range of imbalances were detected, including gains of regions of the chromosomes 7, 8, 12, 14, 15, 17 and X (Looijenga et al, 2000;Summersgill et al, 2001;Ottesen et al, 2003;Ottesen et al, 2004a;Ottesen et al, 2004b). A recurrent gain of 12p material was demonstrated in the vast majority of overt TGCTs, together with chromosomal aberrations established as typical for TGCTs (Atkin & Baker 1982;Summersgill et al, 2001; and reviewed in Page 7 of 22 A c c e p t e d M a n u s c r i p t 7 von Eyben, 2004).…”

“…Due to technical problems only a small number of cases of CIS have been examined for chromosomal aberrations, however a range of imbalances were detected, including gains of regions of the chromosomes 7, 8, 12, 14, 15, 17 and X (Looijenga et al, 2000;Summersgill et al, 2001;Ottesen et al, 2003;Ottesen et al, 2004a;Ottesen et al, 2004b). A recurrent gain of 12p material was demonstrated in the vast majority of overt TGCTs, together with chromosomal aberrations established as typical for TGCTs (Atkin & Baker 1982;Summersgill et al, 2001; and reviewed in Page 7 of 22 A c c e p t e d M a n u s c r i p t 7 von Eyben, 2004). Fascinatingly, the extra 12p material was also observed in several cases of CIS adjacent to overt tumours but was absent in CIS cells with no evidence of invasive growth (Looijenga et al, 2000;Ottesen et al, 2003;Ottesen et al, 2004a;Ottesen et al, 2004b;Skotheim et al, 2006).…”

Syndromic aspects of testicular carcinoma

“…In addition, complex rearrangements have been found with increases and decreases of specific chromosomal material: (parts of) chromosomes 4, 5, 11, 13, 18, and Y are under-represented, whereas (parts of) chromosomes 7, 8, 12, 21, and X are overrepresented. [22][23][24][25] The search for genes in these regions that are responsible for testicular carcinoma, including 12p, is still in its early stages, and it remains unknown which of these genes also may carry germline mutations. 26 To date, linkage studies on these regions have isolated only Xq27 as the locus for a gene (TGCT1) that may be responsible for familial clustering of testicular carcinoma.…”

Germ cell neoplasia in situ: The precursor cell for invasive germ cell tumors of the testis

“…It is not known definitively whether malignant capacity exists from inception, though it seems likely that a second 'hit' in the form of chromosomal aberrations is required to reach this potential. Gain of the short arm of chromosome 12 (or smaller parts thereof) is present in an estimated 80-100% of invasive seminoma and non-seminoma tumors and also in GCNIS cells adjacent to these neoplasms (Summersgill et al, 2001). GCNIS cells that are not in the physical vicinity of tumorigenic lesions generally lack short arm of chromosome 12 gain, suggesting that it is a key transformative event.…”

“…This chromosomal region harbors a 200-kb gene cluster containing bona fide stem cell-related genes NANOG, STELLA and GDF3, which are also expressed and associated with pluripotency in human ES cells, and presumably similarly promote pluripotency in GCNIS (Clark et al, 2004). In GCNIS cells associated with invasive seminoma and non-seminoma there is also a typical gain of material from chromosomes 1,5,7,8,12 and X and lack of material from 4 and 13 (Summersgill et al, 2001). …”