Cytogenetic and molecular analysis of a family with three brothers afflicted with germ‐cell cancer

Abstract

A thorough cytogenetic investigation and an analysis of detailed questionnaires were performed in a family with three brothers afflicted with germ-cell tumors (GCTs), in an attempt to detect a congenital factor related either to a hereditary genetic background or an environmental/lifestyle influence. One brother had an intracranial tumor in the pineal region and the two others had testicular tumors. Peripheral blood was studied by traditional karyotyping, multicolor-FISH, high-resolution comparative genomic hybridization (HR-CGH), and molecular analysis of selected loci on sex chromosomes (Yq11 region, TSPY, and the androgen receptor gene); however, no abnormalities were detected. The HR-CGH analysis of microdissected histological components of the overt tumors and the adjacent carcinoma in situ demonstrated a pattern of genomic imbalances characteristic for sporadic GCTs, including gain of 12p. The questionnaire and interview revealed a history of different cancers in the extended family, and a possible in utero and/or infantile exposure of the three brothers with GCTs to compounds suspected of endocrine-disrupting properties. Although no genetic aberration was detected in this family, we suspect the presence of a recessive hereditary factor pre-disposing to cancer, which probably was manifested as GCTs in the three brothers because of an adverse effect of an environmental factor on the early germ-cell differentiation.

Constitutional Cytogenetic Analysis in Men with Hereditary Testicular Germ Cell Tumor: No Evidence of Disease-Related Abnormalities

“…Results were reported using the International System for Human Cytogenetic Nomenclature (17). A literature review was also done via PubMed, using all languages and the search terms hereditary testicular cancer, familial testicular, and genetics and testicular cancer, to identify HTGCT cases that have previously been evaluated using these cytogenetic techniques; three reports were identified (18)(19)(20).…”

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

“…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). Whereas gains of 17q were only detected in a few CIS cases (Ottesen et al, 2003;Ottesen et al, 2004b), a recurrent gain of 17q has been associated with non-seminomas in particular, perhaps illustrating the high proliferation potential of this more aggressive tumour (Kraggerud et al, 2002;Skotheim et al, 2002).…”

“…This is supported by the high expression of SOX2 in EC (Perrett et al in press), for example, while in seminoma this marker is virtually negative (Sperger et al, 2003;Santagata et al, 2007). A further somatic differentiation of EC is observed in nearly all nonseminomas and this event is associated with down-regulation/inactivation of the embryonic pluripotency genes ( CIS cells are known to undergo polyploidization and DNA content in the triploid to hypotetraploid range has been identified in CIS adjacent to both seminoma and non-seminoma (Ottesen et al, 2004b). 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.…”

“…A further somatic differentiation of EC is observed in nearly all nonseminomas and this event is associated with down-regulation/inactivation of the embryonic pluripotency genes ( CIS cells are known to undergo polyploidization and DNA content in the triploid to hypotetraploid range has been identified in CIS adjacent to both seminoma and non-seminoma (Ottesen et al, 2004b). 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).…”

“…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).…”