Molecular cytogenetic analysis of i(12p)‐negative human male germ cell tumors

Abstract

The i( I2p) chromosome has been shown to characterize more than 80% of male germ cell tumors (GCTs) and is an important diagnostic marker. Although recent cytogenetic analyses of GCTs have defined nonrandom chromosome abnormalities in these tumors, no attempt has so far been made to compare i( I2p)-positive and -negative tumors in terms of their cytogenetic, histologic, and clinical features. During a 5-year period, we have ascertained 202 GCTs, of which I17 had clonally abnormal karyotypes. Among the latter, 9 I had one or more copies of i( I2p), whereas 26 lacked an i( I2p). We report here the karyotypic analysis of these 26 i( I2p)-negative GCTs. In this group, nonrandom sites of chromosomal rearrangements included I2p I 3 (9/26) and I p I I -q I I (5126). Comparison of the cytogenetic features of i( I2p)-negative tumors with i( I2p)-positive tumors revealed the only significant difference t o be rearrangements affecting I2pl3 in the former (35%) as compared t o their absence in the latter (3%). Hybridization of metaphase preparations of 9 i( I 2p)-negative tumors with a chromosome I 2 painting probe and with a microdissected I2p painting probe revealed extra copies of chromosome I 2 segments incorporated into marker chromosomes whose composition could not otherwise be resolved by banding analysis; all were shown t o be derived from I2p. These data demonstrate that both i( I 2p)-negative and -positive groups are characterized by an increased copy number of I 2p, which is consistent with a lack of significant clinical or biological difference between them. An increased I2p copy number thus is a specific aberration of significance t o the development of germ cell tumors.

Origins and molecular biology of testicular germ cell tumors

“…66,67 Approximately 80% of cases have i(12p) and the remainder have excess 12p genetic material in derivative chromosomes. 68 The consistent gain of 12p genetic material is supported by gene array and comparative genomic hybridization data. 69,70 The presence of i(12p) in IGCNU is a matter of controversy with most investigators suggesting it is not present.…”

“…Since the formation of the isochromosome includes the centromeric/pericentromeric region of chromosome 12, the abnormality can be detected using commercially available chromosome 12 centromeric fluorescent in situ hybridization (FISH) probes. 67,68,71 In a metaphase spread these will show the isochromosome nicely. In interphase cells one can detect a numerical abnormality (normal chromosome 12 plus the number of isochromosomes present) but it is more difficult if not impossible to state that an isochromosome is indeed present.…”

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults

“…It has been known for more than a decade that the majority of TGCTs contains one or more isochromosomes of the short arm of chromosome 12 (Mukherjee et al, 1991;Rodriquez et al, 1993a;Van Echten et al, 1995;Mostert et al, 1996b). Moreover, it has been demonstrated, that TGCTs without i(12p) also show over-representation of 12p-sequences (Suijkerbuijk et al, 1993;Rodriquez et al, 1993b;Smolarek et al, 1995). Since in those studies a paint for the whole short arm of chromosome 12 was used, or a probe which was not mapped in detail, it was not possible to localize the region involved.…”

“…In the majority of TGCTs tested this was due to the presence of one or more copies of isochromosome 12p [i(12p)]. In addition, it was found using¯uorescence in situ hybridization (FISH) that TGCTs without i(12p) always show overrepresentation of 12p-sequences cryptically hidden in the genome (Suijkerbuijk et al, 1993;Rodriquez et al, 1993b;Smolarek et al, 1995). We showed that i(12p) may also be present in CIS (Vos et al, 1990), indicating that over-representation of 12p-sequences is probably a relatively early event in the pathogenesis of this cancer, not related to invasive growth.…”

Fluorescence in situ hybridization analysis of chromosome 12p in paraffin-embedded tissue is useful for establishing germ cell origin of metastatic tumors

“…Abnormalities of 12p have been shown to occur early in the evolution of germ cell tumor, with some evidence that 12p amplification is required for the development of an invasive tumor. [6][7][8][9][10] There are many studies which have evaluated 12p abnormalities in testicular germ cell tumors. These studies include classic cytogenetic analyses, FISH on metaphase cells of fresh tissue, FISH on interphase cells from paraffin-embedded tissue, and comparative genomic hybridization.…”