1.Tumour Molecular Genetics Group, Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK
Immature teratomas frequently have chromosomal abnormalities (63%), of which gains of chromosomes 3, 8, 12 and 14, losses of chromosomes 4 and 13, and several structural rearrangements including i(12p) are common. It has been proposed that cytogenetically abnormal immature teratomas are more likely to recur than their cytogenetically normal counterparts.
Over 300 mature teratomas have undergone cytogenetic analysis and only 4% have had aberrant karyotypes, displaying numerical alterations only, none of which are recurrent. The few cases in which abnormalities have been identified were as follows: trisomy of chromosome 8 (2 cases), 13 (1 case), 15 (1 case), 20 (1 case) and double trisomy of chromosomes 7 and 12; losses of chromosomes 3, 6, 7, 11, 16, 17, 21 and 22; structural rearrangements involving +mar (2 cases), add(1)(q11) (1 case), der(6)(t1;6)(q11q22) (1 case), i(12)(p10) (1 case) and +del(20)(q11) (1 case).
Mature teratomas that have undergo malignant transformation display multiple numerical and structural chromosomal anomalies principally involving chromosomes X, 1, 3, 4, 5, 9, 10 and 11. Several similarities were found when comparing the benign cystic and malignant component of an ovarian teratoma. It is noteworthy that the benign component had multiple anomalies (13 non-random structural and numerical changes), which raises the possibility that multiple anomalies in the benign component predispose the tumour to malignant transformation.
Complex numerical and structural chromosome changes were apparent in mixed mesodermal tumors, but there is insufficient data to address whether this tumour subtype has a different composition of chromosomal abnormalities than the other subtypes. Abnormalities of chromosome 12 were found in two of six cases of ovarian choriocarcinomas. Monosomy 22 was identified as the sole anomaly in a mixed germ cell-sex cord stromal tumour in the ovary, by both karyotyping and CGH, which may suggest a common pathogenetic mechanism for both tumour types.
From the cytogenetic data available to date, it appears that similarities exist between OGCT and TGCT. Isochromosome 12p, i(12p), gains of chromosomes 1, 8, 21 and loss of chromosomes 6 and 13 have been reported in both.
27 ovarian GCT were analysed by CGH, of which 12 were dysgerminomas, 6 were ESTs, 3 were mixed GCT and the remainder were immature teratomas. The data was grouped for the dysgerminomas, ESTs and mixed GCT and the most frequent finding was gain of 12p, (14/19), 8 of which showed gain of 12p only, (which may result from i(12p)), 4 showed gains of the entirety of chromosome 12 and 2 showed high level amplification of 12p11-p12. 12p gain is a frequent finding in TGCT, and amplification of 12p11-p12 has also been found in a few such cases. Other recurrent abnormalities were found in this group which have also been previously reported as recurrent findings in TGCT. These include gain of entire chromosome 21 (42 % of malignant OGCT vs. 45% TGCT), gain of chromosome 8 (42% OGCT vs. 45% TGCT), gain of 1q (32% OGCT vs. 36 TGCT) and loss of chromosome 13 (26% OGCT vs. 38% TGCT). There did not appear to be a correlation between the pattern of chromosomal imbalances and histological subtype, except for distal 1p deletion, which was exclusively found in two ESTs. Meanwhile, only 1 of the 6 immature teratomas revealed an abnormality, gain of chromosome 14.
A study summarised these findings according to histological entity. Every dysgerminoma (n=12) analysed showed chromosomal imbalances, with an average number of 10 changes per case. Gains were more common than losses. The most frequent anomalies were gains of 12p (8/12), 12q (9/12), 21q (8/12), 22q (7/12), 20q (6/12), 15q (5/12), 1p (4/12) and 6p (4/12) and the whole of chromosomes 19 (6/12), 7 (5/12), 8 (5/12) and 17 (5/12). Losses of chromosome 13 were seen in 7/12 of the cases. All 4 ESTs analysed displayed copy number changes, with an average of 6 per case. These included gain of 12p (3/4), 1q (3/4), 3p (2/4), 11q (2/4), Xp (2/4), and loss of 18q (2/4). Fewer changes were observed in the immature teratomas, with an average of 1.4 per case. 4 of the 9 immature teratomas had no copy number change. Gain of all or parts of 1p, 16p, 19 and 22 were identified in 2 of the cases with anomalies.
Thus both studies frequently found 12p gains in several subtypes of OGCT, except for immature teratomas, and suggest that immature teratomas follow a different pathway to that taken by other malignant OGCT (and TGCT).
Several interphase cytogenetic studies have been performed on paraffin sections using centromeric probes to determine the copy number of chromosomes, and probes specifically designed to identify the i(12p). A study showed over-representation of chromosomes 7 and 12, and under-representation of chromosome 18, all of which are characteristic features in the male counterpart testicular seminoma.
Ovarian teratomas develop in transgenic mice lacking a functional c-mos proto-oncogene. However, analysis of twenty teratomas for mutations of c-MOS did not identify any, suggesting that mutations of c-MOS do not play a significant role in the development of human ovarian teratomas.
Amplification of MYCN was found in 3/3 immature teratomas, but in 0/5 dermoid cysts and 0/5 mature teratomas. Less than 3% of GCT have mutations of p53. A somatic novel missense mutation (G to C at nucleotide 2467) of c-KIT has been identified in one ovarian mixed dysgerminoma/EST, which resulted in constitutive activation of KIT kinase activity.
There has been a single report of a germline BRCA1 mutation in a 16 year-old woman with dysgerminoma. This mutation was present in numerous relatives with different cancers including breast and ovarian cancer. It is unclear whether the dysgerminoma was a consequence of the germline mutation, or whether germline BRCA1 mutations are responsible for a small proportion of dysgerminomas and other types of OGCT.
Lisa Lee-Jones
Ovary: Germ cell tumors
Atlas Genet Cytogenet Oncol Haematol. 2003-08-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/5067/ovary-germ-cell-tumors