Adult Testicular Germ Cell Research Articles

Molecular Cytogenetic Analysis of Adult Testicular Germ Cell Tumours and Identification of Regions of Consensus Copy Number Change

Molecular Cytogenetic Analysis of Adult Testicular Germ Cell Tumours and Identification of Regions of Consensus Copy Number Change

Molecular cytogenetic analysis of adult testicular germ cell tumours and identification of regions of consensus copy number change

A series of adult testicular germ cell tumours consisting of eight seminomas, 14 non-seminomas (including two cell lines) and two combined tumours was analysed by comparative genomic hybridization and, in some cases, by interphase fluorescence in situ hybridization. The gain of 12p was identified in all cases and additional material from chromosomes 7 and 8 was found in over 70% of cases, in keeping with previous analyses. Other consistent regions of gain included 1q24-q31 (50%), 2p16-pter (41%), 2q22-q32 (45%) and Xq11-q21 (50%). The loss of 1p32-p36 (36%), 9q31-qter (36%), 11q14-qter (50%), 16p (36%) and 18p (45%) and the loss of material from chromosomes 4 and 5 (50% and 36% respectively) were also found in all histological subtypes. The loss of 1p material was confirmed in four cases by interphase FISH analysis and shown, with one exception, not to involve the loss of the D1Z2 locus at 1p36.3, which is commonly deleted in paediatric germ cell tumours. An association between gain of 6q21-q24 with cases resistant to chemotherapy (P < 0.01) was observed. In addition, loss of chromosome 19 and 22 material and gain of 5q14-q23, 6q21-q24 and 13q were found at a significantly lower frequency in seminoma than non-seminoma. These regions may contain genes involved in the divergent development of seminoma and non-seminoma.

The origin and biology of CIS cells: general discussion.

Participants at the 4th Copenhagen Workshop on Carcinoma in situ and Cancer of the Testis, representing cell biologists and tumour biologists, met together to discuss the similarities and differences between primordial germ cells (PGCs) of the embryo, and the carcinoma in situ (CIS) stem cell of human testicular germ cell tumours (GCTs). Much has been discovered about PGCs in the last 10 years and we still do not know the exact nature of CIS cells. Knowledge of PGCs comes mainly from mouse experiments and knowledge of CIS comes from the study of human tumours. A mouse model of human GCT would help to investigate the nature of CIS cells. Grafting mouse male genital ridges into mouse fetal testes results in the development of testicular tissue and the formation of teratomatous tumour components. Amplification of PGCs in culture is possible but this results in their transformation into embryonic germ (EG) cells. CIS cells die by apoptosis if they are isolated, and short-term culture is only possible if the CIS cells are cultured in their normal environment within seminiferous tubules. It may be possible for CIS cells to differentiate in culture although they cannot be maintained in culture as isolated cells. Human CIS cells are likely to be formed as a result of in utero factors rather than agents acting on normal adult testicular germ cells. EG cells stimulate feeder cells by paracrine factors but it is not known if these cells produce autocrine factors.

Cytogenetics of the progression of adult testicular germ cell tumors

This article, written on the occasion of Dr. Avery Sandberg's 75th birthday, is intended to give a general and short overview of the cytogenetic data about testicular germ cell tumors of adolescents and adults we obtained from 1983 till now. The first and last author of this manuscript visited Dr. Sandberg's lab in 1984 to improve their skills in culturing and karyotyping solid tumor cells. Knowing that cancer and progression of cancer is caused by genetic changes (i.e. changes at the chromosomal or gene level), we investigated the karyotypes of about 140 testicular germ cell tumors of the adult and adolescent male (TGCTs). The chromosomal analyses of these tumors may shed light on oncogenesis, tumor progression, pathogenetic relationship, and therapy-related differentiation. We will focus on what we think our cytogenetic data have taught us about the progression of TGCTs. Of course, a way of thinking is always influenced or even determined by the results of others. This article is not intended as a review of the literature. For this the reader should consult a recent and excellent review by Sandberg et al. [1], the manuscripts of others, and our previous publications about germ cell tumors.

High expression of the tec gene product in murine testicular germ cells and erythroblasts.

Tec is a novel non-receptor-type protein tyrosine kinase that was originally identified from a murine liver cDNA library. While the function of Tec remains unknown, it was shown recently that two Tec-related kinases are involved directly in the growth and differentiation of bone marrow stem cells. As the localization of Tec protein has not been reported yet, immunohistochemical and immunochemical studies of various murine organs were conducted in the present study to clarify which cells express this kinase protein. An intense immunohistologic reaction was observed in neonatal and adult testicular germ cells, and neonatal and fetal hepatic erythroblasts. In addition, a clear immunostaining was noted in neonatal and adult tubal epithelial cells, hepatocytes, basal cells of the non-glandular stomach, foveolar epithelium of the glandular stomach, sebaceous cells of the skin and fetal cartilage. The immune reaction of germ cells and erythroblasts was observed in the cell membrane, although this protein does not have a transmembrane domain. Supportive western blotting of testis, adult liver, spleen and heart of adult C.B-17 mice with the use of anti-Tec antibody demonstrated a heavy 70 kDa band in the liver and testis, and a much weaker, small band in the heart and spleen. These results suggest that Tec protein has a specific role in testicular germ cells and erythroblasts.

Immunohistochemical Expression of P53 Tumor Suppressor Gene Protein in Adult Germ Cell Testis Tumors: Clinical Correlation in Stage I Disease

P53 tumor suppressor gene protein immunostaining was evaluated in the primary tumor of adult testicular germ cell cancer to assess if P53 expression would serve as a clinically useful tumor marker. Representative archival tissues from 152 orchiectomy specimens were studied for P53 immunohistochemistry. Seminoma and nonseminomatous germ cell tumor constituents revealed P53 expression via immunohistochemistry in 90% and 94% of the cases, respectively. For seminoma, there was a trend toward decreased P53 expression with advancing stage. For nonseminomatous germ cell tumor, although all cellular components showed variable P53 expression, P53 expression in embryonal carcinoma constituents increased among stages of disease. A third of pathological stage I cancer patients exhibited 2+ or greater P53-embryonal staining compared with 61% with stage II (p = 0.0670) and 67% with stage III (p = 0.0815) disease, respectively (Kruskal-Wallis, 2-sided test).As a secondary objective, we wanted to determine if P53 immunohistochemistry would be useful to predict occult disease in clinical stage I nonseminomatous germ cell tumor. This group was studied for P53-embryonal immunohistochemistry, the presence of vascular invasion and the quantitative determination of percentage of embryonal carcinoma in the primary tumor in a multivariate fashion to assess if these tests could be clinically useful to predict occult disease. Degree of P53 immunostaining of the embryonal component in the primary tumor was statistically greater for stage II by univariate logistic regression analysis (p = 0.0362). Similarly, the per cent embryonal cancer (p = 0.0002) and vascular invasion (p = 0.0005) were highly significant as predictors of occult stage II disease via the univariate testing. By multivariate logistic regression analysis, the model consisting of per cent embryonal cancer and vascular invasion provided the best prediction of occult disease in the clinical stage I cohort. In addition, this model had the highest sensitivity and specificity of all multivariate models considered. The addition of P53-embryonal staining did not improve predictability nor sensitivity/specificity.The P53 tumor suppressor gene protein is expressed to some degree in most testicular germ cell tumors and degree of staining/expression varies according to stage of disease. From the standpoint of a clinically useful primary tumor risk factor for predicting occult disease, vascular invasion by the tumor and percentage of embryonal carcinoma component in the tumor are more useful than P53 immunohistochemistry.

LINE-1 retrotransposon expression in pediatric germ cell tumors

Human LINE-1 (L1Hs) is a retrotransposon that is known to cause insertion mutations. Previous work demonstrated that at least 10% of adult testicular germ cell cancers expressed the L1Hs element. Pediatric germ cell tumors were assayed for L1Hs expression by in situ immunohistochemical methods using an antibody directed against one of the L1Hs-encoded proteins. Approximately 10% of pediatric germ cell tumors express abundant amounts of the L1Hs protein. The element was expressed in 1 of 19 ovarian tumors, 1 of 20 testicular tumors, and 4 of 19 extragonadal tumors. The reactive cells in all cases appeared to be embryonal carcinoma or yolk sac tumor cells. None of 32 ovarian immature teratomas gave positive results, suggesting that more differentiated tissues do not express L1Hs abundantly. It appears that neither the age nor sex of the patient, nor the location of the tumor, has a significant influence on the degree of L1Hs expression.

Pathogenesis of adult testicular germ cell tumors: A cytogenetic model

In essence, two models exist of the pathogenetic relationship between seminomas and nonseminomatous germ cell tumors (NSGCTs). In the first model, the histogenesis of seminomas is assumed to diverge from that of the other testicular germ cell tumors (TGCTs) at an early stage. The neoplastic pathway of seminomas and NSGCTs is different, with limited or no crossover. The second model suggests that seminomas and NSGCTs have a common origin with a single neoplastic pathway on which seminomas are an intermediate stage in development of NSGCTs. Our data on the cytogenetics and ploidy of seminomas, combined tumors, and NSGCTs lend support to the model of pathogenesis of seminomas and NSGCTs in which all TGCTs (with the possible exception of spermatocytic seminoma and infantile yolk sac tumor) have a single origin and neoplastic pathway, with seminomas representing an intermediate stage in development of NSGCT components, as opposed to the model in which seminomas and NSGCTs develop separately. The progression of TGCTs probably proceeds from high to lower numbers of chromosomes and is therefore accompanied by a net loss of chromosomal material. This decrease will be the end result of loss of specific chromosomes, gain of some other chromosomes (or part of chromosomes), and development of structural abnormalities.

Karyotyping and DNA flow cytometry of an orchidoblastoma

The first karyotype of an orchidoblastoma is described. The most striking finding is the absence of the i(12p) marker chromosome, considered specific for testicular germ cell tumors of adults. Differences between infantile and adult testicular germ cell tumors are discussed, as are features that infantile testicular germ cell tumors have in common with extragonadal germ cell tumors.