Differential expression of protooncogenes in human germ cell tumors of the testis

Abstract

Background. It has been suggested that tumorigenesis of the germ cell tumor of the testis includes abnormal and developmentlike differentiation of primordial germ cells to several mature type tumors. Methods. To clarify roles of protooncogenes in the unique tumorigenic mechanism in the human germ cell tumor, the authors examined the expression of 15 protooncogenes in human primary germ cell tumors of the testis with Northern blot analyses. Results. Fifteen (94%) of 16 seminomas and 5 (83%) of 6 embryonal carcinomas had a significant levels of N‐myc expression, whereas they did not express two receptor type protooncogenes, c‐erbB‐1 and c‐erbB‐2. In contrast, some immature teratomas had a high level of c‐erbB‐1 expression, and an advanced case showed a significant level of c‐erbB‐2 expression. Immature teratomas did not show N‐myc expression. Higher levels of c‐mos expression were observed in several cases of seminomas and embryonal carcinomas. Expression of c‐Ki‐ras or N‐ras was observed in all histologic subgroups and normal testes. Conclusion. A significant level of N‐myc expression may be essential for undifferentiated tumors including seminoma and embryonal carcinoma, whereas c‐erbB‐1 and possibly c‐erbB‐2 may have important roles in the differentiated tumors such as immature teratoma. These results suggest that some of the protooncogene expression may be switched critically during the differentiation from seminomas or embryonal carcinomas to the more differentiated‐type tumor.

Reviews of Chromosome Studies in Urological Tumors. III. Cytogenetics and Genes in Testicular Tumors

“…tumors: 7 of 9 seminomas (78%) were positive, whereas 22 of 31 nonseminomas (71%) were negative for c-KIT and SCF genes.206 Considering th at expression of c-KIT is present in the normal testis but lost or decreased during differentiation from seminomas to nonseminomatous testicular germ cell tumors, it has been suggested that this oncogene may inter fere with differentiation in these tumors. 207 Such an involve ment in the pathogenesis of testicular germ cell tumors has also been suggested for the SCF gene.206 Intriguingly, the SCF gene has been mapped to the long arm of chromosome 12 at the q22 locus, a region presumed to undergo alterations in the pathogenesis of testicular germ cell tumors.…”

“…The c-KIT oncogene (or stem cell factor [SCF] receptor gene), which encodes a tyrosine kinase receptor that has a funda mental role in the regulation of early hematopoiesis, sper matogenesis and melano gene sis, has been found to be ex pressed significantly in seminomas only. 207 Likewise, the SCF gene shows altered expression in testicular germ cell . tumors: 7 of 9 seminomas (78%) were positive, whereas 22 of 31 nonseminomas (71%) were negative for c-KIT and SCF genes.206 Considering th at expression of c-KIT is present in the normal testis but lost or decreased during differentiation from seminomas to nonseminomatous testicular germ cell tumors, it has been suggested that this oncogene may inter fere with differentiation in these tumors.…”

“…207 Conversely, the HST-1 gene product, which belongs to the family of human fibroblast growth factors, is absent in nor mal nonmalignant nonseminomatous testicular germ cell tu mors.113»163 An inverse relationship between expression of HST-1 and c-KIT oncogenes in testicular germ cell tumors has been suggested. 163 The INT-2 gene, which is 61% homol ogous to the HST-1 gene, showed no expression.113 Several additional proto-oncogenes (L-MYC, c-MYB and INT-1) showed no expression in any type of testicular germ cell tumors, whereas others (c-RAF and c-FMS) were expressed in all types and in normal testis tissue.…”

“…163 The INT-2 gene, which is 61% homol ogous to the HST-1 gene, showed no expression.113 Several additional proto-oncogenes (L-MYC, c-MYB and INT-1) showed no expression in any type of testicular germ cell tumors, whereas others (c-RAF and c-FMS) were expressed in all types and in normal testis tissue. 207 Other examples of significant differential expression of proto-oncogenes in adult testicular germ cell tumors have been described. N-MYC is expressed in more than 80% (20 of 22) of the less differentiated histological types (that is semi nomas and embryonal carcinomas), 207 In contrast, the rela tively more differentiated testicular germ cell tumors (that is immature teratomas) showed no N-MYC expression but re vealed a high level of c-ERBB-1 expression, which in turn (like c-ERBB-2) was absent or at minimum level in semino mas, embryonal carcinomas and normal testes.207 Another interesting finding was the type specificity of testicular germ cell tumors in the expression of the PTHLH gene, which is mapped to the short arm of chromosome 12.109-111 The on cofetal PTHLH gene was expressed in all 20 tumor samples containing elements of seminoma and choriocarcinoma but its product was not detected in embryonal carcinomas or teratomas as revealed by immunohistochemistry, in situ hy bridization and Northern blot analysis.113 Together, it has been amply demonstrated that the expression of several proto-oncogenes is switched critically during the differentia tion from seminomas or embryonal carcinomas to the more relatively differentiated nonseminomatous tumor types and, therefore, they may have important roles in differentiation of testicular germ cell tumors.…”

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors

“…Upon di erentiation to the mature B cell stage, coincident with completion of immunoglobulin (Ig) gene expression, N-myc expression turns o and remains o (Reth et al, 1985;Zimmerman et al, 1986;Smith et al, 1992;Morrow et al, 1992). The oncogenic potential of the human N-myc gene has been implicated in various tumors including neuroblastoma (Brodeur et al, 1984;Kohl et al, 1984), Wilms' tumor (Nisen et al, 1986), retinoblastoma (Lee et al, 1984), small cell lung carcinoma , medullary thyroid carcinoma (Roncalli et al, 1994), testis (Shuin et al, 1994), brain (Hirvonen et al, 1994), and breast (Mizukami et al, 1995). Human N-myc gene expression has been observed to be elevated in several AML and ALL leukemias and leukemic cell lines (Hirvonen et al, 1991) while not detectable in pre-preB and preB leukemic cell lines (Wetherall and Vogler, 1992).…”