Chromosomes and Expression in Human Testicular Germ-Cell Tumors: Insight into Their Cell of Origin and Pathogenesis (original) (raw)
Related papers
Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults
Genes, Chromosomes and Cancer, 2008
Testicular germ cell tumors (TGCTs) of adults and adolescents are thought to be derived from primordial germ cells or gonocytes. TGCTs develop postpuberty from precursor lesions known as intratubular germ cell neoplasia undifferentiated. The tumors can be divided into two groups based on their histology and clinical behavior; seminomas resemble primordial germ cells or gonocytes and nonseminomas resemble embryonic or extraembryonic tissues at various stages of differentiation. The most undifferentiated form of nonseminoma, embryonal carcinoma, resembles embryonic stem cells in terms of morphology and expression profiling, both mRNAs and microRNAs. Evidence supports both environmental factors and genetic predisposition underlying the development of TGCTs. Various models of development have been proposed and are discussed. In TGCTs, gain of material from the short arm of chromosome 12 is invariable: genes from this region include the proto-oncogene KRAS, which has activating mutations in 10% of tumors or is frequently overexpressed. A number of different approaches to increase the understanding of the development and progression of TGCTs have highlighted the involvement of KIT, RAS/RAF/ MAPK, STAT, and PI3K/AKT signaling. We review the role of these signaling pathways in this process and the potential influence of environmental factors in the development of TGCTs. V
Genes, Chromosomes and Cancer, 1995
Malignant transformation may be caused by gene deregulation resulting from specific chromosomal rearrangements, by amplification, by mutations in proto-oncogenes, by loss of tumor suppressor genes, or a combination of these. We investigated the role of numerical and structural chromosomal abnormalities in I02 cytogenetically abnormal cases of primary testicular germ cell tumors of adolescents and adults (TGCT) [32 seminomas (SE) and 70 nonseminomatous germ cell tumors (NS)]. We confirmed that an isochromosome for I2p. i( I 2p), is the only consistent structural chromosomal abnormality in TGCT, present in about 70% of our cases. Both the frequency and the number of copies of i( I2p) are higher in NS than in SE. This may suggest that i( I2p) is involved in tumor progression. Besides i( I2p), several clonal structural chromosomal abnormalities were found, but none appeared t o be specific. SE and NS had chromosome numbers in the triploid range, with significantly higher numbers in SE than in NS (average modal chromosome number of 73.4 in SE and 65.0 in NS). Both in SE and NS, some chromosomes were significantly underrepresented (e.g., I I, 13, 18, and Y) and others overrepresented (e.g., 7, 8, 12, 2 I, and X). In SE, a significantly higher copy number of chromosomes 7, 15, 19, and 22 was found and a significantly lower number of chromosome 17, compared with NS. These chromosomes may play an important role in the differentiation of TGCT. Genes Chromosom Cancer /4:/33-/44 (1995). 0 1995 Wiley-Liss, Inc.
On the Origin of Testicular Germ Cell Tumors: From Gonocytes to Testicular Cancer
Frontiers in Endocrinology
Human primordial germ cells (PGCs) have been described in the yolk sac wall around the beginning of the third week. From week 4 to 5, they migrate under control of SCF/c-KIT signaling pathway to the genital ridge, where they become gonocytes. PGCs and gonocytes express classic pluripotency markers, such as KIT, NANOG, and OCT3/4 that, during spermatogonia differentiation, are gradually suppressed, and substituted by the expression of some germ cell specific genes, such as VASA, SOX17, and TSPY. These genes, during normal development of germ cells, are tightly regulated by epigenetic modification, in terms of microRNA expression and DNA methylation. In adolescents and young adults, testicular germ cell tumors (TGCT) have a common precursor, the germ cell neoplasia in situ (GCNIS); the hypothesis of their origin from PGCs or gonocytes, whose maturation is altered, is widely accepted. The origin of TGCT, probably starting at early stages of embryogenesis, seems to be a part of the Testicular Dysgenesis Syndrome (TDS) where some early PGC/gonocytes, for still unclear reasons, are blocked in their differentiation, retaining their early marker profile. In this paper, current knowledge on the combination of epidemiological and genomic factors, involved in the development of testicular germ cell tumors, is reviewed.
Molecular and Cellular Endocrinology, 2008
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Exploring the molecular aspects associated with testicular germ cell tumors: a review
Oncotarget, 2018
Testicular germ cell tumors (TGCTs) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recent preclinical data regarding biological signaling machinery as well as genetic and epigenetic mechanisms associated with molecular patterns of tumors have contribute to explain the pathogenesis and the differentiation of TGCTs and to understand the mechanisms responsible for the development of resistance to treatment. In this review, we discuss the main genetic and epigenetic events associated with TGCTs development in order to better define their role in the pathogenesis of these tumors and in cisplatin-acquired resistance.
Human testicular germ cell tumors (TGCTs) are histologically heterogenous neoplasms with a variable malignant potential. Two main groups of germ cell tumors occur in men: seminomas and nonseminomas. In the present study, a set of four tumor suppressor genes was investigated in testicular cancers. CDH1, APC, p53, and nm23-H1 genes were tested for loss of heterozygosity (LOH). Thirty-eight testicular germ cell tumors (17 seminomas and 21 nonseminomas) were analyzed by PCR using restriction fragment length polymorphism or the dinucleotide/tetranucleotide repeat poly-morphism method. An allelic loss of p53 at exon 4 was detected in five nonseminomas, whereas LOH of p53 at intron 6 occurred in one of the seminoma and two of the nonseminoma samples. Allelic losses of the APC gene were present in three seminomas and one nonseminoma, whereas one seminoma and three nonseminomas showed LOH of CDH1. The analysis of allelic losses showed no common structural genetic alterations in tumor tissues, although a different pattern of LOH was observed between the two main histological groups of TGCTs.
Chapter 6 Molecular and Cell Biology of Testicular Germ Cell Tumors
2009
Although testicular germ cell tumors (TGCTs) are relatively uncommon, they are particularly important as they tend to affect children and young men, representing the most common tumor in male aged from 20 to 40years. TGCTs are a heterogeneous group of tumors, with specific peculiarities reflecting on epidemiologic distribution and clinic-pathological features. TGCTs show a high-cure rates in both seminomas and nonseminomas and represent the model of a curable neoplasia: sensitive serum tumor markers, accurate prognostic classification, contribute to a high effectiveness of cancer therapy. However, up to 30% of patients diagnosed with metastatic nonseminomas do not achieve a durable remission, and in metastatic teratomas cisplatin-based treatment resistance has been observed. These different prognostic and therapeutic features of TGCTs highlight the need for a better understanding of the molecular biology of TGCT, that could help to improve disease management and to tailor aggressive...