A molecular model for the development of germ cell cancer

Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas

“…Because of these data, hiwi might be an interesting candidate gene to explain the genetic linkage between the development of TGCTs and the telomeric end of chromosome 12. Moreover, this could explain the ®nding of gain of this chromosomal region in some TGCTs (Looijenga et al, 1999a(Looijenga et al, , 2000Rosenberg et al, 1999;and Lothe, personal communication). Increased hiwi dose might elevate the number or the mitotic activity of spermatogenic stem cells, just like when piwi is overexpressed (Cox et al, 2000).…”

“…Within the human adult testis, two types of germ cell tumors are distinguished. The ®rst type of tumors are the seminomas and nonseminomas of adolescents and adults, also known as TGCTs, while the second type are the spermatocytic seminomas of the elderly (reviewed in Looijenga et al, 1999a;Looijenga and Oosterhuis, 1999b). Although these tumors have separate pathogenesis, as demonstrated by their clinical behavior (reviewed in Bosl and Motzer, 1997;Burke and Mosto®, 1993) and chromosomal constitution Looijenga et al, 2000;Rosenberg et al, 1998Rosenberg et al, , 1999van Echten et al, 1995), they all originate from the germ cell lineage.…”

“…These tumor cells are characterized by a high glycogen content (Mosto® and Sesterhenn, 1998), positive staining for c-KIT (the stem cell factor receptor; Rajpert-De Meyts et al, 1996) and germ cell/placental alkaline phosphatase (Roelofs et al, 1999), all of which are also positive in normal primordial germ cells. TGCTs are the most frequently occurring malignancy in Caucasian males in the age between 15 ± 45 years (reviewed in Looijenga et al, 1999a;Looijenga and Oosterhuis, 1999b), where they account for a signi®cant number of cancer deaths. In contrast, the spermatocytic seminomas are found at elder ages (Burke and Mosto®, 1993).…”

“…For example, an isochromosome 12p and de®ciencies in the short arms of chromosomes 1, 3, and 11 are concurrent with TGCTs (reviewed in Looijenga et al, 1999a;Looijenga and Oosterhuis, 1999b), implicating the presence of potential TGCT suppressor genes in these de®ciency regions. Recently, seminomas have also been correlated to the altered activities of speci®c genes such as glial cell line-derived neurotrophic factor (GDNF), members of placental alkaline phosphatase family, Zinc ®nger genes on chromosome 19, eukaryotic initiation factor 3 p110 mRNA, and Testis Speci®c Protein Y Encoded (TSPY; Ogawa et al, 1998;Rothe et al, 2000;Lau et al, 2000;Meng et al, 2001;Shigenari et al, 1998).…”

Origins and molecular biology of testicular germ cell tumors

“…14,62,65 This model suggests that fetal gonocytes (primordial germ cells) may undergo abnormal cell division (polyploidization) due to mostly environmental factors in utero and give rise to IGCNU. Polyploidization precedes the formation of i(12p).…”