Testicular teratomagenesis from primordial germ cells with overexpression of germinal center‐associated nuclear protein

Abstract

Testicular teratomas are the major histologic type of testicular germ cell tumors and their incidence continues to grow. Moreover, teratomas can develop from undifferentiated cells in induced pluripotent stem (iPS) cell transplantation therapy, seriously hampering the progress of regenerative medicine. Germinal center‐associated nuclear protein (GANP) is thought to be important to the biogenetic control of primordial germ cells and is among the genes susceptible to testicular germ cell tumors. Thus, we analyzed the expression of GANP in human testicular postpubertal‐type teratomas and established a novel mouse model to reveal the association between GANP and teratomagenesis. We analyzed 31 cases of human testicular postpubertal‐type teratomas and, in all cases, GANP was overexpressed. The aberrant expression was also detected in germ cell neoplasia in situ accompanied by the teratoma. GANP expression was particularly high in the epithelia of the epidermis, cutaneous appendages, and trachea‐like ciliated epithelium. To further clarify the association between GANP and teratomagenesis, we established a novel teratomagenesis mouse model (CAG‐ganpTg mice). In the GANP−teratoma mice, GANP‐overexpressing teratomas were more frequent at the testes and the middle portion of the uterus than has been seen in the previously established mouse models. In conclusion, GANP is overexpressed in testicular postpubertal‐type teratomas and is an essential teratomagenic factor. We also found that CAG‐ganpTg mice are useful mouse models of teratomagenesis that mimics human midline teratomas and that teratomas may originate from the overexpression of GANP in primordial germ cells.

Carcinogenesis caused by transcription‐coupled DNA damage through GANP and other components of the TREX‐2 complex

“…The expression levels of ganp transcripts and GANP protein are extremely low in most normal tissues; however, GANP levels are markedly high in normal mammary ducts. 12 GANP expression is increased in some tumors, such as lymphomas, 47,48 melanomas, 49 liver fluke-associated cholangiocarcinomas, 50,51 and testicular teratomas 52 ; however, it is decreased in breast cancers 53,54 and diffuse gliomas. 55 Overexpression and underexpression of GANP may also affect the chemosensitivity and prognosis of cancers.…”

“…Interestingly, although GANP is seldom expressed in the normal epidermis and cutaneous appendages, it is markedly expressed in teratomatous epidermal and appendiceal components (Figure 6). 52 Teratomagenesis remain mysterious. For years, it is known that congenital testicular teratomas occasionally develop in the inbred mouse strain 129 +Ter /Sv.…”

“…62 On the other hand, approximately one-fourth of male CAGganp transgenic C57BL/6 strain mice (CAG-ganp Tg mice), in which GANP is ubiquitously expressed in many organs including the testes, develop testicular teratomas. 52 This suggests that the association of ganp with testicular teratomagenesis is more significant than that of Ter. In addition, genome-wide metaanalysis revealed that ganp is among the genes associated with testicular germ cell tumors, and a single nucleotide pleomorphism rs2839186 is positively correlated with tumor incidence.…”

“…In CAG-ganp Tg mice, teratomas develop in the testes of males and the uterus of females, both at the midline of the body, but not in the ovaries. 52 One hypothesis is that midline germ cell tumors, such as those on the mediastinum, retroperitoneum, epiphysis, and neurohypophysis, are derived from primordial germ cells. These cells stray to the midline when they migrate from the yolk sac via the hindgut to the genital ridge.…”

“…However, in CAG-ganp Tg mice, it is aberrantly overexpressed in primordial germ cells. 52 Aberrant overexpression of GANP in primordial germ cells may disrupt migration to the genital ridge in embryos and cause testicular teratomagenesis.…”