Analysis of the adenomatous polyposis coli (APC) gene in childhood and adolescent germ cell tumors

Okpanyi, Vera; Schneider, Dominik T.; Zahn, Susanne; Sievers, Sonja; Calaminus, Gabriele; Nicholson, James C.; Palmer, Roger D.; Leuschner, Ivo; Borkhardt, Arndt; Schönberger, Stefan

doi:10.1002/pbc.22669

Cited by 19 publications

(15 citation statements)

References 43 publications

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“…An LOH in 5q22 encompassing the ACP gene, which is often mutated in colon neoplasms, was reported in a small series of YSTs and teratomas but mutations have not been identified. 50 In recent genome-wide association studies of adult GCTs, susceptibility loci near KITLG, SPRY4, DMRT1, and BAK1 have been identified. [51][52][53] The loci play a role in the survival of PGCs during migration (KIT-KITLG), inhibiting MAP kinase pathway downstream to KIT (SPRY4), promotion of apoptosis (BAK1), and regulation of sexually dimorphic meiotic entry (DMRT1).…”

Section: Genetic Aberrations Gene Polymorphisms and Epigenetic Featmentioning

confidence: 99%

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

Mosbech

Rechnitzer

Brok

et al. 2014

Journal of Pediatric Hematology/Oncology

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Pediatric germ cell tumors (GCTs) are rare neoplasms arising predominantly in the gonads and sacrococcygeal, mediastinal, and intracranial localizations. In this article, we review current knowledge of pathogenesis of pediatric GCTs, which differs from adult/adolescent GCTs. One distinctive feature is the absence of a progenitor stage, such as carcinoma in situ or gonadoblastoma, which are seen in adult/adolescent GCTs, except spermatocytic seminoma. The primordial germ cell (PGC) is the suggested origin of all GCTs, with variations in histology reflecting differentiation stage. Expression of pluripotency transcription factors OCT-3/4, NANOG, and AP-2γ in germinomas/seminomas/dysgerminomas is consistent with retaining a germ cell phenotype. Teratomas, in contrast, develop through a pathway of aberrant somatic differentiation of immature germ cells, and the yolk sac tumors and choriocarcinomas result from abnormal extraembryonic differentiation. In pediatric GCTs, origin is suggested at an earlier developmental stage because of predisposing genetic factors, although responsible genes remain largely unknown. Some extragonadal GCTs have been linked to overexpression of the KIT/KITLG system, allowing for survival of aberrantly migrated ectopic PGCs. Infant gonadal/sacrococcygeal GCTs may be caused by apoptosis-related pathways, consistent with an association with polymorphisms in BAK1. Although recent advances have identified candidate pathways, further effort is needed to answer central questions of pathogenesis of these fascinating tumors.

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Section: Genetic Aberrations Gene Polymorphisms and Epigenetic Featmentioning

confidence: 99%

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

Mosbech

Rechnitzer

Brok

et al. 2014

Journal of Pediatric Hematology/Oncology

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“…Several embryonic signaling pathways have been implicated in the development of germ cells, somatic gonadal cells, or both, including wnt, Hedgehog, Notch, FGF, and TGF-β/bone morphogenetic protein (BMP) (4)(5)(6)(7)(8). The wnt/β-catenin pathway is differentially activated in subsets of childhood GCTs (9), and the wnt pathway regulator, APC, is subject to regulation by epigenetic mechanisms or loss-of-heterozygosity in childhood GCTs (10).…”

mentioning

confidence: 99%

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

Neumann

Chandler²,

Damoulis³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.non-seminoma | SMAD | teleost | haplotype

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“…The results are summarized in Figure 2B and Supplemental Table 3. A total of 6 articles described microsatellite analysis of mOGCTs (150, 159–163). …”

Section: Methods Of the Reviewmentioning

confidence: 99%

“…Ten articles studied gene mutations, both germline and somatic, in more than 1 patient, and these are included in this review as well as illustrated in Figure 5B (55, 144, 156, 163, 177–182). A further 8 articles reported mutations detected in single patients only and are listed in Supplemental Table 6 as germline or somatic, along with the reported effect of the change, if any.…”

Section: Methods Of the Reviewmentioning

confidence: 99%

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Molecular Characteristics of Malignant Ovarian Germ Cell Tumors and Comparison With Testicular Counterparts: Implications for Pathogenesis

et al. 2013

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This review focuses on the molecular characteristics and development of rare malignant ovarian germ cell tumors (mOGCTs). We provide an overview of the genomic aberrations assessed by ploidy, cytogenetic banding, and comparative genomic hybridization. We summarize and discuss the transcriptome profiles of mRNA and microRNA (miRNA), and biomarkers (DNA methylation, gene mutation, individual protein expression) for each mOGCT histological subtype. Parallels between the origin of mOGCT and their male counterpart testicular GCT (TGCT) are discussed from the perspective of germ cell development, endocrinological influences, and pathogenesis, as is the GCT origin in patients with disorders of sex development. Integrated molecular profiles of the 3 main histological subtypes, dysgerminoma (DG), yolk sac tumor (YST), and immature teratoma (IT), are presented. DGs show genomic aberrations comparable to TGCT. In contrast, the genome profiles of YST and IT are different both from each other and from DG/TGCT. Differences between DG and YST are underlined by their miRNA/mRNA expression patterns, suggesting preferential involvement of the WNT/β-catenin and TGF-β/bone morphogenetic protein signaling pathways among YSTs. Characteristic protein expression patterns are observed in DG, YST and IT. We propose that mOGCT develop through different developmental pathways, including one that is likely shared with TGCT and involves insufficient sexual differentiation of the germ cell niche. The molecular features of the mOGCTs underline their similarity to pluripotent precursor cells (primordial germ cells, PGCs) and other stem cells. This similarity combined with the process of ovary development, explain why mOGCTs present so early in life, and with greater histological complexity, than most somatic solid tumors.

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Analysis of the adenomatous polyposis coli (APC) gene in childhood and adolescent germ cell tumors

Cited by 19 publications

References 43 publications

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

Molecular Characteristics of Malignant Ovarian Germ Cell Tumors and Comparison With Testicular Counterparts: Implications for Pathogenesis

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