Browsing by Subject "Neoplasms, Germ Cell and Embryonal"
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Item BMP Signaling Regulates Germ Cell Pluripotency, Sexual Differentiation, and Cancer Susceptibility(2016-10-14) Sanchez, Angelica; Castrillon, Diego H.; Amatruda, James F.; Cobb, Melanie H.; Cleaver, OndineTesticular germ cell tumors are the most common malignancy found in young men between the ages of 14-40. While these tumors are highly curable with cisplatin based combined chemotherapies, the treatments come with very detrimental side effects and ultimately fail in up to 15% of patients. These patients have no other avenues of treatment and often times succumb to the disease. Very little is currently known about the biology of the tumors but risk factors highlight possible mechanisms of action. For example, patients with Disorders of Sex Development (DSD) have increased risk for developing malignant germ cell tumors. DSDs manifest at birth and present with atypical gonadal or anatomical sex as well as chromosomal aberrations[1, 2]. Some cases are explained by the presence of chromosomal aberrations, but the cause of many others remains unknown. Such syndromes thus highlight the potential links between germ cell pluripotency, sexual differentiation and cancer susceptibility. A recent GWAS study [3] identified association of BMP7 with testicular dysgenesis syndrome; however the molecular mechanisms behind this association remain unknown. Previously, we described the development of testicular germ cell tumors in zebrafish carrying a mutation in bmpr1bb, a BMP family receptor, and demonstrated that human GCTs have defects in BMP signaling. Here I use this model and next-generation sequencing analysis in a cross-species comparative oncology approach to identify genes and pathways with fundamental importance to the development of the human disease. I further defined the role of specific BMP ligands in mediating germ cell differentiation and identified reciprocal somatic- and germ cell BMP signaling events that regulate germ cell differentiation and maturation. Using genetic crosses to further impair BMP signaling, I found that zebrafish doubly heterozygous for mutations in bmpr1bb and bmp2b, bmp7a or smad5 have profoundly impaired gonadogenesis and altered male:female sex ratios. Affected fish also exhibit markedly abnormal gonadal differentiation, including the presence of undifferentiated gonadal tissue and the occurrence of biphenotypic gonads, as well as greatly increased germ cell tumor susceptibility. Our findings implicate defective BMP pathway signaling as a potential factor in DSDs and GCT susceptibility. Our goals are to identify biological mechanisms that govern germ cell differentiation and to understand how defects in this process cause human disease.Item Malignant Childhood Ovarian Cancer: A Ten-Year Retrospective Review(2024-01-30) Laboret, Bretton; Bonnyman, Claire; Murphy, Joseph T.BACKGROUND: Although pediatric ovarian cancer is rare (2.1-2.6/ 100,000 females per year), 10-30% of masses are malignant. Our primary aim was to confirm the incidence and type of ovarian malignant and borderline neoplasms over a ten-year period, and to describe their presentation and clinical characteristics. Furthermore, through analysis of pre-operative workups, we sought to elucidate better predictive indicators of malignancy to help guide future treatment. METHODS: Retrospective analysis of patients (<19 years old) who underwent surgery for borderline or malignant ovarian tumors from 01/01/2009 to 12/31/2018 was performed. Patient records were analyzed for age, presentation, serum marker levels, imaging findings, treatment (surgical plan and therapy), and patient outcomes. RESULTS: A total of 42 malignant and 7 borderline ovarian tumors were included in this study. Germ cell tumors were the most common malignancy (64%) followed by stromal tumors (31%), while one epithelial mucinous tumor and one small cell tumor were found (2% each). Of the borderline tumors, serous (71 %) were more common than mucinous tumors (29%). Average patient age was 13 ± 3.9 years, and the primary presenting symptoms were pain (45%) or abdominal distension (43%). Significant elevations in alpha fetoprotein, beta human chorionic gonadotropin, lactate dehydrogenase and cancer antigen-125 serum tumor markers were noted in malignancies. Eighty-eight percent of surgeries were performed as laparotomies, and the most common operation was salpingo-oopherectomy (67%). The average tumor size was 14.6 cm. ±6.6 cm. and the majority were characterized as heterogeneous (80%). All tumors were resected, and 21 (50%) malignant tumors received postoperative chemotherapy, while no borderline cases received therapy. Average postoperative follow-up time was 38.6 months, and forty-five (92%) patients were alive at the time of data collection. CONCLUSIONS: Germ cell tumors were confirmed as the most common pediatric ovarian malignancy, followed by stromal tumors. Very few epithelial tumors were noted, as compared to prior studies. Borderline neoplasms were uncommon and had favorable outcomes. In treating pediatric ovarian malignancy, we aim to maximize patient survival while preserving fertility. We recommend a standardized preoperative workup consisting of multi-modal imaging studies and a complete tumor marker panel for all patients presenting with suspicion for an ovarian tumor.Item A Mutation in Alk6b Causes Impaired Germ Cell Differentation and Testicular Germ Cell Tumors in Zebrafish(2010-11-02) Neumann, Joanie; Amatruda, James F.Germ cell tumors (GCTs) affect infants, children and young adults and are increasing in incidence worldwide. GCTs arise from pluripotent germ cells and can exhibit differentiated and undifferentiated histologies, which vary in their malignant potential and response to treatment. The pathways that determine tumor cell differentiation are not known, impeding the development of new therapies. Thus, the treatment of GCTs has remained static since the introduction 30 years ago of cisplatin which, while effective, causes severe side effects including hearing loss, infertility and kidney damage. We identified a zebrafish mutant line with a high incidence of GCT during a forward genetic screen to identify cancer susceptibility loci. Homozygous adult males develop tumors consisting of undifferentiated spermatogonia by 4 months of age while heterozygous males develop tumors around 7 to 9 months of age. We used interval haplotype analysis and high-resolution recombinational mapping to localize the mutation to a 0.82 cM interval on zebrafish chromosome 10. We identified a premature termination codon in Alk6b (Activin Receptor-like Kinase 6b) in the mutant animals. Alk6b is a member of the TGF-beta/BMP superfamily of receptors. BMP signaling has diverse roles including regulation of cell proliferation, differentiation, embryonic development, germ cell specification and gonadogenesis. Misregulation of the BMP signaling pathway has been implicated in various human cancers. In agreement with a critical role for Alk6b in controlling germ cell differentiation, we find evidence of impaired BMP signal transduction in the zebrafish GCTs, as well as evidence of alterations in the expression level of BMP target genes. We have also examined BMP signaling in a series of 40 clinically-annotated human GCTs of diverse histologic subtypes. In agreement with the predictions made from our zebrafish model, we find that undifferentiated GCTs such as dysgerminomas lack BMP signaling activity, whereas signaling is maintained in the differentiated subtype of Yolk Sac Tumors. These results confirm the relevance of the zebrafish model for understanding germ cell tumorigenesis, and will foster the development of improved, targeted therapy of human GCTs.Item The Role of HNF4A in Germ Cell Tumor Development(2017-08-10) Pierce, Joshua Logan; Burma, Sandeep; Amatruda, James F.; Abrams, John M.; Castrillon, Diego H.Yolk sac tumor is a histological category of germ cell tumors, which represent the most frequent malignancy in young men. Little is known about the molecular mechanisms responsible for the aberrant differentiation and oncogenic potential of yolk sac tumors. Multiple recurrent chromosomal copy number variations are the primary genetic lesions discovered in yolk sac tumors. Frequent gains of chromosome 20q13 provide clues as to the identity of important YST driver genes. We have determined that the Hepatocyte Nuclear Factor 4 alpha locus, which resides in this region, is frequently amplified in YSTs. Overexpression of HNF4A in an undifferentiated GCT line is sufficient to drive extraembryonic endodermal gene programs. This endodermal program subsequently utilizes endogenous WNT signaling to grow. Additionally, isoform specific manipulation of HNF4A revealed differential oncogenic potential amongst HNF4A isoforms. This isoform specific manipulation was involved in modulation of the WNT pathway which has previously been identified as active in YSTs. These results allowed us to uncover HNF4A isoform specific differences in histological samples from YST patients. Our findings reveal a possible new drug target in YST treatment and reveal an interesting isoform dependent mechanism for understanding tumor development.Item Using Molecular and Clinical Data to Stratify Cancer Patients for Precision Medicine(2019-04-15) Ci, Bo; Skapek, Stephen X.; Minna, John D.; Zhan, Xiaowei; Xie, Yang; Xiao, GuanghuaCancers are heterogeneous across different individuals. Insights derived from clinical and/or molecular data could be used to develop robust patient stratification models to tailor treatments for each individual patient, in order to improve patient outcome and reduce deleterious side effects. My thesis research mainly focused on using computational methods to understand the biological/clinical differences between disease subgroups and their clinical implications in two diseases, lung cancer and germ cell tumor. A comprehensive analysis using The Cancer Genomic Atlas (TCGA) lung adenocarcinoma datasets showed that FOXM1 was likely to play an important role in the morphology differences among different morphological subgroups in invasive lung adenocarcinoma. In collaboration with the Malignant Germ Cell International Consortium (MaGIC), I developed the MaGIC data dictionary as a uniform data standard to build a germ cell tumor data commons. The MaGIC data commons was then used to harmonize and integrate the patient and genomic data from both MaGIC and the public domain. Concurrently, I also developed a prognostic model for pediatric extracranial germ cell tumor using the integrated dataset, identifying older age, higher disease stage and extragonadal site as adverse prognostic factors. The model was evaluated in an independent dataset of data combined from Brazilian and French clinical trials.