Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematolo...

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Veröffentlicht in:	The Journal of clinical investigation Jg. 130; H. 12; S. 6668 - 6676
Hauptverfasser:	Taylor, Justin, Donoghue, Mark T.A., Ho, Caleb, Petrova-Drus, Kseniya, Al-Ahmadie, Hikmat A., Funt, Samuel A., Zhang, Yanming, Aypar, Umut, Rao, Pavitra, Chavan, Shweta S., Haddadin, Michael, Tamari, Roni, Giralt, Sergio, Tallman, Martin S., Rampal, Raajit K., Baez, Priscilla, Kappagantula, Rajya, Kosuri, Satyajit, Dogan, Ahmet, Tickoo, Satish K., Reuter, Victor E., Bosl, George J., Iacobuzio-Donahue, Christine A., Solit, David B., Taylor, Barry S., Feldman, Darren R., Abdel-Wahab, Omar
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.12.2020
Schlagworte:	Adolescent Adult Biomedical research Blood cancer Cancer therapies Care and treatment Chemotherapy Cloning Deoxyribonucleic acid Development and progression DNA Evolution & development Female Gene expression Gene mutation Genetic aspects Genotypes Germinoma Health aspects Hematologic Neoplasms - genetics Hematologic Neoplasms - metabolism Hematologic Neoplasms - pathology Hematological diseases Histology Humans Identification and classification Leukemia Malignancy Mediastinum Medical prognosis Middle Aged Mutation Neoplasms, Germ Cell and Embryonal - genetics Neoplasms, Germ Cell and Embryonal - metabolism Neoplasms, Germ Cell and Embryonal - pathology Neoplasms, Second Primary - genetics Neoplasms, Second Primary - metabolism Neoplasms, Second Primary - pathology p53 Protein Patients Signal Transduction - genetics Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors United States Genetics Hematology Leukemias Cancer
ISSN:	0021-9738, 1558-8238, 1558-8238
Online-Zugang:	Volltext
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Zusammenfassung:	Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3 Authorship note: JT, MTAD, DRF, and OAW contributed equally to this work.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI139682