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

Taylor, Justin; Donoghue, Mark T.A.; Ho, Caleb; Petrova‐Drus, Kseniya; Al‐Ahmadie, Hikmat; Funt, Samuel A.; Zhang, Yanming; Aypar, Umut; Rao, Pavitra; Chavan, Shweta S.; Haddadin, Michael; Tamari, Roni; Giralt, Sergío; Tallman, Martin S.; Rampal, Raajit K.; Baez, Priscilla; Kappagantula, Rajya; Kosuri, Satyajit; Doğan, Ahmet; Tickoo, Satish K.; Reuter, Victor E.; Bosl, George J.; Iacobuzio‐Donahue, Christine A.; Solit, David B.; Feldman, Darren R.; Abdel‐Wahab, Omar

doi:10.1172/jci139682

Cited by 38 publications

(65 citation statements)

References 29 publications

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“…However, it is consistent with the results of Dorssers et al who found that metastases, to which the patient succumbed, were derived from a precursor ECC that was not detected in the primary testicular nonseminoma (14). An important "bycatch" of Taylor, Donoghue, et al (12) is the data on mutations in primary mediastinal seminomas and PMNs, which allows comparison with similar data for primary type II GCTs of the testis and brain. Testicular type II GCTs have a low rate of driver mutations, which provide a growth advantage and occur mainly in the KIT/RAS signaling pathway (in about 30% of seminomas, and 10% of nonseminomas) (13,15).…”

Section: Intriguing Questions That Remainsupporting

confidence: 88%

“…Taylor, Donoghue, et al (12) make two important points, both of which have clinical implications. First, they show that the treatment-refractory HSTMs that may complicate PMNs as yet cannot be diagnosed from the primary tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps because around puberty PGCs in the thymus degenerate, as with germ cells in the testis. Therefore, even with oncogenic mutations (12), their neoplastic counterparts will not survive unless reprogrammed to an ECC that will develop into a nonseminoma. The reason why seminomas of the brain do exist in Klinefelter syndrome (26) may be that these tumors develop before puberty, before PGCs degenerate.…”

Section: Discussionmentioning

confidence: 99%

“…In this issue of the JCI, Taylor, Donoghue, et al (12) assumed that the common precursor of PMNs and HSTMs was most likely a transformed PGC reprogrammed into an ECC within the mediastinum/thymus. ECCs diverged into clones observed in the PMNs, and parallel clones, not detected in the PMNs, formed HSTMs (12), possibly (11).…”

Section: The Common Precursor Of Pmns and Hstmsmentioning

confidence: 99%

“…Taylor, Donoghue, and researchers (12) clarify some important issues; however, many intriguing questions remain, such as, why were all the patients evaluated via a (transient) yolk sac tumor stage. This disparate clonal pattern was not observed in the phylogenetic reconstructions of treatment-resistant testicular nonseminomas (13).…”

Section: Intriguing Questions That Remainmentioning

confidence: 99%

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Mediastinal germ cell tumors: many questions and perhaps an answer

Oosterhuis

Looijenga

2020

Journal of Clinical Investigation

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Germ cell tumors Earlier studies determined that hematologic somatic-type malignancies (HSTMs) and the primary mediastinal nonseminomas (PMNs) from which they originate (1) may share an isochromosome 12p (duplication of the short arm of chromosome 12) (2). Isochromosome 12p characterizes seminomas and nonseminomas regardless of anatomical site (3-6), while it is not a feature of hematologic malignancies (7). The current assumption is that elements present in the PMNs progress into HSTMs, possibly from hematopoietic foci within the yolk sac tumor component (8). Effectively considering which cells give rise to germ cell tumors (GCTs) and blood cancers requires a brief introduction to the family of GCTs (9). GCTs comprise a seemingly heterogeneous group of neoplasms occurring at various anatomical localizations, both in females and males

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Section: Intriguing Questions That Remainsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Common Precursor Of Pmns and Hstmsmentioning

confidence: 99%

Section: Intriguing Questions That Remainmentioning

confidence: 99%

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Mediastinal germ cell tumors: many questions and perhaps an answer

Oosterhuis

Looijenga

2020

Journal of Clinical Investigation

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Severe graft‐versus‐host disease post allogeneic hematopoietic stem cell transplantation due to loss of HLA heterozygosity in recipient lymphocytes after full graft rejection

Xue

Miao²,

Gong

et al. 2023

Cancer Innovation

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Germ cell tumors complicated by hematological malignancy (HM) are a rare clinical phenomenon. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a potentially effective therapy, but graft‐versus‐host disease (GVHD) is a life‐threatening complication. We report a case of a 13‐year‐old female patient diagnosed with germ cell tumors followed by acute lymphoblastic leukemia. After chemotherapy, she received allo‐HSCT and her chimerism rate decreased rapidly to near zero by 6 months without evidence of HM recurrence. However, she developed severe, multiorgan GVHD‐like manifestations. DNA analysis revealed the pathogenesis of GVHD to be loss of HLA heterozygosity in recipient hematopoietic cells.

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Ovarian germ cell tumor/mastocytosis with KIT mutation: A unique clinicopathological entity

Xiao

Chen²,

Lang³

et al. 2021

Genes Chromosomes & Cancer

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Most tumors are sporadic and originated from somatic mutations. Some rare germline mutations cause familial tumors, often involving multiple tissues or organs.Tumors from somatic mosaicism during embryonic development are extremely rare. We describe here a pediatric patient who developed both an ovarian germ cell tumor and systemic mastocytosis. Targeted DNA next-generation sequencing analysis revealed similar genomic changes including the same KIT D816V mutation in both tissues, suggesting a common progenitor cancer cell. The KIT

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

Cited by 38 publications

References 29 publications

Mediastinal germ cell tumors: many questions and perhaps an answer

Mediastinal germ cell tumors: many questions and perhaps an answer

Severe graft‐versus‐host disease post allogeneic hematopoietic stem cell transplantation due to loss of HLA heterozygosity in recipient lymphocytes after full graft rejection

Ovarian germ cell tumor/mastocytosis with KIT mutation: A unique clinicopathological entity

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