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dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorCruz Paula, Arnaud Da
dc.contributor.authorSilva, Edaise M. da
dc.contributor.authorSegura, Sheila E.
dc.contributor.authorPareja, Fresia
dc.contributor.authorBi, Rui
dc.contributor.authorSelenica, Pier
dc.contributor.authorKim, Sarah H.
dc.contributor.authorFerrando, Lorenzo
dc.contributor.authorVahdatinia, Mahsa
dc.contributor.authorSoslow, Robert A.
dc.contributor.authorVidal, August
dc.contributor.authorPrzybycin, Christopher G.
dc.contributor.authorAbu-Rustum, Nadeem R.
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorRubin, Brian P.
dc.contributor.authorReis-Filho, Jorge S.
dc.contributor.authorDeLair, Deborah F.
dc.contributor.authorWeigelt, Britta
dc.date.accessioned2020-11-19T17:54:47Z
dc.date.available2020-11-19T17:54:47Z
dc.date.issued2020
dc.identifier.issn0893-3952
dc.identifier.urihttp://hdl.handle.net/10459.1/69925
dc.description.abstractAdult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n=7), primary aGCTs that subsequently recurred (n=9) and their matched recurrences (n=9), and aGCT recurrences without matched primary tumors (n=10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, 3 primary non-recurrent aGCTs and 9 aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p=0.017). In addition, mutations affecting TP53, MED12 and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12 and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.ca_ES
dc.format.extentca_ES
dc.language.isoengca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1038/s41379-020-0514-3ca_ES
dc.relation.ispartofModern Pathology, 2020, vol. 33, núm.8, p.1606-1617ca_ES
dc.rights(c) Paula Arnaud Da Cruz et al., 2020ca_ES
dc.rights.uri*
dc.subject.otherCàncer--Diagnòsticca_ES
dc.subject.otherCàncer--Detecció precoçca_ES
dc.subject.otherCicle cel·lularca_ES
dc.subject.otherOvaris--Càncerca_ES
dc.titleGenomic profiling of primary and recurrent adult granulosa cell tumors of the ovaryca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.type.versioninfo:eu-repo/semantics/acceptedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.identifier.doihttps://doi.org/10.1038/s41379-020-0514-3


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