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Journal Articles Cancer Research Communications Year : 2023

Dissecting the Origin of Heterogeneity in Uterine and Ovarian Carcinosarcomas

Anne-Sophie Sertier
Anthony Ferrari
Roxane Pommier
Isabelle Treilleux
Sandrine Boyault
Janice Kielbassa
Emilie Thomas
Laurie Tonon
Vincent Le Texier
Amandine Charreton
Anne-Pierre Morel
Anne Floquet
Dominique Berton-Rigaud
Sabrina Croce
Guillaume Bataillon
Pierre Saintigny
Christine Sagan
Ivo Gut
Fabien Calvo
Alain Viari
Isabelle Ray-Coquard

Abstract

Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.
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hal-04104571 , version 1 (07-06-2023)

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Anne-Sophie Sertier, Anthony Ferrari, Roxane Pommier, Isabelle Treilleux, Sandrine Boyault, et al.. Dissecting the Origin of Heterogeneity in Uterine and Ovarian Carcinosarcomas. Cancer Research Communications, 2023, 3 (5), pp.830-841. ⟨10.1158/2767-9764.CRC-22-0520⟩. ⟨hal-04104571⟩
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