title: Molecular genetic heterogeneity in undifferentiated endometrial carcinomas.
abstract: Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value.
authors: Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain.
authors: Juan M
authors: JM
authors: Rosa-Rosa
authors: Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain.
authors: Susanna
authors: S
authors: Leskelä
authors: Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain.
authors: Eva
authors: E
authors: Cristóbal-Lana
authors: Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain.
authors: Almudena
authors: A
authors: Santón
authors: Department of Pathology, Hospital Universitario Virgen del Rocío and Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain.
authors: Ma Ángeles
authors: MÁ
authors: López-García
authors: UCA en Genómica Traslacional, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
authors: Gloria
authors: G
authors: Muñoz
authors: Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain.
authors: Belen
authors: B
authors: Pérez-Mies
authors: Department of Pathology, Hospital Universitario Virgen del Rocío and Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain.
authors: Michele
authors: M
authors: Biscuola
authors: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors: Jaime
authors: J
authors: Prat
authors: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors: Oliva
authors: O
authors: Esther
authors: Department of Pathology, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Robert A
authors: RA
authors: Soslow
authors: Department of Pathology and Molecular Genetics HUAV, Dept de Ciències Mèdiques Bàsiques, Institut de Recerca Biomedica de Lleida, Univeristy of Lleida, IRB Lleida, Lleida, Spain.|Department of Pathology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors: Xavier
authors: X
authors: Matias-Guiu
authors: Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain.
authors: Jose
authors: J
authors: Palacios
mesh_terms: D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans