Early Genetic Divergence of High-Grade Carcinomas Originating from Low-Grade Serous Ovarian Neoplasms.

Autor:	Chui MH; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: chuim1@mskcc.org., Song Q; State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China., Zhu J; State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China., Jiao Y; State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China., Wang B; Department of Pathology, Inova Fairfax Hospital, Falls Church, Virginia., Wang Y; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland., Wang TL; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland., Vang R; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Gynecology/Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland., Shih IM; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Gynecology/Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2024 Oct 09; Vol. 38 (1), pp. 100629. Date of Electronic Publication: 2024 Oct 09.
DOI:	10.1016/j.modpat.2024.100629
Abstrakt:	The current paradigm implicates a fallopian tube precursor as the origin of most ovarian high-grade serous carcinomas (HGSCs). However, a rare subset of HGSCs develop via a distinct pathway from low-grade serous ovarian neoplasms (namely, serous borderline tumors and low-grade serous carcinoma). This alternate pathway for the development of HGSC and other poorly differentiated carcinomas of the ovary is not well understood. To elucidate the molecular pathogenesis and evolutionary trajectory of histologic transformation of low-grade serous neoplasms, we performed whole exome sequencing on microdissected low-grade and higher-grade components from 7 cases of serous borderline tumor or low-grade serous carcinoma associated with a synchronous or metachronous indeterminate/high-grade carcinoma. In most cases, there were relatively few somatic mutations shared between matched low-grade and higher-grade tumors compared with private mutations specific to each component (ie, phylogenetic trees with short trunks and long branches). Truncal mutations, present across all tumor samples from a given patient, included known drivers of low-grade serous neoplasms: KRAS (G12D, n = 4), BRAF (G469A, n = 1), NF2 (n = 1), and USP9X (n = 1). Transformation to HGSC was associated with a TP53 mutation with bi-allelic inactivation in 3 cases, all with severe nuclear atypia, and associated with genome-wide copy number alterations and allelic imbalances. TP53-wildtype tumors comprised a morphologic spectrum, which included indeterminate-grade serous carcinomas with moderate nuclear atypia and high mitotic activity, although lacking extensive chromosomal instability (n = 2) and poorly differentiated carcinomas (n = 2, including a high-grade Mullerian carcinoma and an undifferentiated carcinoma with sarcomatoid features). In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with TP53 mutations, suggests that high-grade transformation may be a relatively early molecular event. (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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