Synapse - Molecular characterization of endometrial carcinomas in black and white patients reveals disparate drivers with therapeutic implications

Molecular characterization of endometrial carcinomas in black and white patients reveals disparate drivers with therapeutic implications Journal Article

Authors:	Weigelt, B.; Marra, A.; Selenica, P.; Rios-Doria, E.; Momeni-Boroujeni, A.; Berger, M. F.; Arora, K.; Nemirovsky, D.; Iasonos, A.; Chakravarty, D.; Abu-Rustum, N. R.; Da Cruz Paula, A.; Dessources, K.; Ellenson, L. H.; Liu, Y. L.; Aghajanian, C.; Brown, C. L.
Article Title:	Molecular characterization of endometrial carcinomas in black and white patients reveals disparate drivers with therapeutic implications
Abstract:	Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark, with the highest mortality rates observed among Black patients. Here, analysis of 1,882 prospectively sequenced ECs using a clinical FDA-authorized tumor–normal panel revealed a significantly higher prevalence of high-risk histologic and molecular EC subtypes in self-identified Black (n = 259) compared with White (n = 1,623) patients. Clinically actionable alterations, including high tumor mutational burden/microsatellite instability, which confer benefit from immunotherapy, were less frequent in ECs from Black than from White patients. Ultramu-tated POLE molecular subtype ECs associated with favorable outcomes were rare in Black patients. Results were confirmed by genetic ancestry analysis. CCNE1 gene amplification, which is associated with aggressive clinical behavior, was more prevalent in carcinosarcomas occurring in Black than in White patients. ECs from Black and White patients display important differences in their histologic types, molecular subtypes, driver genetic alterations, and therapeutic targets. SIGNIFICANCE: Our comprehensive analysis of prospectively clinically sequenced ECs revealed signifi-cant differences in their histologic and molecular composition and in the presence of therapeutic targets in Black versus White patients. These findings emphasize the importance of incorporating diverse populations into molecular studies and clinical trials to address EC disparities. © 2023 American Association for Cancer Research.
Keywords:	adult; controlled study; human tissue; unclassified drug; major clinical study; sequence analysis; single nucleotide polymorphism; somatic mutation; genetics; mutation; comparative study; endometrium carcinoma; endometrial neoplasms; gene; cancer immunotherapy; gene amplification; prevalence; epidermal growth factor receptor 2; pathology; protein p53; histology; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; chromosomal instability; molecular biology; point mutation; molecular characterization; racial disparity; protein msh6; endometrium tumor; mismatch repair protein pms2; caucasian; carcinosarcoma; copy number variation; protein kinase b beta; mortality rate; pi3k/akt signaling; ccne1 gene; immune checkpoint inhibitor; cancer prognosis; ctnnb1 protein; exploratory behavior; humans; human; female; article; arid1a protein; black person; mutl protein homolog 1; med12 gene; dna mismatch repair protein msh2; whole genome doubling; akt/mtor signaling; endometrioid histology; black people; white people; kmt2b gene; nsmp protein; protein phosphatase type 2a; cancer genome evolution; cancer related gene; clear cell chondrosarcoma; combinations of mutually exclusive alterations; genetic ancestry analysis; msk impact sequencing
Journal Title:	Cancer Discovery
Volume:	13
Issue:	11
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2023-11-01
Start Page:	2356
End Page:	2369
Language:	English
DOI:	10.1158/2159-8290.Cd-23-0546
PUBMED:	37651310
PROVIDER:	scopus
PMCID:	PMC11149479
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85175741960&doi=10.1158%2f2159-8290.CD-23-0546&partnerID=40&md5=5813697d7f3bc9151a73abbe903c930d
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding authors are MSK authors: Britta Weigelt, Carol L. Brown -- Source: Scopus