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1183 ZFHX3 mutations in uterine endometrioid carcinoma: disease and genomic associations
  1. Ashaar Al-Akhras1,
  2. Marah Bassam Akhdar1,
  3. Sara Zytoon2 and
  4. Basil Obeidat1
  1. 1Jordan University of Science and Technology, Irbid, Jordan
  2. 2Yarmouk University, Irbid, Jordan


Introduction/Background Uterine endometrioid carcinoma (UEC) is the predominant histological type of endometrial cancer, constituting around 85% of cases. Although UEC progresses slowly with relatively good prognosis, its genetic heterogeneity represents a diverse subset of endometrial cancer. ZFHX3 is a transcriptional gene frequently mutated in UEC. In this study, we investigated associations related to ZFHX3 mutations using a database of UEC cases.

Methodology We queried the Endometrial Carcinoma Ancestry (MSK, Cancer Discovery 2023) dataset from cBioPortal. UEC cases profiled for ZFHX3 mutations were extracted. Samples were divided according to ZFHX3 mutation status into ZFHX3-mutated (ZFHX3-mut) and those without an alteration, and compared for race, grade, molecular subtype, tumor mutational burden (TMB), mutation count, and associations with other commonly mutated genes.

Results A total of 1,002 cases of UEC were extracted, of which 184 harbored a ZFHX3 mutation (18%). While most patients were white (93%), ZFHX3 mutations were detected in 28% of black patients and 18% of white patients (p = 0.032). Of G3 grade tumors, 26.4% harbored a ZFHX3 mutation (52/197) compared with 16.4% of G1/G2 tumors (132/805), p = 0.001. ZFHX3-mut patients also had more frequent microsatellite instability-high (MSI-H) tumors compared with non-mutated cases (72% vs. 28%, p<0.001), a higher median mutation count (16 vs. 6, p<0.001), and a higher median TMB (13.8 vs. 5.2, p<0.001). Compared with unaltered tumors, ZFHX3-mutations demonstrated a co-occurrence with mutations in PTEN (92% vs. 74%, p<0.001), ARID1A (81% vs. 59%, p<0.001), and CTCF (38% vs. 23%, p<0.001). PIK3CA and KRAS mutations on the other hand did not show a significant association with ZFHX3.

Conclusion Our study identified several clinicopathological features associated with ZFHX3 mutations suggesting a complex molecular profile of UEC and unfavorable outcomes. Due to the mutation’s high occurrence in UEC, detailed research on its implications is crucial to understand the behavior of these tumors.

Disclosures None.

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