Sequencing of fallopian tube p53 signature found concurrently with p53 mutant uterine cancers and their somatic mutation profiles.

Abstract

5610 Background: The tumor protein 53 gene (p53) encodes a protein that suppresses replication of DNA-damaged cells. Mutations resulting in protein dysfunction are common in many cancers. A p53 signature is an aberrant immunohistochemical expression in 12 or more consecutive epithelial cells in the fallopian tube (FT) and is thought to be an early precursor lesion in a spectrum to high grade serous ovarian carcinoma (HGSOC). P53 mutations have also been described in endometrial cancer (EC), specifically high grade histologies such as uterine papillary serous carcinoma (UPSC). NextGen Sequencing of UPSC tumors and concurrent FT lesions has identified overlapping p53 mutations, raising the possibility that these could represent a precursor lesion. The objective of this study was to delineate the clonal relationship between p53-mutation harboring epithelial lesions in the FT and other histologic subtypes of EC, which could have implications for risk stratification, counseling, and treatment. Methods: We identified 7 patients with EC and a concurrent p53 FT signature. DNA extraction (Qiagen) from FFPE samples was performed and sent for whole genome sequencing (Novogene) on the paired FT and endometrial tissues to identify the specific p53 mutations. Using a position-wise comparison, we evaluated the clonal relationship between the specific p53 mutations identified in each pair. Results: In this cohort, 4 patients had endometrioid adenocarcinoma, 1 had mixed endometrioid and carcinosarcoma, 1 had high grade endometrial stromal sarcoma (ESS), and 1 had UPSC. All 7 patients had a p53 signature identified in the FT. Four patients had p53 overexpression while 3 had heterogenous p53 expression in the endometrium on IHC. Among the 7 patients, sequencing revealed 5 pairs with at least 1 shared somatic mutation identified in both the endometrium and FT. A shared mutation was identified in patients with carcinosarcoma, high grade ESS, UPSC, and two endometrioid adenocarcinomas. As of 9/2025 or last follow-up, no patients had developed a primary peritoneal malignancy, but 2 patients had disease recurrence. Both patients who had disease recurrence were among those with a shared somatic mutation identified. Conclusions: To our knowledge, this is the first study evaluating the relationship between concurrent FT p53 signatures and uterine cancer beyond serous. We identified 5 patients with at least 1 shared somatic p53 mutation. While these specific mutations have not been described as known pathogenic driver mutations in the literature to date, further exploration into these alleles is needed. A clonal relationship between FT lesions and endometrial cancer could have important implications on clinical counseling and management, thus further research into the specific p53 mutations identified and validation within a larger cohort is warranted.