Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma

Abstract

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gyneco-logical malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mu-tations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in in-tracellular p53 dynamics throughout ovarian can-cer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression be-ginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepi-thelial lesions (STIL), progress into late pre-malig-nant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transfor-mation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from pre-neoplastic le-sions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes pre-neoplastic early lesions from late pre-malignant and malig-nant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.