High expression of the multifunctional proto-oncogene BMI1 predicts poor outcome in high-grade serous carcinoma

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OBJECTIVE: Tubo-ovarian high-grade serous carcinoma (HGSC) has a poor prognosis due to limited treatment options, therapy resistance, and high recurrence rates. One proposed mechanism underlying treatment failure is the survival of cancer stem cells (CSCs) following chemotherapy. In previous in vitro studies, we identified ALDH1A1, SOX2, MYC, and BMI1 as putative CSC markers, with increased expression linked to platinum resistance. This study aimed to evaluate the expression and prognostic relevance of these four markers in diagnostic, treatment-naïve HGSC tissue specimens. METHODS: We performed immunohistochemistry (IHC) on adnexal and extrapelvic samples from patients with stage III-IV HGSC. The expression levels of ALDH1A1, SOX2, MYC and BMI1 were manually scored and correlated with clinical parameters, including platinum-free interval (PFI) and overall survival (OS). Significant findings were validated with RNA in situ hybridization scoring, using an AI-assisted image analysis tool developed in this project. RESULTS: We found that all four proteins are widely expressed across tumor samples. High MYC and high BMI1 protein expression are each significantly associated with reduced PFI and OS. Higher expression levels are noted in extrapelvic tumor sites as compared to adnexal. In multivariable analysis, BMI1 expression remains an independent predictor of poor outcome. The significance of BMI1 as a prognostic marker is further demonstrated by RNA-ISH analysis, again showing independent association with outcome. CONCLUSIONS: Our findings highlight BMI1 as a clinically applicable prognostic marker in HGSC and suggests its potential as a therapeutic target.

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