High prevalence of “non‐pathogenic” POLE mutation with poor prognosis in a cohort of endometrial cancer from South India

• Published in: International journal of gynecology and obstetrics Vol. 166; no. 3; pp. 1263 - 1272
• Main Authors: Kuriakose, Santhosh, Dhanasooraj, Dhananjayan, Shiny, P. M., Shammy, S., Sona, V. P., Manjula, Anupama A., Ramachandran, Amrutha, Vijaykumar, Bindu, Susan, Nayana, Dinesan, M., Sankar, Uma V., Ramachandran, Kavitha, Sreedharan, P. S.
• Format: Journal Article
• Language: English
• Published: United States 01.09.2024
• Subjects: Adult; Aged; DNA Polymerase II - genetics; endometrial carcinoma; Endometrial Neoplasms - genetics; Endometrial Neoplasms - mortality; Endometrial Neoplasms - pathology; Female; Humans; India; Middle Aged; Mutation; Neoplasm Staging; POLE mutation; Poly-ADP-Ribose Binding Proteins - genetics; polymerase epsilon (POLE) gene; Prevalence; Prognosis; Retrospective Studies; Sanger sequencing; India; polymerase epsilon (POLE) gene; POLE mutation; endometrial carcinoma; Sanger sequencing; prognosis
• ISSN: 0020-7292; 1879-3479; 1879-3479
• DOI: 10.1002/ijgo.15486

Objective The Cancer Genome Atlas (TCGA) project identified favorable prognosis regarding the ultra‐mutated endometrial cancer (EC) subtype linked to polymerase epsilon gene (POLE) mutations. This study investigated POLE mutations in EC of Indian patients. Methods This retrospective analytical study was conducted between January 2016 and January 2023 at the Government Medical College, Kozhikode, and the MVR Cancer Center, Kozhikode, Kerala. Sanger sequencing of POLE gene exons 9 and 13 in 151 EC patients was carried out to analyze the relationship between mutations and epidemiological factors, clinicopathologic features, and treatment outcomes. Results Among 151 cases enrolled, 39 were unique POLE‐mutated cases. Significant associations were high‐grade tumors, myometrial invasion >50%, and Lymph‐vascular space invasion (LVSI). The median follow‐up was 40 months (95% confidence interval [CI], 34–46). A lower mean disease‐specific survival (DSS) of 51.7 months (95% CI, 43.7–59.6) was noted in the POLE‐mutated group compared with 72.11 months (95% CI, 67.60–76.62) for the POLE wild‐type. A statistically significant hazard ratio (HR) of 2.683 for DSS in the POLE‐mutated group was noted. In advanced stages (FIGO stages II–IV), a nine‐fold HR for DSS and overall survival (OS) compared with POLE wild‐type was identified. After controlling for treatment effects using Cox proportional HR, advanced‐stage POLE‐mutated tumors had a significantly higher HR of 8.67 for DSS compared with POLE‐wild‐type tumors of the same stage. Conclusion This study identified a unique set of POLE mutations in Indian EC patients associated with poor prognosis, which were particularly pronounced in advanced stages. Advanced stage of presentation, type of POLE mutations, and possibly ethnicity are predictors of adverse outcomes in POLE‐mutated EC. The present study highlights ethnicity as a determinant of phenotypic expression of genetic change. Synopsis The present study identified unique POLE mutations, termed “non‐pathogenic”, in an endometrial cancer cohort of Indian ethnicity, characterized by poor survival, which was pronounced in advanced stages.