Clinicogenomic Landscape of Histologic Subtypes in Ovarian Cancer: Real-World Evidence From a Japanese Nationwide Cohort.

Abstract

The frequency of histologic subtypes in epithelial ovarian cancer (EOC) varies by geographic region. In Western countries, high-grade serous ovarian cancer (HGSOC) is the most common and well characterized, whereas non-HGSOC subtypes, particularly clear cell ovarian cancer (CCOV), are more prevalent in Asia. However, their clinicogenomic features remain poorly defined. This retrospective study analyzed real-world data from Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database. The cohort included 5,395 patients diagnosed with ovarian cancer between January 2016 and June 2025. Clinical characteristics, treatment patterns, and real-world overall survival (rwOS) were evaluated in histologic subtypes. Comprehensive genomic profiling was used to characterize mutational landscapes and to identify genomic biomarkers associated with rwOS. EOCs were classified into five histologic subtypes: HGSOC (51%), low-grade serous (LGSOC; 2.7%), CCOV (30%), endometrioid (EOV; 8.9%), and mucinous (MOV; 7.3%). Compared with Western cohorts, HGSOC was less frequent and CCOV more prevalent. Distinct mutational profiles were observed across subtypes: <i>TP53</i> mutations in 94% of HGSOC, frequent <i>ARID1A</i> and <i>PIK3CA</i> mutations in CCOV and EOV, <i>KRAS</i> mutations in LGSOC and MOV, and enriched <i>CDKN2A</i> and <i>CDKN2B</i> deletions in MOV. <i>KEAP1</i> and <i>NFE2L2</i> mutations in HGSOC and CCOV, respectively, increased in post-treatment tumors, suggesting ferroptosis-mediated therapeutic resistance. Biomarker analyses identified subtype-specific associations with rwOS: <i>PIK3CA</i> mutations in HGSOC and <i>CDKN2A</i>/<i>CDKN2B</i> deletions in CCOV, EOV, and MOV with shorter rwOS, <i>BRCA1</i>, and <i>BRCA2</i> alterations in HGSOC with longer rwOS. A subclass of <i>TP53</i> mutations that destabilize p53 protein structure was associated with shorter survival in HGSOC and EOV. This large clinicogenomic study in an Asian population highlights unique mutational landscapes and survival associations, which may inform personalized treatment strategies.