T F M Chang, Yen‐Wei Chien, S. S. Chen, Annelise Sokolow, Yeh Wang, Brant G. Wang, Tricia Numan, M. Herman Chui, Rebecca L. Stone, Thomas R. Pisanic, Nickolas Papadopoulos, Tian‐Li Wang, Christopher Douville, Leslie Cope, Ie‐Ming Shih
Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. In this study, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathologic features in 166 ovarian precancerous lesions. Four precancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immunoregulatory gene expression, and histologic features. Notably, the immunoreactive subtype upregulated immunoregulatory genes, exhibited chronic inflammation, and was enriched in cases with germline BRCA1/2 mutations and deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double "two-hit" involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial-mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive precancerous lesions. SIGNIFICANCE: Integrated spatial multiomics analysis of ovarian precancerous lesions reveals molecular subtypes and mechanisms underlying tumor initiation, offering a foundation for future risk stratification and prevention. See related commnetary by Soong et al. p. 1537.