Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions

Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. Here, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathological features in 166 ovarian precancerous lesions. Four pre-cancerous 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, immune-regulatory gene expression, and histological features. Notably, the immunoreactive subtype upregulated immune-regulatory genes, exhibited chronic inflammation, and was enriched in cases with germline-BRCA1/2 mutations, 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 pre-cancerous lesions. Overall design: Fallopian tube tissues diagnosed with STICs, STILs, and p53 signatures were collocted. A total of 68 patients with 294 epithelial samples consisting of 162 STIC/STIL and four p53 signatures, along with 29 concurrent carcinoma lesions, 99 paired histologically unremarkable or normal fallopian tube epithelia (NFT), and 144 diagnosis-paired stromal samples, were included in this study.