Abstract 1207: Multimodal profiling of STIC lesions identifies precursor states with genomic features of high grade serous ovarian cancer.

Abstract High-grade serous ovarian cancer (HGSC) is a lethal malignancy marked by near-universal TP53 mutation and chromosomal instability (CIN) due late stage diagnosis. Surgical removal of fallopian tubes (FT) is the only effective prevention strategy. Even after surgery, a subset of individuals develops primary peritoneal carcinoma (PPC). When serous tubal intraepithelial carcinoma (STIC) is identified in the FT, PPC risk exceeds 30-fold. To study the steps required for HGSC initiation and identify features of high risk STICs, we assembled a 201-patient cohort spanning HGSC development from normal FT, p53 signatures, STIC, early and advanced-stage HGSC. All specimens underwent multiplexed immunofluorescence (mpIF), and 45 samples from 36 patients were profiled by Visium HD spatial transcriptomics generating 20million 8μM bins of data. We analyzed epithelial state transitions and inferred copy number variation (CNV) using inferCNV. In one case we validated CNV calls with matched FFPE single-cell whole-genome sequencing. mpIF revealed variable emergence of cGAS staining in STIC lesions, indicating evolving tolerance to CIN prior to invasion. Using unsupervised clustering of the epithelial bins, we found that STIC lesions formed distinct transcriptional clusters that faithfully mapped to STIC histologic features. Trajectory analyses suggests a putative precursor state bridging ciliated and secretory lineages. STIC clusters were enriched for NFκB and TGF-β signaling but lacked evidence of JAK/STAT signaling observed in advanced HGSC. inferCNV showed that normal fallopian tube/p53 signature lesions were largely chromosomally stable, whereas STICs displayed broad, genome-wide alterations, reminiscent of advanced HGSC, including losses affecting TP53, BRCA1, and BRCA2 and amplifications of MYC and CCNE1. In a germline BRCA2 patient, we identified polyclonal STICs with distinct CNV profiles. Pseudotime trajectory analysis in this case suggested early copy number changes within an expanded secretory population, followed by loss of chromosome 17 (TP53), loss of chromosome 13 (BRCA2), and subsequent oncogene amplifications (e.g., MYC). As STIC lesions become invasive, we observed spatial bins with unique inferred copy number profiles, indicating the emergence of neighborhoods of clonally related invasive cells. These tumor neighborhoods exhibit different microenvironments, including differences in fibroblast phenotypes and vascularization. This multimodal map of fallopian tube transformation supports a model in which TP53 loss precedes BRCA1/2 inactivation and indicates that STICs are genomically similar to advanced HGSC. Together, these data provide a framework for studying early HGSC evolution and may inform strategies for risk reduction and early interception. Citation Format: Duaa Hassan Al-Rawi, Nataly Naser Al Deen, Cristina Sotomayor-Vivas, Kerstin Thol, Herman Chui, Aveline Filliol, Areej Alsaafin, Hunter Green, Danguole Norkunaite, Mercedes Duran, Nicholas Ceglia, Kara Long-Roche, Britta Weigelt, Andrew McPherson, Scott W. Lowe, Sohrab Shah. Multimodal profiling of STIC lesions identifies precursor states with genomic features of high grade serous ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1207.