Yen-Wei Chien

Aneuploidy Landscape in Precursors of Ovarian Cancer

Abstract Purpose: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. Experimental Design: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. Results: We found that nearly all p53 signatures lost the entire Chr17, offering a “two-hit” mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. Conclusions: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially “aggressive” STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions

Abstract 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 commentary by Soong et al. p. 1537