Abstract PR-004: The evolution of ovarian high grade serous carcinoma from STIC lesions

Abstract The majority of high-grade serous carcinomas (HGSC) originate in the fallopian tube. Secretory epithelial cells carrying a TP53 mutation, known as "p53 signatures", are the earliest precursor lesions of HGSC. According to current theories, p53 signatures then evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that spreads to the ovary and other metastatic sites. We recently investigated the genomic landscape of early and late-stage HGSC and demonstrated that the presence of whole-genome duplication (WGD) and high ploidy distinguishes late stage from early-stage disease. However, it remains unclear whether these high ploidies and WGD states are simply markers of evolutionary fitness or occur very early in the evolution of HGSC. To investigate this further, we analyzed p53 signatures, STICs, invasive carcinoma, and distant metastases from five cases of HGSC. p53 signature and STIC lesions were identified using morphology, and p53 and Ki67 immunohistochemistry. These samples were microdissected and analyzed using shallow whole genome sequencing (sWGS). Invasive HGSC samples from the ovary and distant metastatic sites underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing (Illumina Ampliseq platform). Analysis of genome-wide copy number profiles of p53 signatures, STIC, invasive and metastatic HGSC tumors in the five patients revealed highly similar patterns of global copy number gains/loss between different anatomic sites. However, we found that ploidy changes (average ploidy=2. 65) could be observed in STIC lesions from three patients. Moreover, in cases with high ploidy in invasive and metastatic tumors, there was evidence of similar ploidy changes in STIC lesions. The reconstruction of sample phylogeny from relative copy numbers for each patient indicated that high ploidy occurs very early in the evolution of HGSC, which was further validated by copy number signatures in three patients with invasive and metastatic tumors. Moreover, the absolute copy numbers of TP53 reflect the ploidy status of HGSC, suggesting that early p53 loss is likely to be an initiator of genomic instability. These findings suggest that WGD is likely to arise as early as STIC lesions and could be a driving factor in the development of poor prognosis, high ploidy HGSC. By identifying and characterizing the evolutionary process of five patients, these data improve the understanding of the evolution of HGSC, which may help to stratify patients with early-stage disease and potentially help to provide prognostic information for patients with incidental STIC lesions. Citation Format: Zhao Cheng, Darren P. Ennis, Bingxin Lu, Hasan Mirza, Chishimba Sokota, Baljeet Kaur, Naveena Singh, Olivia Le Saux, Gaia Giannone, Laura Tookman, Jonathan Krell, Jacqueline McDermott, Chris Barnes, Iain A. McNeish. The evolution of ovarian high grade serous carcinoma from STIC lesions abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr PR-004.