Abstract 3398: Gene-level and global genomic insights into colorectal cancer ovarian metastasis: Molecular mechanisms and determinants

Abstract Background: Approximately 5% of female patients with colorectal cancer (CRC) develop ovarian metastasis (OM), predominantly in young women and leading to poorer survival. As the molecular mechanisms underlying OM remain unclear, this study aimed to identify the genetic determinants of OM and to investigate the mechanisms of synchronous and metachronous metastasis. Methods: We retrospectively enrolled 81 patients with CRC who had developed OM (28 with matched primary and metastatic lesion samples, 30 with primary lesion, 23 with metastatic samples). Treatment-naïve primary and metastatic lesion tissue samples underwent next-generation sequencing targeting 437 genes to identify gene-level and global genomic determinants of OM. Two external CRC cohorts (MSKCC cohort, N=643; TCGA cohort, N=448) were analyzed for further mechanism exploration. Results: Among 81 included patients, copy number variations (CNVs) of SMAD4 (p<0.01) and SMAD2 (p<0.01) were more frequently detected in metastatic lesions than primary lesions, with similar findings in 28 pairs of matched samples (SMAD4, p=0.05; SMAD4, p=0.02). Associations of SMAD4 (p<0.001) and SMAD2 (p=0.09) CNV loss with unfavorable overall survival were observed in the MSKCC cohort. RNA sequencing data from the TCGA cohort demonstrated up-regulated angiogenesis pathway related to SMAD4 (q=0.03) and SMAD2 (q<0.001) CNV loss. Higher chromosome instability was observed in metastatic lesions than primary lesions in the study cohort (p<0.01; matched samples, p=0.08), consistent with the findings in the MSKCC cohort (p<0.001). The APOBEC mutational signature was related to OM synchronous metastasis, with heavier burdens in both the primary (p=0.04) and metastatic (p=0.01) lesions of synchronous metastasis than those of metachronous metastasis; however, primary lesions of metachronous metastasis exhibited higher whole-genome doubling fraction (p=0.04) and ploidy (p=0.02). Moreover, in metastatic lesions, FLT1 (17.6%, p=0.05) and ZNF217 (17.6%, p=0.05) CNV gains were exclusively detected of synchronous metastasis when compared to metastatic lesions of metachronous metastasis. Conclusions: SMAD4/2 CNV loss and chromosome instability may drive OM in CRC. Synchronous metastasis displays distinct gene-level and global genome features different from metachronous metastasis. Citation Format: Ying Fang, Yan Sun, Xiaotian Zhao, Xiaoying Wu, Jiaohui Pang, Haimeng Tang, Qiuxiang Ou, Che Chen, Ziwei Xu. Gene-level and global genomic insights into colorectal cancer ovarian metastasis: Molecular mechanisms and determinants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3398.