Abstract 3373: Analysis of the “centrosome-ome” reveals potential causes of centrosome amplification in human cancer

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Abstract The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions. This includes the organization of the mitotic spindle for faithful chromosome segregation during mitosis, cell polarization and migration, and primary cilia formation. A numerical increase in centrosomes, or centrosome amplification (CA), is common in cancer and correlates with aggressive clinical features and poor patient outcomes. CA is thought to arise by two major mechanisms: (1) centriole overduplication and (2) cell doubling events. To better assess the relative contributions of these two mechanisms, we analyzed 79 melanomas compared to 17 benign nevi and 60 prostate cancers compared to 20 benign prostate samples. We probed these samples for pericentrin (to mark all centrosomes) and CEP170 (to mark centrosomes with mature centrioles). CEP170 is expected on most or all amplified centrosomes with cell doubling, but not with overduplication (1 per cell expected). We find fewer CEP170-positive centrosomes in cancer samples compared to benign samples, indicating that centriole overduplication is the predominant mechanism leading to CA in human cancer. Given this finding, we next sought to identify the predominant molecular mechanisms leading to centriole overduplication. To address this question, we analyzed mutations, copy number alterations, and RNA expression data in the 366 proteins reported to localize to the centrosome using TCGA data. We identified a list of candidate centrosome proteins that are most frequently altered in cancer. Furthermore, given that cells with CA undergo cell cycle arrest unless other compensatory alterations are made, such as loss of p53, we ranked alterations in centrosome genes by the fold enrichment in p53 mutant versus p53 wild-type tumors. We identified the following candidates: CEP19, CEP72, NDRG1, PTK2, SPATC1, and TBCCD1 (gain-of-function mutations) and AKAP9, CEP76, CTNNB1, MCPH1, NEURL4, and NPM1 (loss-of-function mutations or deletion). In cellulo analysis of these candidates reveals that loss of MCPH1 (microcephalin) causes the most robust increase in centriole number. MCPH1 mutations are known to give rise to microcephaly and CA. MCPH1 gene deletions and/or mRNA downregulation (Z score < 2) are seen in 5-15% of human cancers, depending on the anatomic site of the tumor. We conclude that a myriad of different alterations in centrosome genes can give rise to CA in human cancer, and that loss of MCPH1 is a common and penetrant cause of CA in human cancer. Citation Format: Ryan A. Denu, Justin C. Jagodinsky, Mark E. Burkard. Analysis of the “centrosome-ome” reveals potential causes of centrosome amplification in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3373.