The genomic diversity of circulating tumor cells (CTCs) and its clinical implications remain poorly understood. In this study, we characterized the mutational landscape of CTC pools stemming from 29 metastatic colorectal cancer (mCRC) patients and examined its relationship with disease progression. Our analysis revealed substantial variation in mutational burden among patients, with all CTC pools harboring non-silent mutations in key CRC driver genes. Importantly, higher genomic diversity in CTC pools was significantly associated with reduced overall survival. Furthermore, the presence of non-silent mutations in BCL9L emerged as a strong predictor of patient survival. Taken together, these findings underscore the potential of CTC genomic profiling as a promising prognostic tool in mCRC and highlight the need for further research into its clinical applications.

The authors have declared no competing interest.

This work was supported by an AXA Research Fund postdoctoral grant (awarded to J.M.A), and by the Spanish Ministry of Science and Innovation - MICINN (PID2019-106247GB-I00 awarded to D.P.). J.M.A. is currently supported by the AECC (INVES20007FERN). D.P. receives further support from Xunta de Galicia. J.C. received grants from Spain's Carlos III Health Care Institute (Co-funded by European Regional Development Fund/European Social Fund: A way to make Europe/Investing in your future), No. PI17/00837 and PI21/01771. J.C. is additionally funded by the Agencia Gallega de Innovacion (N607B-2020/02). R.P. received support from Roche-Chus Joint Unit (IN853B 2018/03) funded by Axencia Galega de Innovacion (GAIN), Conselleria de Economia, Emprego e Industria.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All samples were obtained and collected after written informed consent from all subjects using a protocol approved by the Clinical Ethics Committee of Pontevedra-Vigo-Ourense (2018/301 approved 19/06/2018). This study was approved by the Clinical Ethics Committee of Pontevedra-Vigo-Ourense

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All data produced in the present study will be made publicly available upon publication