Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression. ### Competing Interest Statement S.C. receives consulting fees from Novartis, Lilly, Sanofi and research funding from Daiichi-Sankyo and Paige.ai. J.J.H. receives consulting fees from Bristol Myers Squibb, Merck, Exelexis, Eisai, QED, Cytomx, Zymeworks, Adaptiimmune, ImVax and research funding from Bristol Myers Squibb. C.I.D. receives research funding from Bristol Myers Squibb. P.R. received consultation/Ad board/Honoraria from Novartis, Foundation Medicine, AstraZeneca, Epic Sciences, Inivata, Natera, and Tempus and institutional grant/funding from Grail, Illumina, Novartis, Epic Sciences, ArcherDx. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Astra Zeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros, and serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. D.Z. receives research funding from Astra Zeneca, Plexxikon, and Genentech and consulting fees from Merck, Synlogic Therapeutics, GSK, Bristol Myers Squibb, Genentech, Xencor, Memgen, Immunos, Agenus, Hookipa, Calidi, Synthekine. B.W. has a ad hoc membership advisory board Repare Therapeutics. W.A. receives speaking honoraria from Roche, Medscape, Aptitude Health, Clinical Education Alliance and consulting fees from Clovis Oncology, Janssen, ORIC pharmaceuticals, Daiichi Sankyo and reserach funding from AstraZeneca, Zenith Epigenetics, Clovis Oncology, ORIC pharmaceuticals, Epizyme. G.K.A. receives research funding from Arcus, Agios, Astra Zeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Sillajen, Yiviva, and consulting fees from Adicet, Agios, Astra Zeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, Cend, Celgene, CytomX, Eisai, Eli Lilly Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MINA, Nerviano,QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Twoxar, Vector, Yiviva. E.M.O. receives research Funding from Genentech/Roche, Celgene/BMS, BioNTech, BioAtla, AstraZeneca, Arcus, Elicio, Parker Institute, AstraZeneca and consulting fees from Cytomx Therapeutics (DSMB), Rafael Therapeutics (DSMB), Sobi, Silenseed, Tyme, Seagen, Molecular Templates, Boehringer Ingelheim, BioNTech, Ipsen, Polaris, Merck, IDEAYA, Cend, AstraZeneca, Noxxon, BioSapien, Bayer (spouse), Genentech-Roche (spouse), Celgene-BMS (spouse), Eisai (spouse). M.A.P. receive consulting fees from BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro, Eisai, Pfizer and honoraria from BMS and Merck and research support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis, AstraZeneca. G.J.R. has insitutional research funding from Mirait, Takeda, Merck, Roche, Novartis, and Pfizer. A.N.S. has advisory board / personal fees from Bristol-Myers Squibb, Immunocore, Castle Biosciences and research support from Bristol-Myers Squibb, Immunocore, Xcovery, Polaris, Novartis, Pfizer, Checkmate Pharmaceuticals and research funding from OBI-Pharma, GSK, Silenseed, BMS, Lilly. R.Y. receives consulting fees from Array BioPharma/Pfizer, Mirati Therapeutics, Natera and research funding from Pfizer, Boehringer Ingelheim. D.R.J. is member of the Advisory Council for Astra Zeneca and member of the Clinical Trial Steering Committee for Merck. D.M. reports disclosures from AstraZeneca, Johnson & Johnson, Boston Scientific, Bristol-Myers Squibb, Merck. S.P.D. is shareholder and consultant for Canexia Health Inc. M.F.B receives consulting fees from Roche, Eli Lilly, PetDx and research funding from Grail. D.B.S. has received consulted for and received honoraria from Pfizer, Lilly/Loxo Oncology, Vividion Therapeutics, Scorpion Therapetuics and BridgeBio.