Identifying the Genomic Basis of Organ-Specific Metastasis
Although most cancer deaths are due to metastatic disease, we are still unable to predict if, when, and where an early-stage tumor will metastasize. We aim to address this question by analyzing genomic data for 10,000 patients with metastatic cancer that have undergone targeted sequencing at Memorial Sloan Kettering Cancer Center. We will curate detailed clinical annotations including timing and multiple sites of metastasis per patient, as well as response to treatment. Our final dataset will be made publicly available. We will investigate associations between genomic profiles and metastatic patterns. We will also build predictive models that assess the risk of metastatic spread at target-organ resolution and can be used to improve patient care and clinical practice.
Summary:
As part of this project, we assembled MSK-MET, which is a pan-cancer cohort of over 25,000 patients across 50 different cancer types with targeted DNA sequencing and detailed information about metastatic patterns. The whole dataset, including clinical and genomic information, is publicly available through cBioPortal (https://www.cbioportal.org/study/summary?id=msk_met_2021). By analyzing these data, we identified associations between genomic alterations and patterns of metastatic dissemination. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression. The main conclusions from our pan-cancer study were summarized in a manuscript published in Cell. We also published a follow-up manuscript in Cancer Cell that focused on the genomic characterization of metastatic organotropism in lung adenocarcinoma.
Publications
Nguyen B, Fong C, Luthra A, Smith SA, DiNatale RG, Nandakumar S, Walch H, Chatila WK, Madupuri R, Kundra R, Bielski CM, Mastrogiacomo B, Donoghue MTA, Boire A, Chandarlapaty S, Ganesh K, Harding JJ, Iacobuzio-Donahue CA, Razavi P, Reznik E, Rudin CM, Zamarin D, Abida W, Abou-Alfa GK, Aghajanian C, Cercek A, Chi P, Feldman D, Ho AL, Iyer G, Janjigian YY, Morris M, Motzer RJ, O'Reilly EM, Postow MA, Raj NP, Riely GJ, Robson ME, Rosenberg JE, Safonov A, Shoushtari AN, Tap W, Teo MY, Varghese AM, Voss M, Yaeger R, Zauderer MG, Abu-Rustum N, Garcia-Aguilar J, Bochner B, Hakimi A, Jarnagin WR, Jones DR, Molena D, Morris L, Rios-Doria E, Russo P, Singer S, Strong VE, Chakravarty D, Ellenson LH, Gopalan A, Reis-Filho JS, Weigelt B, Ladanyi M, Gonen M, Shah SP, Massague J, Gao J, Zehir A, Berger MF, Solit DB, Bakhoum SF, Sanchez-Vega F*, Schultz N.* Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell. 2022 Feb 3;185(3):563-575.e11. doi: 10.1016/j.cell.2022.01.003. PubMed PMID: 35120664.
Lengel HB, Mastrogiacomo B, Connolly JG, Tan KS, Liu Y, Fick CN, Dunne EG, He D, Lankadasari MB, Satravada BA, Sun Y, Kundra R, Fong C, Smith S, Riely GJ, Rudin CM, Gomez DR, Solit DB, Berger MF, Li BT, Mayo MW, Matei I, Lyden DC, Adusumilli PS, Schultz N, Sanchez-Vega F*, Jones DR*. Genomic mapping of metastatic organotropism in lung adenocarcinoma. Cancer Cell. 2023 May 8;41(5):970-985.e3. doi: 10.1016/j.ccell.2023.03.018. Epub 2023 Apr 20. PubMed PMID: 37084736.
Additional coverage of this study:
Coulton A, Turajlic S. Metastasis and organotropism: A look through the lens of large-scale clinical sequencing data. Cancer Cell. 2022 Feb 14;40(2):134-135. doi: 10.1016/j.ccell.2022.01.011. Epub 2022 Feb 3. PMID: 35120602.
Genomic Alterations Distinguish Patterns of Metastatic Dissemination. Cancer Discov 1 April 2022; 12 (4): 881.
https://doi.org/10.1158/2159-8290.CD-RW2022-023
The Mystery of Metastasis: Can a Tumor’s Genetic Mutations Predict Whether and Where Cancer Will Spread?https://www.mskcc.org/news/mystery-metastasis-can-tumor-s-genetic-mutations-predict-whether-and-where-cancer-will-spread?_subsite=research-ski%20%28Cell%29