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

• Published in: Cell Vol. 185; no. 3; pp. 563 - 575.e11
• Main Authors: Nguyen, Bastien, Fong, Christopher, Luthra, Anisha, Smith, Shaleigh A., DiNatale, Renzo G., Nandakumar, Subhiksha, Walch, Henry, Chatila, Walid K., Madupuri, Ramyasree, Kundra, Ritika, Bielski, Craig M., Mastrogiacomo, Brooke, Donoghue, Mark T.A., Boire, Adrienne, Chandarlapaty, Sarat, Ganesh, Karuna, Harding, James J., Iacobuzio-Donahue, Christine A., Razavi, Pedram, Reznik, Ed, Rudin, Charles M., Zamarin, Dmitriy, Abida, Wassim, Abou-Alfa, Ghassan K., Aghajanian, Carol, Cercek, Andrea, Chi, Ping, Feldman, Darren, Ho, Alan L., Iyer, Gopakumar, Janjigian, Yelena Y., Morris, Michael, Motzer, Robert J., O’Reilly, Eileen M., Postow, Michael A., Raj, Nitya P., Riely, Gregory J., Robson, Mark E., Rosenberg, Jonathan E., Safonov, Anton, Shoushtari, Alexander N., Tap, William, Teo, Min Yuen, Varghese, Anna M., Voss, Martin, Yaeger, Rona, Zauderer, Marjorie G., Abu-Rustum, Nadeem, Garcia-Aguilar, Julio, Bochner, Bernard, Hakimi, Abraham, Jarnagin, William R., Jones, David R., Molena, Daniela, Morris, Luc, Rios-Doria, Eric, Russo, Paul, Singer, Samuel, Strong, Vivian E., Chakravarty, Debyani, Ellenson, Lora H., Gopalan, Anuradha, Reis-Filho, Jorge S., Weigelt, Britta, Ladanyi, Marc, Gonen, Mithat, Shah, Sohrab P., Massague, Joan, Gao, Jianjiong, Zehir, Ahmet, Berger, Michael F., Solit, David B., Bakhoum, Samuel F., Sanchez-Vega, Francisco, Schultz, Nikolaus
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2022
• Subjects: cancer; clinical sequencing; Cohort Studies; DNA sequencing; Female; Genomics; High-Throughput Nucleotide Sequencing; Humans; Male; metastasis; molecular profiling; mutations; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; next-generation sequencing; Organ Specificity - genetics; organotropism; pan-cancer; Prospective Studies; clinical sequencing; mutations; pan-cancer; metastasis; next-generation sequencing; genomics; cancer; DNA sequencing; molecular profiling; organotropism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.01.003

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between 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+/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. [Display omitted] •A large clinico-genomic database to study metastatic patterns across 50 tumor types•Oncogenic alteration frequency and chromosomal instability are increased in metastases•Correlations between chromosomal instability and metastatic burden depend on cancer type•Genomic features associated with metastasis are identified for specific target organs Clinico-genomic analysis of MSK-MET, a cohort of over 25,000 patients with metastasis across 50 cancer types, identifies somatic alterations associated with organ-specific metastasis and highlights that chromosomal instability correlates with metastatic burden in a cancer type-dependent manner.