Synapse - Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination

Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination Journal Article

Authors:	Zhao, K.; Vos, J.; Lam, S.; Boe, L. A.; Muldoon, D.; Han, C. Y.; Valero, C.; Lee, M.; Fitzgerald, C.; Lee, A. S.; Prasad, M.; Jain, S.; Deng, X.; Chan, T. A.; Berger, M. F.; Bandlamudi, C.; Zhou, X. K.; Morris, L. G. T.
Article Title:	Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination
Abstract:	To understand genetic evolution in cancer during metastasis, we analyzed genomic profiles of 3,732 cancer patients in whom several tumor sites were longitudinally biopsied. During distant metastasis, tumors were observed to accumulate copy number alterations (CNAs) to a much greater degree than mutations. In particular, the development of whole genome duplication was a common event during metastasis, emerging de novo in 28% of patients. Loss of 9p (including CDKN2A) developed during metastasis in 11% of patients. To a lesser degree, mutations and allelic loss in human leukocyte antigen class I and other genes associated with antigen presentation also emerged. Increasing CNA, but not increasing mutational load, was associated with immune evasion in patients treated with immunotherapy. Taken together, these data suggest that CNA, rather than mutational accumulation, is enriched during cancer metastasis, perhaps due to a more favorable balance of enhanced cellular fitness versus immunogenicity. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
Keywords:	adult; human tissue; treatment response; primary tumor; gene mutation; major clinical study; genetics; mutation; cancer localization; cancer growth; systemic therapy; cancer patient; pancreas cancer; endometrium cancer; neoplasm; neoplasms; colorectal cancer; allele; cancer immunotherapy; melanoma; metastasis; ovary cancer; breast cancer; epidermal growth factor receptor 2; cohort analysis; gene locus; evolution; tumor biopsy; pathology; bladder cancer; distant metastasis; evolution, molecular; prostate cancer; sarcoma; consanguinity; tumor suppressor gene; cancer center; antigen presentation; longitudinal studies; molecular evolution; head and neck cancer; human genome; hla antigen class 1; neoplasm metastasis; mesothelioma; soft tissue sarcoma; gene duplication; gene loss; stomach cancer; heterozygosity loss; salivary gland cancer; cyclin dependent kinase inhibitor 2a; kidney cancer; estrogen receptor; progesterone receptor; esophagus cancer; longitudinal study; pancreas islet cell tumor; dna copy number variations; non small cell lung cancer; tumor microenvironment; bone sarcoma; copy number variation; immune evasion; hepatobiliary system cancer; soft tissue cancer; tumor immunogenicity; immune checkpoint inhibitor; humans; human; male; female; article; germ cell cancer; mutational load; malignant neoplasm; tumor mutational burden; genetic profile; immunoselection; mutation accumulation; metastasis in breast; metastasis site
Journal Title:	Nature Genetics
Volume:	57
Issue:	6
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2025-06-01
Start Page:	1504
End Page:	1511
Language:	English
DOI:	10.1038/s41588-025-02204-3
PUBMED:	40457077
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105007294157&doi=10.1038%2fs41588-025-02204-3&partnerID=40&md5=89d233c16d01194a7e41c42f389c7838
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Luc Morris -- Source: Scopus