1. Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment
- Author
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Hui Shen, Louis M. Staudt, Viktoriya Korchina, Katherine A. Hoadley, Roy Tarnuzzer, Richard F. Little, Manuel Castro de Moura, Maria F. Cardenas, Irina A. Lubensky, Manel Esteller, Jianhong Hu, Julie M. Gastier-Foster, Jeffrey White, Elise C. Kohn, Paula M. Jacobs, Ninad Dewal, Chris Karlovich, Carol J. Weil, Donna M. Muzny, Geraldine O'Sullivan-Coyne, Lalitha K. Shankar, Adrienne Johnson, Kristen M. Leraas, Alice P. Chen, Jean C. Zenklusen, Shakun Malik, Peter W. Laird, Barbara A. Conley, Harshavardhan Doddapaneni, Lisa M. McShane, Jay Bowen, Vincent A. Miller, S. Percy Ivy, James V. Tricoli, David Piñeyro, Toshinori Hinoue, Tracy S. Nolan, Brian Rodgers, Lyndsay Harris, James H. Doroshow, David A. Wheeler, Paul Williams, Linghua Wang, Alina M Hamilton, Elijah F. Edmondson, and Naoko Takebe
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Biopsy ,Antineoplastic Agents ,Synthetic lethality ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,Combination cancer therapy ,Tumor Microenvironment ,medicine ,Humans ,Gene Regulatory Networks ,Epigenetics ,Exome sequencing ,Tumor microenvironment ,business.industry ,Genetic Variation ,Cancer ,Genomics ,Cell Biology ,Prognosis ,medicine.disease ,Exceptional Responder ,Survival Analysis ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business - Abstract
A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories���DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis���with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy. Profiling multi-platform genomics of 110 cancer patients with an exceptional therapeutic response, Wheeler et al. identify putative molecular mechanisms explaining this survival phenotype in ���23% of cases. Therapeutic success is related to rare molecular features of responding tumors, exploiting synthetic lethality and oncogene addiction.
- Published
- 2021
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