Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.
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.
['Wheeler|David A|DA|', 'Takebe|Naoko|N|', 'Hinoue|Toshinori|T|', 'Hoadley|Katherine A|KA|', 'Cardenas|Maria F|MF|', 'Hamilton|Alina M|AM|', 'Laird|Peter W|PW|', 'Wang|Linghua|L|', 'Johnson|Adrienne|A|', 'Dewal|Ninad|N|', 'Miller|Vincent|V|', 'Piñeyro|David|D|', 'Castro de Moura|Manuel|M|', 'Esteller|Manel|M|', 'Shen|Hui|H|', 'Zenklusen|Jean Claude|JC|', 'Tarnuzzer|Roy|R|', 'McShane|Lisa M|LM|', 'Tricoli|James V|JV|', 'Williams|Paul M|PM|', 'Lubensky|Irina|I|', "O'Sullivan-Coyne|Geraldine|G|", 'Kohn|Elise C|EC|', 'Little|Richard F|RF|', 'White|Jeffrey|J|', 'Malik|Shakun|S|', 'Harris|Lyndsay|L|', 'Weil|Carol|C|', 'Chen|Alice P|AP|', 'Karlovich|Chris|C|', 'Rodgers|Brian|B|', 'Shankar|Lalitha|L|', 'Jacobs|Paula|P|', 'Nolan|Tracy|T|', 'Hu|Jianhong|J|', 'Muzny|Donna M|DM|', 'Doddapaneni|Harshavardhan|H|', 'Korchina|Viktoriya|V|', 'Gastier-Foster|Julie|J|', 'Bowen|Jay|J|', 'Leraas|Kristen|K|', 'Edmondson|Elijah F|EF|', 'Doroshow|James H|JH|', 'Conley|Barbara A|BA|', 'Ivy|S Percy|SP|', 'Staudt|Louis M|LM|']
D000970:Antineoplastic Agents D001706:Biopsy D044127:Epigenesis, Genetic D005260:Female D053263:Gene Regulatory Networks D014644:Genetic Variation D023281:Genomics D006801:Humans D008297:Male D009369:Neoplasms D011379:Prognosis D016019:Survival Analysis D016896:Treatment Outcome D059016:Tumor Microenvironment
exceptional response to therapy synthetic lethality DNA methylation analysis DNA repair mechanisms N of 1 experiment RNA sequencing combination cancer therapy integrating molecular and clinical data multi-platform genomic analyses precision cancer medicine rare mutations whole-exome sequencing