Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies. In many cancers, an antecedent oncogenic mutation drove evolutionarily dependent allele-specific imbalance. In other instances, oncogenic mutations co-opted independent copy-number changes via the evolutionary process of exaptation. Oncogenic allele imbalance is a pervasive evolutionary innovation that enhances fitness and modulates sensitivity to targeted therapy.
Pubmed ID: 30393068 RIS Download
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View all literature mentionsPrecision oncology knowledge base which contains information about the effects and treatment implications of specific cancer gene alterations. OncoKB contains detailed information about specific alterations in 418 cancer genes. Each variant entry contains biological effect, prevalence, prognostic information, and treatment implications. Information is curated from various sources, such as guidelines from the FDA, ClinicalTrials.gov, and scientific literature by a network of clinical fellows, research fellows, and faculty members at Memorial Sloan Kettering Cancer Center.
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View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets p44 / p42 MAPK, phospho (Thr202 / Tyr204)
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View all literature mentionsThis polyclonal targets MEK1/2
View all literature mentionsThis polyclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsCell line SK-BR-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSoftware environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
View all literature mentionsSoftware environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SK-BR-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets MEK1/2
View all literature mentionsThis polyclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsThis recombinant monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets GFP
View all literature mentions