Inherited Disease Genetics Improves the Identification of Cancer-Associated Genes.
The identification of biologically significant variants in cancer genomes is critical to therapeutic discovery, but it is limited by the statistical power needed to discern driver from passenger. Independent biological data can be used to filter cancer exomes and increase statistical power. Large genetic databases for inherited diseases are uniquely suited to this task because they contain specific amino acid alterations with known pathogenicity and molecular mechanisms. However, no rigorous method to overlay this information onto the cancer exome exists. Here, we present a computational methodology that overlays any variant database onto the somatic mutations in all cancer exomes. We validate the computation experimentally and identify novel associations in a re-analysis of 7362 cancer exomes. This analysis identified activating SOS1 mutations associated with Noonan syndrome as significantly altered in melanoma and the first kinase-activating mutations in ACVR1 associated with adult tumors. Beyond a filter, significant variants found in both rare cancers and rare inherited diseases increase the unmet medical need for therapeutics that target these variants and may bootstrap drug discovery efforts in orphan indications.
Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Discovery/Translational Biology, ARIAD Pharmaceuticals, Cambridge, Massachusetts, United States of America.
Boyang
0000-0003-4610-1707
B
Zhao
Discovery/Translational Biology, ARIAD Pharmaceuticals, Cambridge, Massachusetts, United States of America.
Justin R
JR
Pritchard
D030201:Activin Receptors, Type I / Q000235:genetics*; D000595:Amino Acid Sequence; D002460:Cell Line; D024061:Collagen Type III / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D016889:Endometrial Neoplasms / Q000235:genetics*; D059472:Exome / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008545:Melanoma / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics*; D010766:Phosphorylation; D020837:SOS1 Protein / Q000235:genetics*
C439971:COL3A1 protein, human; D024061:Collagen Type III; D020837:SOS1 Protein; D048049:Extracellular Signal-Regulated MAP Kinases; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I