title: How Cancer Genomics Drives Cancer Biology: Does Synthetic Lethality Explain Mutually Exclusive Oncogenic Mutations?
abstract: Large-scale analyses of cancer genomes are revealing patterns of mutations that suggest biologically significant ideas about many aspects of cancer, including carcinogenesis, classification, and preventive and therapeutic strategies. Among those patterns is "mutual exclusivity," a phenomenon observed when two or more mutations that are commonly observed in samples of a type of cancer are not found combined in individual tumors. We have been studying a striking example of mutual exclusivity: the absence of coexisting mutations in theKRASandEGFRproto-oncogenes in human lung adenocarcinomas, despite the high individual frequencies of such mutations in this common type of cancer. Multiple lines of evidence suggest that toxic effects of the joint expression ofKRASandEGFRmutant oncogenes, rather than loss of any selective advantages conferred by a second oncogene that operates through the same signaling pathway, are responsible for the observed mutational pattern. We discuss the potential for understanding the physiological basis of such toxicity, for exploiting it therapeutically, and for extending the studies to other examples of mutual exclusivity.
authors.affiliation: Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065.
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
authors.affiliation: Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065.
authors.forename: Arun M
authors.initials: AM
authors.lastname: Unni
authors.affiliation: BC Cancer Agency and University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000072020:Synthetic Lethal Mutations / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors