title: Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection.
abstract: Different tumor types vary greatly in their distribution of driver substitutions. Here, we analyzed how mutation and natural selection contribute to differences in the distribution of KRAS driver substitutions between lung, colon and pancreatic adenocarcinomas. We were able to demonstrate that both differences in mutation and differences in selection drive variation in the distribution of KRAS driver substitutions between tumor types. By accounting for the effects of mutation on the distribution of KRAS driver substitutions, we could identify specific KRAS driver substitutions that are more favored by selection in specific tumor types. Such driver substitutions likely improve fitness most when they occur within the context of the tumor type in which they are preferentially favored. Fitting with this, we found that driver substitutions that are more favored by natural selection in a specific type of tumor tend to associate with worse clinical outcomes specifically in that type of tumor.
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Genetics and Developmental Biology, the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Sheli L
authors.initials: SL
authors.lastname: Ostrow
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Simon
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Prinz
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Tova
authors.initials: T
authors.lastname: Bick
authors.affiliation: Institute of Oncology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Shentzer
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Sima S
authors.initials: SS
authors.lastname: Nagawkar
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Ben-Izhak
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Genetics and Developmental Biology, the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Hershberg
authors.affiliation: TICC, Technion Integrative Cancer Center at the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Hershkovitz
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D003062:Codon; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D059645:Mutation Rate; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012307:Risk Factors; D012641:Selection, Genetic; D012907:Smoking / Q000235:genetics / Q000503:physiopathology
chemical_list: D003062:Codon; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)