title: A mathematical framework to determine the temporal sequence of somatic genetic events in cancer.
abstract: Human cancer is caused by the accumulation of genetic alterations in cells. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and represent promising targets for therapeutic intervention. Here we describe a computational approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to deduce the temporal sequence of genetic events during tumorigenesis from cross-sectional genomic data of tumors at their fully transformed stage. When applied to a dataset of 70 advanced colorectal cancers, our algorithm accurately predicts the sequence of APC, KRAS, and TP53 mutations previously defined by analyzing tumors at different stages of colon cancer formation. We further validate the method with glioblastoma and leukemia sample data and then apply it to complex integrated genomics databases, finding that high-level EGFR amplification appears to be a late event in primary glioblastomas. RESIC represents the first evolutionary mathematical approach to identify the temporal sequence of mutations driving tumorigenesis and may be useful to guide the validation of candidate genes emerging from cancer genome surveys.
authors.affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Camille Stephan-Otto
authors.initials: CS
authors.lastname: Attolini
authors.forename: Yu-Kang
authors.initials: YK
authors.lastname: Cheng
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
mesh_terms: D000465:Algorithms; D001779:Blood Coagulation Factors / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D018450:Disease Progression; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011956:Receptors, Cell Surface / Q000235:genetics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D001779:Blood Coagulation Factors; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C091963:activated protein C receptor; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins