title: A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis.
abstract: Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer.
authors.affiliation: Aix Marseille Université, CNRS, Centrale Marseille, Marseille, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Remy
authors.affiliation: Institut Curie, PSL Research University, Paris, France. CNRS, UMR 144, Oncologie Moléculaire, Equipe Labellisée Ligue Contre le Cancer, Institut Curie, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Claudine
authors.initials: C
authors.lastname: Chaouiya
authors.affiliation: Institut Curie, PSL Research University, Paris, France. INSERM, U900, Paris, France. Ecole des Mines ParisTech, Fontainebleau, France.
authors.forename: Andrei
authors.initials: A
authors.lastname: Zinovyev
authors.affiliation: Institut Curie, PSL Research University, Paris, France. CNRS, UMR 144, Oncologie Moléculaire, Equipe Labellisée Ligue Contre le Cancer, Institut Curie, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.affiliation: Institut Curie, PSL Research University, Paris, France. INSERM, U900, Paris, France. Ecole des Mines ParisTech, Fontainebleau, France. laurence.calzone@curie.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Calzone
mesh_terms: D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D066264:Datasets as Topic / Q000706:statistics & numerical data; D004843:Epistasis, Genetic; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011336:Probability; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins