title: Multi-organ Mapping of Cancer Risk.
abstract: Cancers are distributed unevenly across the body, but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used Cre-recombination of conditional lineage tracing, oncogene, and tumor suppressor alleles to define populations of stem and non-stem cells in mouse organs and test their life-long susceptibility to tumorigenesis. We show that tumor incidence is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a "perfect storm" that ultimately determines organ cancer risk. VIDEO ABSTRACT.
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: Liqin
authors: L
authors: Zhu
authors: Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: David
authors: D
authors: Finkelstein
authors: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: Culian
authors: C
authors: Gao
authors: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: Lei
authors: L
authors: Shi
authors: Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: Yongdong
authors: Y
authors: Wang
authors: Department of Pathology & Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors: Dolores
authors: D
authors: López-Terrada
authors: Developmental Biology, Regenerative Medicine, and Stem Cell, Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
authors: Kasper
authors: K
authors: Wang
authors: Developmental Biology, Regenerative Medicine, and Stem Cell, Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
authors: Sarah
authors: S
authors: Utley
authors: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: Stanley
authors: S
authors: Pounds
authors: Hartwell Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Geoffrey
authors: G
authors: Neale
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: David
authors: D
authors: Ellison
authors: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: arzu.onar@stjude.org.
authors: Arzu
authors: A
authors: Onar-Thomas
authors: Department of Oncology and CRUK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, England. Electronic address: richard.gilbertson@cruk.cam.ac.uk.
authors: Richard James
authors: RJ
authors: Gilbertson
mesh_terms: D000483:Alleles; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D019426:Integrases; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D016296:Mutagenesis; D009857:Oncogenes; D011995:Recombination, Genetic; D012306:Risk; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C045073:Cre recombinase; D019426:Integrases