title: Understanding Intratumoral Heterogeneity: Lessons from the Analysis of At-Risk Tissue and Premalignant Lesions in the Colon.
abstract: Advances in DNA sequencing have created new opportunities to better understand the biology of cancers. Attention is currently focused on precision medicine: does a cancer carry a mutation that is targetable with already available drugs? But, the timing at which multiple, targetable mutations arise during the adenoma to carcinoma sequence remains unresolved. Borras and colleagues identified mutations and allelic imbalance in at-risk mucosa and early polyps in the human colon. Their analyses indicate that mutations in key genes can arise quite early during tumorigenesis and that polyps are often multiclonal with at least two clones. These results are consistent with the "Big Bang" model of tumorigenesis, which postulates that intratumoral heterogeneity is a consequence of a mutational burst in the first few cell divisions following initiation that drives divergence from a single founder with unique but related clones coevolving. Emerging questions center around the ancestry of the tumor and impact of early intratumoral heterogeneity on tumor establishment, growth, progression, and most importantly, response to therapeutic intervention. Additional sequencing studies in which samples, especially at-risk tissue and premalignant neoplasms, are analyzed from animal models and humans will further our understanding of tumorigenesis and lead to more effective strategies for prevention and treatment. Cancer Prev Res; 9(8); 638-41. ©2016 AACRSee related article by Borras, et al., Cancer Prev Res 2016;9(6):417-427.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Chelsie K
authors.initials: CK
authors.lastname: Sievers
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Leystra
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Linda
authors.initials: L
authors.lastname: Clipson
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin. Laboratory of Genetics, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: William F
authors.initials: WF
authors.lastname: Dove
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. rbhalberg@medicine.wisc.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Halberg
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D003106:Colon / Q000473:pathology*; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D017491:Genes, APC; D018740:Genetic Heterogeneity; D006801:Humans; D051379:Mice; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology