Project 3: Phylogenetic Analysis of Progression in Barrett's Esophagus It is generally accepted that cancer develops through a process of neoplastic evolution over time and space in the body, yet studying these evolutionary processes has proven nearly impossible, since tissue that is at risk for developing into cancer is almost always removed. We propose to characterize these evolutionary processes in Barrett's esophagus, a precursor to esophageal adenocarcinoma, which develops in the esophagus as an adaptation to chronic reflux. This premalignant tissue is not removed from the body when detected;instead, patients are enrolled in surveillance programs, allowing biopsies to be collected and genomic changes that evolve over time and space in vivo to be studied. We hypothesize that the initial expansion of Barrett's epithelium persists for a lifetime in most individuals with Barrett's and is associated with a low risk of progression to cancer. In a small percentage of Barrett's patients, a secondary expansion of cell populations with greatly increased genomic alterations spreads across in the already established Barrett's segment, and in this secondary expansion cancer develops. We propose to use phylogenetic analysis, a method adapted from evolutionary biology, to characterize the processes that determine the evolutionary pathway (stable, benign disease or progression to esophageal adenocarcinoma) that occurs in an individual. This will be accomplished using somatic genomic alteration data from high density SNP arrays and from whole genome sequencing of samples taken at multiple time points from a cohort of 248 patients, 79 of whom progressed to cancer during followup. Phylogenies can distinguish between gradual versus punctuated dynamics in the accumulation of genomic alterations. Phylogenies also allow inference ofthe genomic makeup of ancestral cell populations, providing novel targets for early detection and prevention strategies. These analyses will address a critical question that has been almost impossible to study: what are the processes that govern the evolution of cancer in vivo.
Our study will allow us to characterize the genetic changes that occur in cancer cells from very eariy on in the process of cancer development. It has been neariy impossible to study how cancer cells change and evolve over time in actual patients. What we learn from this study will help identify when and what kind of treatments are most likely to help prevent the development of cancer.
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|Andor, Noemi; Graham, Trevor A; Jansen, Marnix et al. (2016) Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat Med 22:105-13|
|Kostadinov, Rumen; Maley, Carlo C; Kuhner, Mary K (2016) Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content. PLoS Comput Biol 12:e1004413|
|Reid, Brian J (2016) Surrogate Markers: Lessons from the Next Gen? Cancer Prev Res (Phila) 9:512-7|
|Kuhner, Mary K; Kostadinov, Rumen; Reid, Brian J (2016) Limitations of the Driver/Passenger Model in Cancer Prevention. Cancer Prev Res (Phila) 9:335-8|
|Ek, Weronica E; Lagergren, Katarina; Cook, Michael et al. (2016) Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Int J Cancer 138:1146-52|
|Palles, Claire; Chegwidden, Laura; Li, Xinzhong et al. (2015) Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus. Gastroenterology 148:367-78|
|Nunney, Leonard; Maley, Carlo C; Breen, Matthew et al. (2015) Peto's paradox and the promise of comparative oncology. Philos Trans R Soc Lond B Biol Sci 370:|
|Li, Xiaohong; Paulson, Thomas G; Galipeau, Patricia C et al. (2015) Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus. Cancer Prev Res (Phila) 8:845-56|
|Walther, Viola; Hiley, Crispin T; Shibata, Darryl et al. (2015) Can oncology recapitulate paleontology? Lessons from species extinctions. Nat Rev Clin Oncol 12:273-85|
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