Christopher Douville1, Helen R Moinova2, Prashanthi N Thota3, Nicholas J Shaheen4, Prasad G Iyer5, Marcia Irene Canto6, Jean S Wang7, John A Dumot2, Ashley Faulx2, Kenneth W Kinzler1, Nickolas Papadopoulos8, Bert Vogelstein9, Sanford D Markowitz10, Chetan Bettegowda11, Joseph E Willis12, Amitabh Chak13. 1. Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. 2. Department of Medicine, Case Western Reserve University, Cleveland, Ohio. 3. Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio. 4. Center for Esophageal Diseases and Swallowing, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina. 5. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 6. Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland. 7. Department of Medicine, Washington University in St. Louis, St. Louis, Missouri. 8. Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 9. Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. 10. Department of Medicine, Case Western Reserve University, Cleveland, Ohio; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio; Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio. Electronic address: sxm10@case.edu. 11. Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. 12. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio; Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio; Department of Pathology, Case Western Reserve University, Cleveland, Ohio. 13. Department of Medicine, Case Western Reserve University, Cleveland, Ohio; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio; Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio. Electronic address: amitabh.chak@uhhospitals.org.
Abstract
BACKGROUND & AIMS: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer. METHODS: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression. RESULTS: Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE. CONCLUSIONS: RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.
BACKGROUND & AIMS: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer. METHODS: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression. RESULTS: Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE. CONCLUSIONS: RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.
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