Somatic Genome Dynamics of Barrett's Esophagus Patients with Non-Cancer and Cancer Outcomes

A case-control study was designed with 80 participants diagnosed with Barrett's Esophagus (BE) selected from a larger case-cohort study (Li et al., 2014, PMID: 24253313) within the Seattle Barrett's Esophagus Program (SBEP) at the Fred Hutchinson Cancer Research Center. The study included 40 cases with BE with non-cancer outcomes, "NCO", who did not progress to esophageal adenocarcinoma (EA), and 40 controls who progressed to an endoscopically detected, incident EA (cancer outcome, "CO"). For each patient, two timepoints were evaluated (T1 and T2). NCO were matched to CO based on age at T1 (T1=first endoscopy with sufficient sample availability), and time between T1 and T2 (T2 in CO=time of diagnosis of incident EA). In 10 NCO, a third time point (T3), a mean of 13.2 years after T1, was also sequenced. Mapped endoscopic biopsies, at 1/3 and 2/3 annotated distances from the gastroesophageal junction within the Barrett's segment, were sampled per patient at each timepoint. Each biopsy was purified to separate BE epithelium from stroma, and DNA was extracted from purified epithelium for 60X WGS and 2.5M SNP array; normal control blood (N=62) or normal gastric sample (N=18) were analyzed by 30X WGS and 2.5M SNP array. An additional seven normal gastric biopsy samples in seven patients with normal control blood were also sequenced at 60X as controls. All research participants contributing clinical data and esophageal samples to this study provided written informed consent, subject to oversight by the Fred Hutchinson Cancer Research Center IRB Committee D (Reg ID 5619).]]>
Inclusion criteria included ≥ 2 endoscopies each with ≥ 3 cm segment of BE and none of the following interventions: no endoscopic mucosal resection, radio frequency ablation, photodynamic therapy, or esophageal surgical resection. Cases ("cancer outcome") were defined as participants who progressed to diagnosis of esophageal adenocarcinoma (EA), N=40. Controls ("non-cancer outcome") were defined as those who did not progress to EA during follow-up. For each case, controls were randomly selected using matching criteria of baseline total somatic chromosomal alterations (SCA) from (Li et al., 2014, PMID: 24253313) and time between timepoints T1 and T2. T1 was defined as either the baseline (N=5) or the baseline+1 (N=75) endoscopy, depending on tissue availability. T2 was defined as endoscopy during which EA was initially diagnosed for cancer outcome patients, or the endoscopy selected for matched follow-up time for non-cancer outcome patients.]]>
The Seattle Barrett's Esophagus Study (SBES), which was founded in 1983 as a prospective observational cohort study of patients with Barrett's esophagus (BE), and now comprises more than 1000 patients and includes a biorepository of biospecimens and associated clinical and epidemiologic data. BE is the only known precursor to esophageal adenocarcinoma (EA), which has an estimated annual incidence of 0.5% to 1.0%, yet BE is primarily an indolent disease that will not progress to cancer during the lifetime of most patients. However the incidence of esophageal adenocarcinoma is known to be increasing at an alarming rate in many western countries, rising nearly 600% in the US over the three decades from 1972 - 2002. The overarching goals of the SBES are to (1) reduce morbidity and mortality of EA by early detection, prevention, or both and (2) elucidate mechanisms of human neoplastic progression in vivo that may be shared by other neoplasms whose early stages are less amenable to investigation. The study has over 35 years of experience in early translational research studies as defined by the NCI Translational Research Working Group.]]>