Mutational load predicts progression in patients with Barrett's esophagus

Genetic mutations at several key loci predicted whether patients with Barrett’s esophagus who had no dysplasia or low-grade dysplasia at baseline would progress to high-grade dysplasia or esophageal adenocarcinoma, according to study results presented at Digestive Disease Week.

“Barrett’s esophagus is a known precursor to esophageal adenocarcinoma, which has a high mortality [rate],” Swathi Eluri, MD, gastroenterology fellow in the division of gastroenterology and hepatology at University of North Carolina School of Medicine, told HemOnc Today. “We currently have inadequate methods of risk-stratifying patients with Barrett’s esophagus.”

Eluri and colleagues conducted a case-control study to assess whether mutational load helped stratify patients with Barrett’s esophagus based on risk for development of high-grade dysplasia or esophageal adenocarcinoma.

The analysis included 69 patients treated at three sites.

The 23 case patients (96% male) had no dysplasia or low-grade dysplasia at baseline, then had high-grade dysplasia or esophageal adenocarcinoma on follow-up biopsy performed at least 1 year later. The 46 control patients (76% male) also had non-dysplastic Barrett’s esophagus or low-grade dysplasia at baseline but did not progress during follow-up.

The case and control groups were comparable with regard to mean age (63.9 years vs. 62.5 years), mean number of microdissected targets (1.87 vs. 1.7) and mean follow-up time between index and outcome biopsies (3.9 years vs. 4.3 years). Researchers also reported similar rates of non-dysplastic and low-grade dysplasia histology in each cohort at index biopsy.

The researchers used polymerase chain reaction and quantitative capillary electrophoresis of DNA to assess the presence of loss of heterozygosity (LOH) and microsatellite instability (MSI) in formalin-fixed, paraffin-embedded tissue.

Eluri and colleagues used the BarreGen test (Interpace Diagnostics) to determine all patients’ mutational load in 10 genomic loci: 1p (CMM1, L-myc), 3p (VHL, HoGG1), 5q (MCC, APC), 9p (CDKN2A), 10q (PTEN, MX11), 17p (TP53), 17q (NME1), 18q (DCC), 21q (TFF1, PSEN2) and 22q (NF2).

Researchers assigned a value of 1 to high-clonality loss of heterozygosity mutations and a value of 0.5 to all low-clonality mutations. They assigned a value of 0.75 for microsatellite instability at the first loci and 0.5 for all subsequent loci.

The total value constituted mutational load, and the investigators used receiver operator characteristic curves to assess the potential for mutational load at various thresholds to predict risk for progression.

Researchers calculated a significantly higher per-patient mutational load in pre-progression biopsies among patients who eventually progressed compared with those who did not progress (2.21 vs. 0.42; P < .0001).

The test demonstrated a 100% sensitivity for distinguishing case patients from controls at a mutational load cutoff of 0.5 or higher, and a 96% specificity at a mutational load cutoff of 1.5 or higher. The test peaked at an accuracy of 89.9% (95% CI, 80.2-95.8%) at a mutational load of 1 or higher.

Eluri and colleagues constructed receiver operator characteristics for various mutational load thresholds, and they determined the corresponding area under the curve was 0.946 (95% CI, 0.89-0.99).

“Mutational load may have utility as a clinical biomarker in Barrett’s esophagus patients to predict progression to high-grade dysplasia and esophageal adenocarcinoma approximately 3 to 4 years prior to histological onset,” Eluri said. “Further validation in larger studies is needed.” – by Mark Leiser

For more information:

Swathi Eluri, MD, can be reached at swath.eluri@unchealth.unc.edu.

Reference:

Eluri S, et al. Abstract Sa1923. Presented at: Digestive Disease Week; May 16-19, 2015; Washington.

Disclosure: Eluri reports no relevant financial disclosures. See the study for a full list of all other researchers’ relevant financial disclosures.