Genomic Test Predicts Malignant Transformation of Barrett's Esophagus

The premalignant condition Barrett's esophagus can transform into esophageal cancer. To determine which patients are at higher or lower risk of having their Barrett's esophagus become cancerous, enabling earlier treatment or reduced endoscopic monitoring, respectively, improved biomarkers are needed. Killcoyne, Gregson, and colleagues employed shallow whole-genome sequencing to investigate whether there was a relationship between genomic copy number and risk of progression in 777 endoscopic samples collected during surveillance endoscopies from 88 patients with Barrett's esophagus. Indeed, the genomes from progressive samples exhibited generalized disorder and copy-number changes that fluctuated from sample to sample over time. Based on this information, a cross-validated elastic net–regularized logistic regression model of progression and classification was developed and subsequently validated using data from two independent cohorts, one with 213 samples from 76 patients and the other with 1,272 samples from 248 patients. Using risk categories derived from this model, samples with the highest relative risk were 30 times more likely than average to progress, whereas those with the lowest relative risk were 10 times less likely than average to progress. By applying the model, it was possible to use genomic copy number to predict malignant transformation years in advance: At least one endoscopy was deemed high-risk using the model in 50% of patients eight years or more before progression, in 62% six years before progression, in 78% two years before progression, in 85% one year before progression, and in 93% by the time of progression. Compared with risk of progression determined using existing methods, which are based on length of the Barrett's esophagus segment and the presence or absence of low- or high-grade dysplasia, 54% of patients with progressive Barrett's esophagus could have received earlier treatment and 51% of patients whose Barrett's esophagus did not progress could have been recommended less-frequent monitoring after their second surveillance endoscopy. Improving this model using larger patient cohorts and combining inexpensive genomic testing with existing surveillance methods may yield better outcomes for high-risk patients while decreasing over-screening for low-risk patients.

Killcoyne S, Gregson E, Wedge DC, Woodcock DJ, Eldridge MD, de la Rue R, et al. Genomic copy number predicts esophageal cancer years before transformation. Nature 2020 Sep 7 [Epub ahead of print].

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