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Esophageal Adenocarcinoma Mutational Subtypes Uncovered by Genome Sequencing

NEW YORK (GenomeWeb) – An international team has characterized mutation patterns in the esophageal adenocarcinoma, providing molecular clues to classifying and treating the disease.

As they reported in Nature Genetics this week, members of the Oesophageal Cancer Clinical and Molecular Stratification consortium did whole-genome sequencing on matched tumor and normal samples from more than 100 individuals with esophageal adenocarcinoma, identifying three subtypes of the disease. Along with frequent copy number alterations and genetic heterogeneity, they uncovered alterations that may explain lack of response to targeted treatments attempted so far.

"[W]e have uncovered possible reasons for the lack of efficacy in molecularly targeted trials and present a novel genomic classification that links etiology to patient stratification with potential therapeutic relevance," corresponding author Rebecca Fitzgerald, a researcher at the University of Cambridge Medical Research Council Cancer Unit, said in a statement.

Given the rising rates of esophageal cancer among Caucasian American men, and the inherent aggressiveness of the disease, the team set out to expand on the molecular profiles available for one of the esophageal cancer subtypes, esophageal adenocarcinoma.

Though some genomic and exome sequencing studies of the disease have been reported in the past, the study's authors explained, "[w]hat is still lacking is an understanding of how to use these complex molecular data to stratify patients in order to help inform clinical decision making."

Through the International Cancer Genome Consortium, the researchers did whole-genome sequencing on tumor samples from 129 individuals with esophageal carcinoma using Illumina instruments, generating 50-fold average coverage of the tumor samples and 30-fold coverage, on average, of matched normal samples from each individual.

The tumor genome sequences were rife with point mutations and genetic heterogeneity. Even so, the team noted, it was the copy number and structural variant changes that appeared to be the most prominent esophageal adenocarcinoma drivers.

For example, rearrangements were over-represented in and around genes such as SMYD3, RUNX1, and CTNNA3, while genes in cell cycle, signaling, and other pathways tended to be marked by mobile element insertions, and still other genes were altered by recurrent amplifications or deletions.

A significant subset of the tumors contained complicated rearrangements, chromothripsis, or other catastrophic changes to the genome.

When the researchers focused in on mutational patterns in the tumors, they saw three subtypes marked by cytosine substitutions, DNA damage repair deficiency, or higher-than-usual mutational burdens — patterns they verified in samples from another 87 individuals with esophageal adenocarcinoma.

The team also took a look at structural changes that might impact response to targeted receptor tyrosine kinase inhibitors. Based on the amplifications identified in genes such as ERBB2 or EGFR, the researchers suggested that combination therapies may be effective, once the specific alterations in an individual's tumor is known.