NEW YORK (GenomeWeb) – Members of the Esophageal Cancer Clinical and Molecular Stratification consortium have characterized molecular alterations in hundreds of esophageal adenocarcinoma (EAC) tumors, identifying driver mutations and potential markers for disease progression and poor patient outcomes.
Using data for 551 esophageal adenocarcinomas profiled for the International Cancer Genome Consortium, or in publicly available exome sequence or whole-genome sequence sets, the researchers identified dozens of driver genes or non-coding drivers in esophageal adenocarcinoma, including some alterations occurring in combination with one another and some found to the exclusion of others.
Beyond that, the team narrowed in on potential treatment targets, and changes to the SMAD4 and GATA4 genes that were significantly associated with esophageal adenocarcinoma outcomes in the ICGC esophageal cancer cases — prognostic relationships that were subsequently validated with data on gastroesophageal or pancreatic cancer cases profiled for the Cancer Genome Atlas project. The results appeared online today Nature Genetics.
The study "provides a detailed compendium of mutations and copy number alterations undergoing selection in EAC that have clinically relevant effects on tumor behavior," corresponding author Rebecca Fitzgerald, a cancer researcher at the University of Cambridge, and her colleagues wrote.
Although past genomic studies have pointed to around a dozen driver genes in esophageal carcinoma, the team noted that the relatively common cancer type tends to be marked by "very high mutations rates but also, paradoxically, by a paucity of recurrently mutated genes."
For their analysis, the researchers focused on 379 esophageal adenocarcinoma cases profiled for the ICGC project, as well as 149 published esophageal adenocarcinoma tumor exomes and nearly two-dozen tumors previously assessed by whole-genome sequencing for another published study.
Together with RNA sequence data for a subset of 116 tumors, the team's analysis of the available exome and genome sequence data revealed more than 11.8 million single nucleotide variants or small insertions and deletions, along with nearly 287,000 copy number changes, close to 134,700 structural variants (in the subset of samples assessed by whole-genome sequencing), and 149 recurrently amplified or deleted sites in the genome.
In particular, the researchers unearthed more than four driver events in each esophageal adenocarcinoma tumor, on average, including alterations — mostly mutations — affecting 76 apparent driver genes and at least 21 non-coding, driver regulatory elements. Both coding and non-coding driver sets overlapped with those documented in pancreatic cancer or in pan-cancer analyses, they reported, and included known drivers and new candidates.
"These events were characterized in terms of their relative impact, related functions, mutual exclusivity, and co-occurrence and expression in comparison to those in normal tissues," the team explained. "We used this set of biologically important gene alterations to identify prognostic biomarkers and actionable genomic events for personalized medicine."
For example, the latter analysis led the team to survival-related changes in two genes: mutations or deletions in SMAD4 and GATA4 amplifications linked to decreased survival times that appeared to have even more dire effects on patient outcomes when found together in tumors.
Meanwhile, based on the presence of recurrent, sensitizing mutations from the Cancer Biomarkers database in more than half of the esophageal cancers considered the researchers suggested it might eventually be possible to target a subset of esophageal adenocarcinoma cases using CDK4 or CDK6 inhibitors such as ribociclib or palbociclib.
That notion was supported by their preliminary analyses on a panel of esophageal adenocarcinoma cell lines or cell lines from Barrett's high-grade dysplasia cases that contained similar mutation profiles, where sensitizing mutations in cell cycle and other pathways appeared to boost response to the CDK4/CDK6 inhibitors.
"This comprehensive study provides insights into the nature of [esophageal adenocarcinoma] tumors and should pave the way for evidence-based clinical trials in this poor-prognosis disease," the authors concluded.