Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

Abstract

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a five-year survival rate of 15%, identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole exome sequencing of 149 EAC tumors/normal pairs, 15 of which have also been subjected to whole genome sequencing. We identify a mutational signature defined by a high prevalence of A to C transversions at AA dinucleotides. Statistical analysis of exome data identified significantly mutated 26 genes. Of these genes, four (TP53, CDKN2A, SMAD4, and PIK3CA) have been previously implicated in EAC. The novel significantly mutated genes include chromatin modifying factors and candidate contributors: SPG20, TLR4, ELMO1, and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 reveal increased cellular invasion. Therefore, we suggest a new hypothesis about the potential activation of the RAC1 pathway to be a contributor to EAC tumorigenesis.

Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study

“…Although TP53 mutation has a high specificity, it will not identify all patients with HGD or early cancer, since the prevalence is 70-80%. 9,11 To increase our sensitivity for detecting high-risk Barrett's patients, we propose including additional molecular biomarkers combined with clinical factors.…”

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…The separation of these mutational signals can give insight into the driving forces behind tumorigenesis. For instance, a study of esophageal cancers has revealed a quite unique signature of (AA>AC) transversions making up to 29% of all substitutions in this tumor [86]. …”

Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

“…This case is, to the best of our knowledge, the first report of a KRAS K117N missense variant in RDD. This variant has been previously reported in the COSMIC mutational database in other tumor types (colorectal cancer, esophageal adenocarcinoma, myelodysplastic syndrome) [35][36][37]. In vitro studies suggest this variant allele activates the RAS/RAF/ERK signaling cascade, leading to cell proliferation and vemurafenib resistance [38,39].…”