Comprehensive genomic profiling (CGP) of advanced stage esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) to reveal similarities and differences.

Abstract

7 Background: ESCC and EAC are relatively rare malignancies in the US with EAC more common than ESCC. Using a sensitive CGP assay, we compared the genomic profiles of ESCC and EAC focused on the search for therapy targets. Methods: DNA was extracted from 40u of FFPE sections from 54 clinically advanced ESCC and 234 EAC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a median coverage depth of 652X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA) including point mutations, short INDELs, copy number alterations and fusions/rearrangements. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: All ESCC and EAC were at an advanced stage (Stage III/IV) at the time of CGP and had similar gender and age (median 63 yrs) distribution. 54 (100%) of ESCC and 233 (99.6%) of EAC featured GA on profiling with 397 GA in ESCC (7.4/sample) and 1,317 GA (5.6/sample) in EAC. The frequency of clinically relevant GA in ESCC (2.7/sample; 93% of cases) and EAC (2.7/sample; 92% of cases) were identical. EAC featured a greater number of CRGA (72) than ESCC (46). CRGA more frequently altered in EAC than ESCC included KRAS (23% vs 7%) and ERBB2 (23% vs 4%). CRGA more frequently identified in ESCC than EAC included PIK3CA (28% vs 10%), PTEN (13% vs 4%) and NOTCH1 (22% vs 3%). Other GA that were significantly different in the 2 tumor types included SMAD4 (14% EAC vs 0% ESCC), RB1 (19% ESCC vs 2% EAC), SOX2 (17% ESCC vs 1% EAC) and NFE2L2(19% ESCC vs 0% EAC). HPV-16 was detected in 2 (4%) and HPV-18 in 1 (2%) of ESCC. HPV was not detected in EAC. Conclusions: ESCC and EAC share high frequencies of total GA and CRGA. However, KRAS and ERBB2 are far more frequently altered in EAC than ESCC and mTOR pathway genes (PIK3CA and PTEN) more frequently altered in ESCC than EAC. CGP shows significant promise to identify CRGA in both ESCC and EAC and drive the potential use of clinical outcome altering targeted therapies in both major types of esophageal cancer.