Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Abstract

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Identification of neoantigens in oesophageal adenocarcinoma

“…The mutational landscape of these OAC patients described by WES is consistent with previous characterizations of high mutational burden [14], mutational signatures with high proportions of C > T substitutions and evidence of chromosomal instability [4, 5, 21]. Gene expression analysis estimating the populations of infiltrating lymphocytes indicated that mutations yielding neoantigens may be detectable.…”

Characterizing isoform switching events in esophageal adenocarcinoma

“…32 Amplification and mutation of KRAS have been previously reported in EAC. 30,54,55 Despite the mutation frequency of KRAS in EAC being less than 20%, it is considered an EAC driver and proposed targeting of KRAS mutations may sensitize a subgroup of EAC patients to targeted treatment. 30 Alternative splicing of KRAS is well documented in other cancers, 33,35,[56][57][58][59][60] resulting in two isoforms, KRAS4A and KRAS4B, 33 both of which can carry KRAS mutations.…”

Network and pathway-based analysis of candidate genes associated with esophageal adenocarcinoma

“…In addition, EGFR tyrosine kinase inhibitors block the abnormal signal transduction of EGFR and tyrosine kinase and induce apoptosis, thereby inhibiting the growth of tumor cells. EGFR tyrosine kinase inhibitors produce resistance via mechanisms such as EGFR mutations (17). Further, proteoglycans, as a sort of extracellular matrix in the tumor microenvironment, regulate the biological behavior of tumor cells via metabolic processes (18).…”