Abstract

Background Esophagogastric adenocarcinoma demands a deeper molecular understanding to advance treatment strategies and improve patient outcomes. Here, we profiled the genome and transcriptome landscape of these cancers, explored molecular characteristics that are invisible to other sequencing platforms, and analyzed their potential clinical ramification.

Methods Our study employed state-of-the-art analyses of whole genome and transcriptome sequencing on 52 matched tumor and germline samples from 47 patients, aiming to unravel new therapeutic targets and deepen our understanding of these cancers’ molecular foundations.

Results The analyses revealed 88 targetable oncogenic mutations and fusions in 62% of the patients, and further elucidated molecular signatures associated with mismatch repair and homologous recombination deficiency. Notably, we identified CDK12-type genomic instability associated with CDK12 fusions, novel NTRK, NRG1, ALK, and MET fusions, and structural variants in relevant cancer genes like RAD51B.

Conclusions Our findings demonstrate the power of integrative whole genome and transcriptome sequencing in identifying additional therapeutic targets, supporting a promising path for precision medicine in treating esophagogastric adenocarcinoma.

Competing Interest Statement

Kevin Hadi, Aditya Deshpande, Minal Patel, and Juan S. Medina-Martinez are employees at Isabl, Inc. Olivier Elemento holds equity in OneThree Biotech, Volastra Therapeutics, Owkin, Champions Oncology, Pionyr Immunotherapeutics, Harmonic Discovery and Freenome. Manish Shah reported receiving grants from Merck, Bristol Meyers Squibb, and Oncolys Biopharma outside the submitted work. No other disclosures were reported.

Funding Statement

This work was supported by the Englander Institute for Precision Medicine. Whole-genome sequencing was performed at the New York Genome Center, supported by an Agreement with Illumina, Inc., and Weill Cornell Medicine.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Patients were enrolled at Weill Cornell Medicine (WCM) under an institutional review board (IRB)approved protocol (Research for Precision Medicine WCM IRB No. 1305013903) with written informed consent. Retrospective tissue samples (year of collection 2014 - 2021) were retrieved and studied under the protocol for Comprehensive Cancer Characterization by Genomic and Transcriptomic Profiling (WCM IRB No. 1007011157).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

Presented in part at the 2023 American Association for Cancer Research (AACR) Annual Meeting in Orlando, FL, and at the 2023 United States and Canadian Academy of Pathology (USCAP) Annual Meeting in New Orleans, LA.

Data Availability

All data produced in the present study are available upon reasonable request to the authors

List of AbbreviationsGEJGastroesophageal junctionSEERSurveillance, epidemiology, end resultsEGACesophagogastric adenocarcinomasMSImicrosatellite instabilityMSI-Hhigh microsatellite instabilityWGTSwhole genome and transcriptome sequencingWCMWeill Cornell MedicineIRBinstitutional review boardEMRelectronic medical recordWGSwhole genome sequencingSNVssingle nucleotide variantsIndelsinsertions/deletionsSVsstructural variantsSBSsingle base substitutionTMBtumor mutational burdenHRDhomologous recombination deficiencyTMB-Hhigh tumor mutational burdenRNA-seq-RNA sequencingFFPEformalin-fixed paraffin-embeddedCNVscopy number variantsROSreactive oxygen species5-FU5-fluorouracilTRKtropomyosin receptor kinase