1580P - Early onset oesophageal adenocarcinoma: A separate biological entity?

Background

There is concern that the incidence of oesophageal adenocarcinoma (OAC) in patients under 50, described as early onset (EO) OAC, may be rising steadily. Epidemiological studies suggest that EO-OAC patients present with higher-stage disease compared to late-onset patients, receive more aggressive treatment but may have poorer survival outcomes. We utilised Whole Genome Sequencing (WGS) and RNA-seq to investigate if EO-OAC represents a distinct biological entity compared to late-onset disease.

Methods

We obtained WGS and clinical data for stage and treatment matched OAC patients who received neoadjuvant chemotherapy prior to surgical resection (n=29 patients ≤50 years and n=144 patients ≥70 years) from the OCCAMS consortium. We performed statistical analysis between age groups using chi-squared testing with FDR correction for copy number aberrations (CNA), insertions and deletions (INDELS) and single nucleotide variants (SNV), assessing gene-level mutations and mutational burden considering coding genes only, prior to assessing 76 OAC driver genes as described by Frankell et al., 2019. Biological pathways between age groups were assessed for n=66 patients using available RNASeq data and Gene Set Enrichment Analysis (GSEA).

Results

Our results indicate that EO-OAC had a lower combined mutational burden (Wilcoxon p=0.0204) and lower indel counts (Wilcoxon p=0.0031) compared to late-onset patients. When considering gene-level mutations for SNV, CNA, INDELS and 76 OAC driver genes (Frankell et al., 2019), multiple analyses showed genes at a nominal p-value <0.05 between age groups yet none reached significance at FDR p-value <0.25. GSEA indicated 179 enriched pathways, several related to immune signalling for EO-OAC at nominal p-value <0.05 and a higher DNA Damage Immune Response (DDIR) assay score in EO-OAC (p=0.012).

Conclusions

Our comparison of early and late-onset OAC using WGS and RNA-seq data highlights the possibility of EO-OAC as a separate biological entity, with potentially enhanced immune signalling. Future work in larger sample cohorts and the investigation of clinically relevant gene and mutational signatures is required to further assess molecular differences between early and late onset OAC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.