Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Abstract

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing due to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrates that this is a heterogeneous cancer dominated by copy number alterations with frequent large scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTKi therapy might be required, as we demonstrate in vitro. However, mutational signatures reveal three distinct molecular subtypes with potential therapeutic relevance, which we verify in an independent cohort (n=87): i) enriched for BRCA signature with prevalent defects in the homologous recombination pathway; ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; iii) C>A/T mutational pattern with evidence of an ageing imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Oesophageal cancer

“…25 OAC has also been characterised into three distinct subgroups using whole genome sequencing based on 129 samples. 26 These subtypes were characterised by defects in homologous recombination repair, a T>G mutation pattern with a high mutational load or a C>A/T mutation pattern associated with an aging imprint. It is possible that each of these subtypes have differential sensitivity to targeted therapy, e.g.…”

“…However, co-amplification of receptor tyrosine kinases, intra-tumour heterogeneity of copy number alteration and mutations in oesophageal cancers also leads to attenuation of the clinical benefit for targeted therapy. 26,131,132 Emerging targets of therapeutic interest in oesophageal cancer include dysregulation cell cycle regulators such as CDK6 which have been successfully targeted in breast cancer by palbociclib and ribocicib, and impaired DNA damage repair mechanisms which have been exploited in ovarian cancer using olaparib and rucaparib). [133][134][135][136] Finally, immunotherapy using checkpoint inhibitors such as programmed cell death protein 1 (anti-PD-1) antibodies has resulted in survival benefits for patients with some other cancers, and gastro-oesophageal cancer is an attractive target for immunooncology intervention due to its relatively high mutation burden.…”

Radiomics in esophageal and gastric cancer

“…Recent genomic analyses have highlighted the genetic heterogeneity present in esophageal, esophago-gastric [10], and gastric cancer [11,12] as an underlying cause for the differences in outcome and heterogeneity of response to therapy. Quality of life also remains poor for many patients post-surgery, taking up to 3 years to return to pre-therapy levels in patients undergoing esophageal resection [13].…”

Esophageal Cancer: New Insights into a Heterogenous Disease

“…The Oesophageal Cancer Clinical and Molecular Stratification Consortium recently published a landscape of mutational patterns in adenocarcinomas, thereby clustering these patterns into 3 dominant subtypes [13], the DNA-damage-response (DDR)-impaired, the C>A/T dominant, and the mutagenic subtype. This classification indicates the molecular heterogeneity within one histological entity.…”