Convergent mutational processes in esophageal and junctional adenocarcinomas across eight countries

Torrens, L., Moody, S., Pang, J., Abedi-Ardekani, B., Zhang, H., Abbasi, A., Nunn, C., Fitzgerald, S., Gallego-Garcia, P., Gaborieau, V., et al.

10.64898/2026.10.21.26365720 · was preprinted

biomedical

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relevance 0.37 openness 0.00 novelty 0.39

Abstract

The incidence distribution of esophageal adenocarcinoma (EAC) and gastroesophageal junction (GEJ) cancers presents important geographic variations, yet the causes of these differences remain unclear. We analyzed 520 whole genomes from EAC/GEJ tumors across eight countries to examine the mutational forces shaping these cancers and their geographic variation. The mutational landscape was highly similar between EAC and GEJ tumors, and was dominated by signatures SBS17a/b, previously associated with reflux in EAC/GEJ. SBS17a/b were linked to obesity in EAC, supporting an indirect role in exacerbating reflux-mediated mutagenesis. Other established risk factors, such as tobacco smoking, did not yield a direct mutational footprint, pointing to non-mutagenic effects in EAC/GEJ. Nonetheless, geographic differences were present, with signatures related to endogenous cellular functions enriched in high-incidence populations. These findings provide new insights into the shared mutational forces that shape EAC and GEJ, as well as their geographic distribution.

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