Abstract Esophageal adenocarcinomas (EAC) and gastroesophageal junction cancers (GEJ) share multiple risk factors such as reflux disease, obesity, and tobacco smoking. Despite their anatomical proximity and overlapping etiology, they are often considered as esophageal and gastric tumors, respectively. This study aims to decipher the mutational processes that have been operative in EAC and GEJ cancer development and determine whether these are shared across tumor sites and geographical regions. Whole-genome sequencing data were generated from 520 EAC/GEJ cases (159 EAC and 361 GEJ) from eight countries (China, Iran, United Kingdom, Canada, Kenya, Malawi, Brazil, and Colombia), with available demographic, lifestyle, and environmental exposure data. Mutational signatures were extracted using SigProfilerExtractor and decomposed into reference signatures. Associations between the mutational signatures and epidemiological or molecular features were assessed using multivariate regression models. Our analysis revealed 17 reference signatures from the COSMIC catalogue, and three signatures described in previous cancer datasets. EAC/GEJ tumors exhibited high burdens of SBS17a and SBS17b, linked to acid reflux, accounting for 26.8% of the median signature burdens. Signature SBS-D, which has been speculated to be caused by DNA repair infidelity, was the second most abundant signature (12% median relative burden), suggesting a relevant role in EAC/GEJ carcinogenesis. EAC and GEJ cancers shared a highly similar mutation, driver, and copy number profile, pointing to shared mutagenic processes, with the exception of SBS-D, which showed enrichment in cancers from the lower and distal esophagus. Signatures SBS17a/b were positively associated with obesity (p-value0.0005), particularly in EAC cases, supporting the epidemiological notion that obesity may exacerbate reflux disease. We observed no differences in signature burdens with other risk factors, such as tobacco, suggesting its carcinogenic effect in this cancer type could be promotional rather than mutagenic. Finally, we found an association between age-standardized incidence and the signatures SBS5, SBS8, and SBS-D, suggesting a potential dysregulation of endogenous cellular functions in high-risk populations. This study delineates the mutational forces driving GEJ/EAC cancers. Our results show an overall shared mutational profile across tissues and suggest that obesity enhances the presence of reflux-related mutagenesis. The observed differences across countries could provide relevant information to aid in the development of global prevention strategies. Citation Format: Laura Torrens, Sarah Moody, Jiali Pang, Behnoush Abedi-Ardekani, Ayesha Noorani, Haoran Zhang, Pilar Gallego-Garcia, Valerie Gaborieau, Thomas Cattiaux, Priscilia Chopard, Stephen Fitzgerald, Calli Latimer, Christine Carreira, Marcos Diaz-Gay, Laura Humphreys, Ludmil B. Alexandrov, Michael R. Stratton, Sandra Perdomo, Paul Brennan, on behalf of the MUTOGRAPHS project. Mutational processes in esophageal and gastroesophageal junction adenocarcinomas across geographical regions abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6295.
Torrens et al. (Fri,) studied this question.