Mutational signatures driven by epigenetic determinants stratify patients for therapeutic interventions in gastric cancer

DNA mismatch repair deficiency (dMMR) leads to increased mutation load, which in turn may impact anti-tumor immune responses and treatment effectiveness. Currently, there are different mutational signatures described in primary cancers that are associated with dMMR. Whether the somatic and epigenetic changes in MMR genes precede one or more dMMR signatures, and if so by which mechanism remains unknown. To investigate the relationship between these changes and dMMR signatures, we performed a de novo extraction of mutational signatures in a large cohort of 787 gastric cancer patients. We detected three dMMR-related signatures, one of which clearly discriminates tumors with MLH1 gene silencing caused by hyper-methylation within its promoter (AUC = 98%). We then demonstrate that samples with the highest exposures to signature share features related to better prognosis, encompassing clinical and molecular aspects, as well as altered immune infiltrate composition, predictive of a better response to immune checkpoint inhibitors. Overall, our analysis explored the impact of modifications in MMR-related genes on shaping specific mutational signatures and we provide evidence that patient classification based on mutational signature exposure can identify a group of patients with a good prognosis and who are potentially good candidates for immunotherapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project received financial support from FAPESP (14-26897-0 and 16/11791-7) ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The raw sequencing data (.fastq files) were deposited in SRA (http://www.ncbi.nlm.nih.gov/sra) under accession numbers PRJNA505810 and