Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention

SIMPLE SUMMARY: Mutational signatures due to DNA mismatch repair deficiency (dMMR) is common in many cancers. However, the prognostic value of dMMR-associated mutational signatures remains to be assessed. Here, we performed a de novo extraction of mutational signatures in a cohort of 787 patients with gastric cancer. We detected three dMMR-related signatures, one of which clearly discriminates tumors with MLH1 gene silencing through hypermethylation of its promoter. We showed evidence that classification based on mutational signature exposure can be used to identify groups of patients with common clinical, immunological, and mutational features related directly to better prognosis. ABSTRACT: DNA mismatch repair deficiency (dMMR) is associated with the microsatellite instability (MSI) phenotype and leads to increased mutation load, which in turn may impact anti-tumor immune responses and treatment effectiveness. Various mutational signatures directly linked to dMMR have been described for primary cancers. To investigate which mutational signatures are associated with prognosis in gastric cancer, we performed a de novo extraction of mutational signatures in a cohort of 787 patients. We detected three dMMR-related signatures, one of which clearly discriminates tumors with MLH1 gene silencing caused by promoter hypermethylation (area under the curve = 98%). We then demonstrated that samples with the highest exposure of this signature share features related to better prognosis, encompassing clinical and molecular aspects and altered immune infiltrate composition. Overall, the assessment of the prognostic value and of the impact of modifications in MMR-related genes on shaping specific dMMR mutational signatures provides evidence that classification based on mutational signature exposure enables prognosis stratification.