Journal
CANCERS
Volume 13, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/cancers13030490
Keywords
mutational signature; gastric cancer; DNA mismatch repair; prognosis
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [14/26897-0, 15/19324-6, 16/11791-7]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [14/26897-0] Funding Source: FAPESP
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This study identified three mutational signatures related to DNA mismatch repair deficiency (dMMR) in gastric cancer, one of which can accurately discriminate tumors with MLH1 gene silencing caused by promoter hypermethylation. Classification based on mutational signature exposure can help identify patients with better prognosis in gastric cancer.
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. 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.
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