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

Jaqueline Ramalho Buttura,Israel Tojal Da Silva,Joanna Loizou,Helano Carioca Freitas,Vladmir C Cordeiro De Lima,Marc Wiedner,Vinicius Fernando Calsavara,Thais Fernanda Bartelli,Kenneth John Gollob,Rafael Rosales,João Paulo Lima,Monize Nakamoto Provisor Santos,Renan Valieris,Alexandre Defelicibus,Diana Noronha Nunes,Rodrigo Duarte Drummond,Emmanuel Dias-Neto

doi:10.3390/cancers13030490

Abstract

Simple SummaryMutational 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.

Highlights

Cancer results from the sequential accumulation of DNA alterations, including singlenucleotide mutations [1] that arise from various endogenous and exogenous processes [2].Distinct DNA-damaging processes leave characteristic nucleotide base-change footprints known as mutational signatures [3]
7–12% of patients with gastric cancers could benefit from platinum or poly-ADP ribose polymerase (PARP) inhibitor therapy
The tumor mutational burden (TMB) and neoantigen load correlated positively with S4 exposure in both groups (Figure 4). These findings suggest that tumors with high S4 exposure were more homogeneous in the S4high group, and that reduced tumor heterogeneity together with a high TMB and high neoantigen load is determinant of a good prognosis

Summary

Introduction

Distinct DNA-damaging processes leave characteristic nucleotide base-change footprints known as mutational signatures [3]. Six mutational signatures have been associated with the BRAC1/2 gene dysfunction, and most likely are predictive of the response to treatment with poly-ADP ribose polymerase (PARP) inhibitors [8]. Homologous recombination repair (HRR) deficiency features based on these signatures allowed the prediction of BRCAness in patients with breast cancer with a 98.7% sensitivity [8]. Given that nucleotide excision repair (NER)-deficient tumors are more sensitive to certain treatments, somatic variations in the ERCC2 gene, which encodes a key protein of the NER pathway, have been linked to characteristic mutational signatures [9,10]. Affected patients are eligible for genetic counseling [12]

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