Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention.
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Embargo End Date
ICR Authors
Authors
Buttura, JR
Provisor Santos, MN
Valieris, R
Drummond, RD
Defelicibus, A
Lima, JP
Calsavara, VF
Freitas, HC
Cordeiro de Lima, VC
Fernanda Bartelli, T
Wiedner, M
Rosales, R
Gollob, KJ
Loizou, J
Dias-Neto, E
Nunes, DN
da Silva, IT
Provisor Santos, MN
Valieris, R
Drummond, RD
Defelicibus, A
Lima, JP
Calsavara, VF
Freitas, HC
Cordeiro de Lima, VC
Fernanda Bartelli, T
Wiedner, M
Rosales, R
Gollob, KJ
Loizou, J
Dias-Neto, E
Nunes, DN
da Silva, IT
Document Type
Journal Article
Date
2021-01-27
Date Accepted
2020-12-20
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.
Citation
Cancers, 2021, 13 (3), pp. 490 -
Source Title
Cancers
Publisher
MDPI
ISSN
2072-6694
eISSN
2072-6694
Collections
Research Team
Target Val & Genome Stab