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

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Buttura, Jaqueline Ramalho ^[1] ; Provisor Santos, Monize Nakamoto ^{[1, 2]} ; Valieris, Renan ^[1] ; Drummond, Rodrigo Duarte ^[1] ; Defelicibus, Alexandre ^[1] ; Lima, Joao Paulo ^[1] ; Calsavara, Vinicius Fernando ^[3] ; Freitas, Helano Carioca ^{[4, 5]} ; Cordeiro de Lima, Vladmir C. ^{[5, 6]} ; Bartelli, Thais Fernanda ^[4] ; Wiedner, Marc ^[7] ; Rosales, Rafael ^[8] ; Gollob, Kenneth John ^[6] ; Loizou, Joanna ^{[7, 9, 10]} ; Dias-Neto, Emmanuel ^{[4, 11]} ; Nunes, Diana Noronha ^[4] ; da Silva, Israel Tojal ^[1]

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^[1] AC Camargo Canc Ctr, Lab Bioinformat & Computat Biol, BR-01508010 Sao Paulo - Brazil

^[2] Fleury Grp, Dept Genom, BR-04344070 Sao Paulo - Brazil

^[3] AC Camargo Canc Ctr, Dept Stat & Epidemiol, BR-01508010 Sao Paulo - Brazil

^[4] AC Camargo Canc Ctr, Lab Med Genom, BR-01508010 Sao Paulo - Brazil

^[5] AC Camargo Canc Ctr, Med Oncol Dept, BR-01508010 Sao Paulo - Brazil

^[6] AC Camargo Canc Ctr, Translat Immunooncol Grp, BR-01508010 Sao Paulo - Brazil

^[7] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna - Austria

^[8] Univ Sao Paulo, Dept Math & Comp Sci, BR-14049900 Ribeirao Preto - Brazil

^[9] Med Univ Vienna, Inst Canc Res, Dept Med, A-1090 Vienna - Austria

^[10] Comprehens Canc Ctr, A-1090 Vienna - Austria

^[11] Univ Sao Paulo, Inst Psychiat, Lab Neurosci, BR-05403903 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 13, n. 3 FEB 2021.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 15/19324-6 - Retrotransposons e enzimas de edição de ácidos nucléicos: ativação, eventos somáticos e associação com o câncer
• Beneficiário: Israel Tojal da Silva
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/11791-7 - Investigação de assinaturas mutacionais em adenocarcinomas gástricos e avaliação de seus possíveis impactos prognósticos
• Beneficiário: Monize Nakamoto Provisor Santos
• Linha de fomento: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/26897-0 - Epidemiologia e genômica de adenocarcinomas gástricos no Brasil
• Beneficiário: Emmanuel Dias-Neto
• Linha de fomento: Auxílio à Pesquisa - Temático