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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Increased Levels of Genomic Instability and Mutations in Homologous Recombination Genes in Locally Advanced Rectal Carcinomas

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do Canto, Luisa Matos [1, 2] ; Larsen, Simon J. [3] ; Catin Kupper, Bruna E. [4] ; Ferreira de Souza Begnami, Maria Dirlei [5] ; Scapulatempo-Neto, Cristovam [6, 7] ; Petersen, Annabeth Hogh [2] ; Aagaard, Mads M. [2] ; Baumbach, Jan [8] ; Aguiar Jr, Samuel ; Rogatto, Silvia R. [9, 2, 10]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] AC Camargo Canc Ctr, CIPE, Int Res Ctr, Sao Paulo - Brazil
[2] Vejle Hosp, Dept Clin Genet, Vejle - Denmark
[3] Univ Southern Denmark, Dept Math & Comp Sci, Odense - Denmark
[4] AC Camargo Canc Ctr, Dept Pelv Surg, Sao Paulo - Brazil
[5] AC Camargo Canc Ctr, Dept Pathol, Sao Paulo - Brazil
[6] Mol Oncol Res Ctr, Barretos - Brazil
[7] Diagnost Amer, Sao Paulo - Brazil
[8] TUM, TUM Sch Life Sci Weihenstephan, Freising Weihenstephan - Germany
[9] Univ Southern Denmark, Inst Reg Hlth Res, Odense - Denmark
[10] Danish Colorectal Canc Ctr South, Vejle - Denmark
Número total de Afiliações: 10
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN ONCOLOGY; v. 9, MAY 14 2019.
Citações Web of Science: 0

Pre-operative 5-fluoracil-based chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Patients with pathological complete response (pCR-0% of tumor cells in the surgical specimen after nCRT) have better overall survival and lower risk of recurrence in comparison with incomplete responders (pIR). Predictive biomarkers to be used for new therapeutic strategies and capable of stratifying patients to avoid overtreatment are needed. We evaluated the genomic profiles of 33 pre-treatment LARC biopsies using SNP array and targeted-next generation sequencing (tNGS). Based on the large number of identified genomic alterations, we calculated the genomic instability index (GII) and three homologous recombination deficiency (HRD) scores, which have been reported as impaired DNA repair markers. We observed high GII in our LARC cases, which was confirmed in 165 rectal cancer cases from TCGA. Patients with pCR presented higher GII compared with pIR. Moreover, a negative correlation between GII and the fraction of tumor cells remaining after surgery was observed (rho = -0.382, P = 0.02). High HRD scores were detected in 61% of LARC, of which 70% were incomplete responders. Using tNGS (105 cancer-related genes, 13 involved in HR and 5 in mismatch repair pathways), we identified 23% of cases with mutations in HR genes, mostly in pIR cases (86% of mutated cases). In agreement, the analysis of the TCGA dataset (N = 145) revealed 21% of tumors with mutations in HR genes. The HRD scores were shown to be predictive of better response to PARP-inhibitors and platinum-based chemotherapy in breast and ovarian cancer. Our results (AU)

Processo FAPESP: 15/25803-4 - Análise integrada (genômica, transcriptômica e metiloma) de câncer de reto para identificar preditores de resposta ao tratamento neoadjuvante
Beneficiário:Luisa Matos Do Canto Alvim
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
Processo FAPESP: 08/57887-9 - Instituto Nacional de Oncogenômica
Beneficiário:Luiz Paulo Kowalski
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 14/06323-9 - Identificação de marcadores moleculares de resposta ao tratamento neoadjuvante em pacientes com adenocarcinoma de reto
Beneficiário:Luisa Matos Do Canto Alvim
Linha de fomento: Bolsas no Brasil - Doutorado Direto