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The Effects of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer-The Impact in Intratumoral Heterogeneity

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Autor(es):
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Bettoni, Fabiana [1] ; Masotti, Cibele [1] ; Correa, Bruna R. [1] ; Donnard, Elisa [1] ; dos Santos, Filipe F. [1] ; Sao Juliao, Guilherme P. [2] ; Vailati, Bruna B. [2] ; Habr-Gama, Angelita [2] ; Galante, Pedro A. F. [1] ; Perez, Rodrigo O. [2] ; Camargo, Anamaria A. [3, 1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Hosp Sirio Libanes, Sao Paulo - Brazil
[2] Inst Angelita & Joaquim Gama, Sao Paulo - Brazil
[3] Ludwig Inst Canc Res, Sao Paulo - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN ONCOLOGY; v. 9, SEP 27 2019.
Citações Web of Science: 0
Resumo

Purpose: Intratumoral genetic heterogeneity (ITGH) is a common feature of solid tumors. However, little is known about the effect of neoadjuvant chemoradiation (nCRT) in ITGH of rectal tumors that exhibit poor response to nCRT. Here, we examined the impact of nCRT in the mutational profile and ITGH of rectal tumors and its adjacent irradiated normal mucosa in the setting of incomplete response to nCRT. Methods and Materials: To evaluate ITGH in rectal tumors, we analyzed whole-exome sequencing (WES) data from 79 tumors obtained from The Cancer Genome Atlas (TOGA). We also compared matched peripheral blood cells, irradiated normal rectal mucosa and pre and post-treatment tumor samples (PRE-T and POS-T) from one individual to examine the iatrogenic effects of nCRT. Finally, we performed WES of 7 PRE-T/POST-T matched samples to examine how nCRT affects ITGH. ITGH was assessed by quantifying subclonal mutations within individual tumors using the Mutant-Allele Tumor Heterogeneity score (MATH score). Results: Rectal tumors exhibit remarkable ITGH that is ultimately associated with disease stage (MATH score stage I/II 35.54 vs. stage III/IV 44.39, p = 0.047) and lymph node metastasis (MATH score NO 35.87 vs. N+ 45.79, p = 0.026). We also showed that nCRT does not seem to introduce detectable somatic mutations in the irradiated mucosa. Comparison of PRE-T and POST-T matched samples revealed a significant increase in ITGH in 5 out 7 patients and MATH scores were significantly higher after nCRT (median 41.7 vs. 28.8, p = 0.04). Finally, we were able to identify a subset of ``enriched mutations{''} with significant changes in MAFs between PRE-T and POST-T samples. These ``enriched mutations{''} were significantly more frequent in POST-T compared to PRE-T samples (92.9% vs. 7.1% p < 0.00001) and include mutations in genes associated with genetic instability and drug resistance in colorectal cancer, indicating the expansion of tumor cell subpopulations more prone to resist to nCRT. Conclusions: nCRT increases ITGH and may result in the expansion of resistant tumor cell populations in residual tumors. The risk of introducing relevant somatic mutations in the adjacent mucosa is minimal but non-responsive tumors may have potentially worse biological behavior when compared to their untreated counterparts. This was an exploratory study, and due to the limited number of samples analyzed, our results need to be validated in larger cohorts. (AU)

Processo FAPESP: 13/07159-5 - Proteínas de ligação a RNA e variações pós-transcricionais: influência no desenvolvimento de glioblastomas multiformes
Beneficiário:Bruna Renata Silva Corrêa
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 15/17208-9 - Retrocópias: origens, polimorfismos e variações somáticas
Beneficiário:Cibele Masotti
Linha de fomento: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
Processo FAPESP: 11/51130-6 - Heterogeneidade genética no tumor de reto: identificação de subpopulações tumorais resistentes ao tratamento neoadjuvante com radio e quimioterapia
Beneficiário:Rodrigo Oliva Perez
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
Processo FAPESP: 10/12658-2 - Análise de biomarcadores em tumores de reto através da utilização de sequenciadores de nova geração
Beneficiário:Elisa Rennó Donnard Moreira
Linha de fomento: Bolsas no Brasil - Doutorado