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High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer
SIMPLE SUMMARY: The overall genomic copy number changes profile of three subgroups of locally advanced rectal carcinoma patients with significantly different response to neoadjuvant treatment with radiochemotherapy (ranging from complete to poor- or no-response) was analyzed and compared with a set...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269103/ https://www.ncbi.nlm.nih.gov/pubmed/34202891 http://dx.doi.org/10.3390/cancers13133166 |
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author | del Carmen, Sofía Corchete, Luís Antonio González Velasco, Cristina Sanz, Julia Alcazar, José Antonio García, Jacinto Rodríguez, Ana Isabel Vidal Tocino, Rosario Rodriguez, Alba Pérez-Romasanta, Luis Alberto Sayagués, José María Abad, Mar |
author_facet | del Carmen, Sofía Corchete, Luís Antonio González Velasco, Cristina Sanz, Julia Alcazar, José Antonio García, Jacinto Rodríguez, Ana Isabel Vidal Tocino, Rosario Rodriguez, Alba Pérez-Romasanta, Luis Alberto Sayagués, José María Abad, Mar |
author_sort | del Carmen, Sofía |
collection | PubMed |
description | SIMPLE SUMMARY: The overall genomic copy number changes profile of three subgroups of locally advanced rectal carcinoma patients with significantly different response to neoadjuvant treatment with radiochemotherapy (ranging from complete to poor- or no-response) was analyzed and compared with a set of normal samples from healthy individuals with negative colonoscopies from the Castilla y León (Spain) region. We identified and validated a novel genetic signature, which combined with clinicopathological features, predicts response to neoadjuvant treatment and clinical outcome. ABSTRACT: Administering preoperative radiochemotherapy (RCT) in stage II-III tumors to locally advanced rectal carcinoma patients has proved to be effective in a high percentage of cases. Despite this, 20–30% of patients show no response or even disease progression. At present, preoperative response is assessed by a combination of imaging and tumor regression on histopathology, but recent studies suggest that various genetic abnormalities may be associated with the sensitivity or resistance of rectal cancer tumor cells to neoadjuvant therapy. In the present study we investigated the relationship between genetic lesions detected by high-density single-nucleotide polymorphisms (SNP) arrays 6.0 and response to neoadjuvant RCT, evaluated according to Dworak criteria in 39 rectal cancer tumors before treatment. The highest frequency of copy-number (CN) losses detected corresponded to chromosomes 18q (n = 27; 69%), 1p (n = 22; 56%), 15q (n = 19; 49%), 8p (n = 18; 48%), 4q (n = 17; 46%), and 22q (n = 17; 46%); in turn, CN gains more frequently involved chromosomes 20p (n = 22; 56%), 8p (n = 20; 51%), and 15q (n = 16; 41%). There was a significant association between alterations in the 1p, 3q, 7q, 12p, 17q, 20p, and 22q chromosomal regions and the degree of response to therapy prior to surgery. However, 4q, 15q11.1, and 15q14 chromosomal region alterations were identified as important by five prediction algorithms, i.e., those with the greatest influence on predicting the tumor response to treatment with preoperative RCT. Multivariate analysis of prognostic factors showed that gains on 15q11.1 and carcinoembryonic antigen (CEA) levels serum at diagnosis were the only independent variables predicting disease-free survival (DFS). Lymph node involvement also showed a prognostic impact on overall survival (OS) in the multivariate analysis. A deep-learning-based algorithm showed a 100% success rate in predicting both DFS and OS at 60 months after diagnosis of the disease. In summary, our results indicate the existence of an association between tumor genetic abnormalities at diagnosis, response to neoadjuvant therapy, and survival of patients with locally advanced rectal cancer. In addition to the clinical and biological characteristics of locally advanced rectal cancer patients, these could be used in the future as therapeutic and prognostic biomarkers, to identify patients sensitive or resistant to preoperative treatment, helping guide therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers. |
format | Online Article Text |
id | pubmed-8269103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82691032021-07-10 High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer del Carmen, Sofía Corchete, Luís Antonio González Velasco, Cristina Sanz, Julia Alcazar, José Antonio García, Jacinto Rodríguez, Ana Isabel Vidal Tocino, Rosario Rodriguez, Alba Pérez-Romasanta, Luis Alberto Sayagués, José María Abad, Mar Cancers (Basel) Article SIMPLE SUMMARY: The overall genomic copy number changes profile of three subgroups of locally advanced rectal carcinoma patients with significantly different response to neoadjuvant treatment with radiochemotherapy (ranging from complete to poor- or no-response) was analyzed and compared with a set of normal samples from healthy individuals with negative colonoscopies from the Castilla y León (Spain) region. We identified and validated a novel genetic signature, which combined with clinicopathological features, predicts response to neoadjuvant treatment and clinical outcome. ABSTRACT: Administering preoperative radiochemotherapy (RCT) in stage II-III tumors to locally advanced rectal carcinoma patients has proved to be effective in a high percentage of cases. Despite this, 20–30% of patients show no response or even disease progression. At present, preoperative response is assessed by a combination of imaging and tumor regression on histopathology, but recent studies suggest that various genetic abnormalities may be associated with the sensitivity or resistance of rectal cancer tumor cells to neoadjuvant therapy. In the present study we investigated the relationship between genetic lesions detected by high-density single-nucleotide polymorphisms (SNP) arrays 6.0 and response to neoadjuvant RCT, evaluated according to Dworak criteria in 39 rectal cancer tumors before treatment. The highest frequency of copy-number (CN) losses detected corresponded to chromosomes 18q (n = 27; 69%), 1p (n = 22; 56%), 15q (n = 19; 49%), 8p (n = 18; 48%), 4q (n = 17; 46%), and 22q (n = 17; 46%); in turn, CN gains more frequently involved chromosomes 20p (n = 22; 56%), 8p (n = 20; 51%), and 15q (n = 16; 41%). There was a significant association between alterations in the 1p, 3q, 7q, 12p, 17q, 20p, and 22q chromosomal regions and the degree of response to therapy prior to surgery. However, 4q, 15q11.1, and 15q14 chromosomal region alterations were identified as important by five prediction algorithms, i.e., those with the greatest influence on predicting the tumor response to treatment with preoperative RCT. Multivariate analysis of prognostic factors showed that gains on 15q11.1 and carcinoembryonic antigen (CEA) levels serum at diagnosis were the only independent variables predicting disease-free survival (DFS). Lymph node involvement also showed a prognostic impact on overall survival (OS) in the multivariate analysis. A deep-learning-based algorithm showed a 100% success rate in predicting both DFS and OS at 60 months after diagnosis of the disease. In summary, our results indicate the existence of an association between tumor genetic abnormalities at diagnosis, response to neoadjuvant therapy, and survival of patients with locally advanced rectal cancer. In addition to the clinical and biological characteristics of locally advanced rectal cancer patients, these could be used in the future as therapeutic and prognostic biomarkers, to identify patients sensitive or resistant to preoperative treatment, helping guide therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers. MDPI 2021-06-24 /pmc/articles/PMC8269103/ /pubmed/34202891 http://dx.doi.org/10.3390/cancers13133166 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article del Carmen, Sofía Corchete, Luís Antonio González Velasco, Cristina Sanz, Julia Alcazar, José Antonio García, Jacinto Rodríguez, Ana Isabel Vidal Tocino, Rosario Rodriguez, Alba Pérez-Romasanta, Luis Alberto Sayagués, José María Abad, Mar High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer |
title | High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer |
title_full | High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer |
title_fullStr | High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer |
title_full_unstemmed | High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer |
title_short | High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer |
title_sort | high-risk clinicopathological and genetic features and outcomes in patients receiving neoadjuvant radiochemotherapy for locally advanced rectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269103/ https://www.ncbi.nlm.nih.gov/pubmed/34202891 http://dx.doi.org/10.3390/cancers13133166 |
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