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Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy
BACKGROUND: Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with sta...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923464/ https://www.ncbi.nlm.nih.gov/pubmed/33653301 http://dx.doi.org/10.1186/s12885-021-07926-1 |
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author | Lin, Peng-Chan Yeh, Yu-Min Chan, Ren-Hao Lin, Bo-Wen Chen, Po-Chuan Pan, Chien-Chang Shen, Meng-Ru |
author_facet | Lin, Peng-Chan Yeh, Yu-Min Chan, Ren-Hao Lin, Bo-Wen Chen, Po-Chuan Pan, Chien-Chang Shen, Meng-Ru |
author_sort | Lin, Peng-Chan |
collection | PubMed |
description | BACKGROUND: Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC). METHODS: A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis. RESULTS: Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related ATM or BRCA2 somatic mutations or non-TP53, APC somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank p-value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8 years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of APC, KRAS and APC, BRCA2 sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in BRCA2, such as TP53 somatic mutations, affected recurrence-free survival. CONCLUSIONS: According to the evolution model, DNA damage response (DDR)-related ATM or BRCA2 somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-07926-1. |
format | Online Article Text |
id | pubmed-7923464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-79234642021-03-02 Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy Lin, Peng-Chan Yeh, Yu-Min Chan, Ren-Hao Lin, Bo-Wen Chen, Po-Chuan Pan, Chien-Chang Shen, Meng-Ru BMC Cancer Research Article BACKGROUND: Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC). METHODS: A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis. RESULTS: Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related ATM or BRCA2 somatic mutations or non-TP53, APC somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank p-value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8 years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of APC, KRAS and APC, BRCA2 sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in BRCA2, such as TP53 somatic mutations, affected recurrence-free survival. CONCLUSIONS: According to the evolution model, DNA damage response (DDR)-related ATM or BRCA2 somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-07926-1. BioMed Central 2021-03-02 /pmc/articles/PMC7923464/ /pubmed/33653301 http://dx.doi.org/10.1186/s12885-021-07926-1 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Lin, Peng-Chan Yeh, Yu-Min Chan, Ren-Hao Lin, Bo-Wen Chen, Po-Chuan Pan, Chien-Chang Shen, Meng-Ru Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
title | Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
title_full | Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
title_fullStr | Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
title_full_unstemmed | Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
title_short | Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
title_sort | sequential and co-occurring dna damage response genetic mutations impact survival in stage iii colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923464/ https://www.ncbi.nlm.nih.gov/pubmed/33653301 http://dx.doi.org/10.1186/s12885-021-07926-1 |
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