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Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer
BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients. METHOD: In this research, we conducted an anal...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680082/ https://www.ncbi.nlm.nih.gov/pubmed/38023196 http://dx.doi.org/10.3389/fonc.2023.1285508 |
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author | Yang, Jinwei Zhao, Sihui Su, Junyan Liu, Siyao Wu, Zaozao Ma, Wei Tang, Ming Wu, Jingcui Mao, Erdong Han, Li Liu, Mengyuan Zhang, Jiali Cao, Lei Shao, Jingyi Shang, Yun |
author_facet | Yang, Jinwei Zhao, Sihui Su, Junyan Liu, Siyao Wu, Zaozao Ma, Wei Tang, Ming Wu, Jingcui Mao, Erdong Han, Li Liu, Mengyuan Zhang, Jiali Cao, Lei Shao, Jingyi Shang, Yun |
author_sort | Yang, Jinwei |
collection | PubMed |
description | BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients. METHOD: In this research, we conducted an analysis using Next-Generation Sequencing (NGS) on samples collected from 111 individuals who had been diagnosed with CRC. We identified somatic and germline mutations and structural variants across the tumor genomes through comprehensive genomic profiling. Furthermore, we investigated the landscape of driver mutations and their potential clinical implications. RESULTS: Our findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, BRAF, ARID2, KMT2C, and GNAQ were associated with CRC prognosis. Patients harboring BRAF, ARID2, or KMT2C mutations exhibited shorter progression-free survival (PFS), whereas those with BRAF, ARID2, or GNAQ mutations experienced worse overall survival (OS). We unveiled 80 co-occurring and three mutually exclusive significant gene pairs, enriched primarily in pathways such as TP53, HIPPO, RTK/RAS, NOTCH, WNT, TGF-Beta, MYC, and PI3K. Notably, co-mutations of BRAF/ALK, BRAF/NOTCH2, BRAF/CREBBP, and BRAF/FAT1 correlated with worse PFS. Furthermore, germline AR mutations were identified in 37 (33.33%) CRC patients, and carriers of these variants displayed diminished PFS and OS. Decreased AR protein expression was observed in cases with AR germline mutations. A four-gene mutation signature was established, incorporating the aforementioned prognostic genes, which emerged as an independent prognostic determinant in CRC via univariate and multivariate Cox regression analyses. Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations. CONCLUSION: The integration of our analyses furnishes crucial insights into CRC’s molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis. |
format | Online Article Text |
id | pubmed-10680082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106800822023-01-01 Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer Yang, Jinwei Zhao, Sihui Su, Junyan Liu, Siyao Wu, Zaozao Ma, Wei Tang, Ming Wu, Jingcui Mao, Erdong Han, Li Liu, Mengyuan Zhang, Jiali Cao, Lei Shao, Jingyi Shang, Yun Front Oncol Oncology BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients. METHOD: In this research, we conducted an analysis using Next-Generation Sequencing (NGS) on samples collected from 111 individuals who had been diagnosed with CRC. We identified somatic and germline mutations and structural variants across the tumor genomes through comprehensive genomic profiling. Furthermore, we investigated the landscape of driver mutations and their potential clinical implications. RESULTS: Our findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, BRAF, ARID2, KMT2C, and GNAQ were associated with CRC prognosis. Patients harboring BRAF, ARID2, or KMT2C mutations exhibited shorter progression-free survival (PFS), whereas those with BRAF, ARID2, or GNAQ mutations experienced worse overall survival (OS). We unveiled 80 co-occurring and three mutually exclusive significant gene pairs, enriched primarily in pathways such as TP53, HIPPO, RTK/RAS, NOTCH, WNT, TGF-Beta, MYC, and PI3K. Notably, co-mutations of BRAF/ALK, BRAF/NOTCH2, BRAF/CREBBP, and BRAF/FAT1 correlated with worse PFS. Furthermore, germline AR mutations were identified in 37 (33.33%) CRC patients, and carriers of these variants displayed diminished PFS and OS. Decreased AR protein expression was observed in cases with AR germline mutations. A four-gene mutation signature was established, incorporating the aforementioned prognostic genes, which emerged as an independent prognostic determinant in CRC via univariate and multivariate Cox regression analyses. Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations. CONCLUSION: The integration of our analyses furnishes crucial insights into CRC’s molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis. Frontiers Media S.A. 2023-11-13 /pmc/articles/PMC10680082/ /pubmed/38023196 http://dx.doi.org/10.3389/fonc.2023.1285508 Text en Copyright © 2023 Yang, Zhao, Su, Liu, Wu, Ma, Tang, Wu, Mao, Han, Liu, Zhang, Cao, Shao and Shang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Yang, Jinwei Zhao, Sihui Su, Junyan Liu, Siyao Wu, Zaozao Ma, Wei Tang, Ming Wu, Jingcui Mao, Erdong Han, Li Liu, Mengyuan Zhang, Jiali Cao, Lei Shao, Jingyi Shang, Yun Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
title | Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
title_full | Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
title_fullStr | Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
title_full_unstemmed | Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
title_short | Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
title_sort | comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680082/ https://www.ncbi.nlm.nih.gov/pubmed/38023196 http://dx.doi.org/10.3389/fonc.2023.1285508 |
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