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Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer
BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive cancer with poor prognosis. The lack of effective targeted therapies for TNBC remains a profound clinical challenge. Fusion transcripts play critical roles in carcinogenesis and serve as valuable diagnostic and therapeutic targe...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239224/ https://www.ncbi.nlm.nih.gov/pubmed/34211850 http://dx.doi.org/10.3389/fonc.2021.682021 |
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author | Wang, Meng-Yuan Huang, Man Wang, Chao-Yi Tang, Xiao-Ying Wang, Jian-Gen Yang, Yong-De Xiong, Xin Gao, Chao-Wei |
author_facet | Wang, Meng-Yuan Huang, Man Wang, Chao-Yi Tang, Xiao-Ying Wang, Jian-Gen Yang, Yong-De Xiong, Xin Gao, Chao-Wei |
author_sort | Wang, Meng-Yuan |
collection | PubMed |
description | BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive cancer with poor prognosis. The lack of effective targeted therapies for TNBC remains a profound clinical challenge. Fusion transcripts play critical roles in carcinogenesis and serve as valuable diagnostic and therapeutic targets in cancer. The present study aimed to identify novel fusion transcripts in TNBC. METHODS: We analyzed the RNA sequencing data of 360 TNBC samples to identify and filter fusion candidates through SOAPfuse and ChimeraScan analysis. The characteristics, including recurrence, fusion type, chromosomal localization, TNBC subgroup distribution, and clinicopathological correlations, were analyzed in all candidates. Furthermore, we selected the promising fusion transcript and predicted its fusion type and protein coding capacity. RESULTS: Using the RNA sequencing data, we identified 189 fusion transcripts in TNBC, among which 22 were recurrent fusions. Compared to para-tumor tissues, TNBC tumor tissues accumulated more fusion events, especially in high-grade tumors. Interestingly, these events were enriched at specific chromosomal loci, and the distribution pattern varied in different TNBC subtypes. The vast majority of fusion partners were discovered on chromosomes 1p, 11q, 19p, and 19q. Besides, fusion events mainly clustered on chromosome 11 in the immunomodulatory subtype and chromosome 19 in the luminal androgen receptor subtype of TNBC. Considering the tumor specificity and frameshift mutation, we selected MFGE8-HAPLN3 as a novel biomarker and further validated it in TNBC samples using PCR and Sanger sequencing. Further, we successfully identified three types of MFGE8-HAPLN3 (E6-E2, E5-E3, and E6-E3) and predicted the ORF of E6-E2, which could encode a protein of 712 amino acids, suggesting its critical role in TNBC. CONCLUSIONS: Improved bioinformatic stratification and comprehensive analysis identified the fusion transcript MFGE8-HAPLN3 as a novel biomarker with promising clinical application in the future. |
format | Online Article Text |
id | pubmed-8239224 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82392242021-06-30 Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer Wang, Meng-Yuan Huang, Man Wang, Chao-Yi Tang, Xiao-Ying Wang, Jian-Gen Yang, Yong-De Xiong, Xin Gao, Chao-Wei Front Oncol Oncology BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive cancer with poor prognosis. The lack of effective targeted therapies for TNBC remains a profound clinical challenge. Fusion transcripts play critical roles in carcinogenesis and serve as valuable diagnostic and therapeutic targets in cancer. The present study aimed to identify novel fusion transcripts in TNBC. METHODS: We analyzed the RNA sequencing data of 360 TNBC samples to identify and filter fusion candidates through SOAPfuse and ChimeraScan analysis. The characteristics, including recurrence, fusion type, chromosomal localization, TNBC subgroup distribution, and clinicopathological correlations, were analyzed in all candidates. Furthermore, we selected the promising fusion transcript and predicted its fusion type and protein coding capacity. RESULTS: Using the RNA sequencing data, we identified 189 fusion transcripts in TNBC, among which 22 were recurrent fusions. Compared to para-tumor tissues, TNBC tumor tissues accumulated more fusion events, especially in high-grade tumors. Interestingly, these events were enriched at specific chromosomal loci, and the distribution pattern varied in different TNBC subtypes. The vast majority of fusion partners were discovered on chromosomes 1p, 11q, 19p, and 19q. Besides, fusion events mainly clustered on chromosome 11 in the immunomodulatory subtype and chromosome 19 in the luminal androgen receptor subtype of TNBC. Considering the tumor specificity and frameshift mutation, we selected MFGE8-HAPLN3 as a novel biomarker and further validated it in TNBC samples using PCR and Sanger sequencing. Further, we successfully identified three types of MFGE8-HAPLN3 (E6-E2, E5-E3, and E6-E3) and predicted the ORF of E6-E2, which could encode a protein of 712 amino acids, suggesting its critical role in TNBC. CONCLUSIONS: Improved bioinformatic stratification and comprehensive analysis identified the fusion transcript MFGE8-HAPLN3 as a novel biomarker with promising clinical application in the future. Frontiers Media S.A. 2021-06-15 /pmc/articles/PMC8239224/ /pubmed/34211850 http://dx.doi.org/10.3389/fonc.2021.682021 Text en Copyright © 2021 Wang, Huang, Wang, Tang, Wang, Yang, Xiong and Gao 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 Wang, Meng-Yuan Huang, Man Wang, Chao-Yi Tang, Xiao-Ying Wang, Jian-Gen Yang, Yong-De Xiong, Xin Gao, Chao-Wei Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer |
title | Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer |
title_full | Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer |
title_fullStr | Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer |
title_full_unstemmed | Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer |
title_short | Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer |
title_sort | transcriptome analysis reveals mfge8-hapln3 fusion as a novel biomarker in triple-negative breast cancer |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239224/ https://www.ncbi.nlm.nih.gov/pubmed/34211850 http://dx.doi.org/10.3389/fonc.2021.682021 |
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