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Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer
BACKGROUND: Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10286324/ https://www.ncbi.nlm.nih.gov/pubmed/37349736 http://dx.doi.org/10.1186/s12885-023-11019-6 |
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author | Schimmelpfennig, Carolin Rade, Michael Füssel, Susanne Löffler, Dennis Blumert, Conny Bertram, Catharina Borkowetz, Angelika Otto, Dominik J. Puppel, Sven-Holger Hönscheid, Pia Sommer, Ulrich Baretton, Gustavo B. Köhl, Ulrike Wirth, Manfred Thomas, Christian Horn, Friedemann Kreuz, Markus Reiche, Kristin |
author_facet | Schimmelpfennig, Carolin Rade, Michael Füssel, Susanne Löffler, Dennis Blumert, Conny Bertram, Catharina Borkowetz, Angelika Otto, Dominik J. Puppel, Sven-Holger Hönscheid, Pia Sommer, Ulrich Baretton, Gustavo B. Köhl, Ulrike Wirth, Manfred Thomas, Christian Horn, Friedemann Kreuz, Markus Reiche, Kristin |
author_sort | Schimmelpfennig, Carolin |
collection | PubMed |
description | BACKGROUND: Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. METHODS: We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan–Meier estimator, log-rank test, and Cox regression. RESULTS: Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05). CONCLUSIONS: Our gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-11019-6. |
format | Online Article Text |
id | pubmed-10286324 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-102863242023-06-23 Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer Schimmelpfennig, Carolin Rade, Michael Füssel, Susanne Löffler, Dennis Blumert, Conny Bertram, Catharina Borkowetz, Angelika Otto, Dominik J. Puppel, Sven-Holger Hönscheid, Pia Sommer, Ulrich Baretton, Gustavo B. Köhl, Ulrike Wirth, Manfred Thomas, Christian Horn, Friedemann Kreuz, Markus Reiche, Kristin BMC Cancer Research BACKGROUND: Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. METHODS: We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan–Meier estimator, log-rank test, and Cox regression. RESULTS: Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05). CONCLUSIONS: Our gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-023-11019-6. BioMed Central 2023-06-22 /pmc/articles/PMC10286324/ /pubmed/37349736 http://dx.doi.org/10.1186/s12885-023-11019-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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 Schimmelpfennig, Carolin Rade, Michael Füssel, Susanne Löffler, Dennis Blumert, Conny Bertram, Catharina Borkowetz, Angelika Otto, Dominik J. Puppel, Sven-Holger Hönscheid, Pia Sommer, Ulrich Baretton, Gustavo B. Köhl, Ulrike Wirth, Manfred Thomas, Christian Horn, Friedemann Kreuz, Markus Reiche, Kristin Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
title | Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
title_full | Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
title_fullStr | Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
title_full_unstemmed | Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
title_short | Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
title_sort | characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10286324/ https://www.ncbi.nlm.nih.gov/pubmed/37349736 http://dx.doi.org/10.1186/s12885-023-11019-6 |
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