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Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations

BACKGROUND: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy numb...

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Autores principales: Böttcher, René, Kweldam, Charlotte F., Livingstone, Julie, Lalonde, Emilie, Yamaguchi, Takafumi N., Huang, Vincent, Yousif, Fouad, Fraser, Michael, Bristow, Robert G., van der Kwast, Theodorus, Boutros, Paul C., Jenster, Guido, van Leenders, Geert J. L. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751811/
https://www.ncbi.nlm.nih.gov/pubmed/29295717
http://dx.doi.org/10.1186/s12885-017-3976-z
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author Böttcher, René
Kweldam, Charlotte F.
Livingstone, Julie
Lalonde, Emilie
Yamaguchi, Takafumi N.
Huang, Vincent
Yousif, Fouad
Fraser, Michael
Bristow, Robert G.
van der Kwast, Theodorus
Boutros, Paul C.
Jenster, Guido
van Leenders, Geert J. L. H.
author_facet Böttcher, René
Kweldam, Charlotte F.
Livingstone, Julie
Lalonde, Emilie
Yamaguchi, Takafumi N.
Huang, Vincent
Yousif, Fouad
Fraser, Michael
Bristow, Robert G.
van der Kwast, Theodorus
Boutros, Paul C.
Jenster, Guido
van Leenders, Geert J. L. H.
author_sort Böttcher, René
collection PubMed
description BACKGROUND: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). METHODS: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set. RESULTS: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs. CONCLUSIONS: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-017-3976-z) contains supplementary material, which is available to authorized users.
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spelling pubmed-57518112018-01-05 Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations Böttcher, René Kweldam, Charlotte F. Livingstone, Julie Lalonde, Emilie Yamaguchi, Takafumi N. Huang, Vincent Yousif, Fouad Fraser, Michael Bristow, Robert G. van der Kwast, Theodorus Boutros, Paul C. Jenster, Guido van Leenders, Geert J. L. H. BMC Cancer Research Article BACKGROUND: Invasive cribriform and intraductal carcinoma (CR/IDC) is associated with adverse outcome of prostate cancer patients. The aim of this study was to determine the molecular aberrations associated with CR/IDC in primary prostate cancer, focusing on genomic instability and somatic copy number alterations (CNA). METHODS: Whole-slide images of The Cancer Genome Atlas Project (TCGA, N = 260) and the Canadian Prostate Cancer Genome Network (CPC-GENE, N = 199) radical prostatectomy datasets were reviewed for Gleason score (GS) and presence of CR/IDC. Genomic instability was assessed by calculating the percentage of genome altered (PGA). Somatic copy number alterations (CNA) were determined using Fisher-Boschloo tests and logistic regression. Primary analysis were performed on TCGA (N = 260) as discovery and CPC-GENE (N = 199) as validation set. RESULTS: CR/IDC growth was present in 80/260 (31%) TCGA and 76/199 (38%) CPC-GENE cases. Patients with CR/IDC and ≥ GS 7 had significantly higher PGA than men without this pattern in both TCGA (2.2 fold; p = 0.0003) and CPC-GENE (1.7 fold; p = 0.004) cohorts. CR/IDC growth was associated with deletions of 8p, 16q, 10q23, 13q22, 17p13, 21q22, and amplification of 8q24. CNAs comprised a total of 1299 gene deletions and 369 amplifications in the TCGA dataset, of which 474 and 328 events were independently validated, respectively. Several of the affected genes were known to be associated with aggressive prostate cancer such as loss of PTEN, CDH1, BCAR1 and gain of MYC. Point mutations in TP53, SPOP and FOXA1were also associated with CR/IDC, but occurred less frequently than CNAs. CONCLUSIONS: CR/IDC growth is associated with increased genomic instability clustering to genetic regions involved in aggressive prostate cancer. Therefore, CR/IDC is a pathologic substrate for progressive molecular tumour derangement. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-017-3976-z) contains supplementary material, which is available to authorized users. BioMed Central 2018-01-02 /pmc/articles/PMC5751811/ /pubmed/29295717 http://dx.doi.org/10.1186/s12885-017-3976-z Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.
spellingShingle Research Article
Böttcher, René
Kweldam, Charlotte F.
Livingstone, Julie
Lalonde, Emilie
Yamaguchi, Takafumi N.
Huang, Vincent
Yousif, Fouad
Fraser, Michael
Bristow, Robert G.
van der Kwast, Theodorus
Boutros, Paul C.
Jenster, Guido
van Leenders, Geert J. L. H.
Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
title Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
title_full Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
title_fullStr Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
title_full_unstemmed Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
title_short Cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
title_sort cribriform and intraductal prostate cancer are associated with increased genomic instability and distinct genomic alterations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751811/
https://www.ncbi.nlm.nih.gov/pubmed/29295717
http://dx.doi.org/10.1186/s12885-017-3976-z
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