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BMC Cancer. 2018 Jan 2;18(1):8. doi: 10.1186/s12885-017-3976-z.

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

Author information

1
Department of Urology, Erasmus MC, Rotterdam, the Netherlands.
2
Department of Pathology, Erasmus University Medical Center, Josephine Nefkens Institute building, Be-222, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands.
3
Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
4
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
5
Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
6
Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
7
Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
8
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
9
Department of Pathology, Erasmus University Medical Center, Josephine Nefkens Institute building, Be-222, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. g.vanleenders@erasmusmc.nl.

Abstract

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.

KEYWORDS:

Aggressive disease; Copy number alteration; Cribriform; Genomic instability; Intraductal carcinoma; Prostate cancer

PMID:
29295717
PMCID:
PMC5751811
DOI:
10.1186/s12885-017-3976-z
[Indexed for MEDLINE]
Free PMC Article

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