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. 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

René Böttcher  1 , Charlotte F Kweldam  2 , Julie Livingstone  3 , Emilie Lalonde  3   4 , Takafumi N Yamaguchi  3 , Vincent Huang  3 , Fouad Yousif  3 , Michael Fraser  5 , Robert G Bristow  4   5   6 , Theodorus van der Kwast  7 , Paul C Boutros  3   4   8 , Guido Jenster  1 , Geert J L H van Leenders  9
Affiliations

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

René Böttcher et al. BMC Cancer. .

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.

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Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Representative images of reference HE slides of GS 6 (a, e) without CR/IDC, and GS 3 + 4 = 7 (b, f), 4 + 3 = 7 (c, g) and 4 + 4 = 8 (d, h) with CR/IDC growth
Fig. 2
Fig. 2
Boxplot of patient-wise PGA stratified by CR/IDC percentage and Gleason score in the TCGA (a) and CPC-GENE (b) cohort
Fig. 3
Fig. 3
Overview heatmap of CNA in TCGA cohort. Clinical variables are displayed on the left, while PGA is displayed on the right. Samples are ordered by CR/IDC percentage, with two thresholds chosen to discriminate between negative (0%), intermediate (1–30%) and high (>30%) CR/IDC growth pattern
See this image and copyright information in PMC

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