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. 2019 Feb;17(2):446-456.
doi: 10.1158/1541-7786.MCR-18-0440. Epub 2018 Oct 17.

Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

Habiba Elfandy  1   2 , Joshua Armenia  3 , Filippo Pederzoli  4 , Eli Pullman  5 , Nelma Pertega-Gomes  1 , Nikolaus Schultz  6 , Kartik Viswanathan  7 , Aram Vosoughi  7   8 , Mirjam Blattner  8   9 , Konrad H Stopsack  10 , Giorgia Zadra  1   11 , Kathryn L Penney  12   13 , Juan Miguel Mosquera  7   8 , Svitlana Tyekucheva  14   15 , Lorelei A Mucci  12 , Christopher Barbieri  8   9 , Massimo Loda  16   11   17
Affiliations

Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate

Habiba Elfandy et al. Mol Cancer Res. 2019 Feb.

Abstract

Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n = 164) had distinctive molecular features when compared with NC4 (n = 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed PTEN and MAP3K7 losses and gains at 3q; (ii) increased SPOP mut and ATMmut ; (iii) enrichment for mTORC1 and MYC pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with SPOPmut (n = 38) and PTENloss (n = 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years; n = 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.

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Conflict of interest statement

Conflict of Interest Statement: The authors declare no potential conflicts of interest.

Figures

Figure 1:
Figure 1:. Frequency (percentage) of the SCNV in Invasive Cribriform Carcinoma (ICC) and Noncribriform Carcinoma (NC4).
ICC is significantly higher in SCNV events. (A) In this figure, dark-blue represents deep deletions, light-blue represents superficial deletions (B) Red represents amplifications, Magenta represents gains and Green represents mutations. N.B. The SCNVs in A & B are the adjusted events for FGA and Gleason score. (C) Landscape of Copy Number Alterations in ICC and NC4: The chromosomes are displayed horizontally, and the frequency is displayed on the y-axis. (D) Distribution of SCNV clusters and SPOP mutation within each ICC and NC4 groups (164 and 102 samples, respectively). In the column sidebar of the figure, blue represents the SCNV clusters and green represents SPOPmut groups. In the heatmap, red represents gains/amplifications and blue represents deletions. Chromosomes are represented in columns and samples are represented in rows. (E) The frequency of SPOPmut and PTENloss in ICC and NC4. N.B. The p-values in E were derived considering deep deletions and mutations of PTEN.
Figure 2.
Figure 2.. Hierarchical Clustering of 266 Samples Based on Differentially Methylated CpG-Islands Between Invasive Cribriform Carcinoma (ICC) & Noncribriform Carcinoma (NC4).
This figure shows the unsupervised hierarchical clustering analysis of ICC and NC4 (top-bar) using differentially methylated CpG-islands (p<0.01 and q<0.05). ICC samples dominate the hypermethylated cluster and while NC4 samples fell in the cluster with the lowest methylation level. Samples are represented in columns and genes in rows.
Figure 3.
Figure 3.. Hierarchical Clustering of Integrated Primary TCGA and Metastatic PCa Datasets (266 and 150 samples, respectively) Based on Genetic Alteration Similarities.
This figure shows the unsupervised clustering analysis of ICC, NC4 and metastatic using binary data of the independent SCNV events with frequency >20% in ICC (q <0.1.5). The dendrogram demonstrates hierarchical separation into four clusters. ICC and metastatic are grouped mainly in clusters 1 and 2 (n=127, both) that is characterized by the highest frequency of genetic alteration at 8p, 6q and 3q. In cluster 1, ICC and metastatic samples constituted together 94.5% (37.8% and 56.9%, respectively) but comprise 100% of cluster 2. Cluster 3 (n=188) is enriched with ICC and metastatic samples (42% and 33%, respectively), designated by 6q and 8p aberrations. The lack of 3q and 8p distinguishes Cluster 4 (n=101) where NC4 samples are mainly condensed (47%). NC4 is minimally represented in cluster 1 and 2 (5.5%). Samples are displayed in columns and genes are represented in rows.
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