1. Prostate Cancer: An Update on Molecular Pathology with Clinical Implications 
George J. Netto, Marie-Lisa Eich, Sooryanarayana Varambally 
European Urology Supplements 
Volume 16, Issue 12, Pages (December 2017)
DOI: /j.eursup
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2. Fig. 1
Etiological factors implicated in prostate cancer development. Chronic inflammation triggered by environmental and lifestyle exposures leads to persistent prostate epithelial cell damage. Inherited genetic predisposition also plays a determining factor in promoting oncogenesis.
PIA=proliferative inflammatory atrophy; PIN=prostatic intraepithelial neoplasia; SNP=single-nucleotide polymorphism; STD=sexually transmitted disease.
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3. Fig. 2
Phosphatase and tensin homolog (PTEN) immunohistochemistry in prostate cancer. (A) PTEN intact in tumor cells “T”, note equivalent staining in adjacent benign glands labeled “B”. Lower frame: higher magnification inset shows positive “P” staining tumor glands. (B) PTEN homogeneous loss in tumor glands “T”, with intact staining in nearby benign glands “B” and stroma. Lower frame: higher magnification inset shows negative “N” staining tumor glands. (C) PTEN heterogeneous loss, with staining loss in some but not all tumor cells “T”. Higher magnification inset below shows positive “P”staining and negative “N” staining tumor glands. (D) PTEN uninterpretable staining. PTEN stain is weaker but not lost in tumor glands and absence of background benign glands for comparison makes it difficult to interpret. Lower frame: higher magnification inset shown below. Adapted with permission from Lotan et al [108].
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4. Fig. 3
(A) Association of phosphatase and tensin homolog (PTEN) deletion, (B) ERG fusion, and (C) the combination of PTEN deletion and ERG fusion or (D) nuclear p53 accumulation with biochemical recurrence in prostate cancer. Adapted with permission from Krohn et al [112].
del.=deletion; neg.=negative; pos.=positive; PSA=prostate-specific antigen.
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5. Fig. 4
Chromoplexy: Circos plots of rearrangement chains in representative tumors, grouped by ETS rearrangements and CHD1 disruption status. Rearrangements in the same chain are depicted in one color. Rearrangements in gray were not assigned to a chain. The inner ring shows copy number gain and loss in red and blue, respectively. Note that rearrangement chains in ETS+ tumors contain a greater proportion of interchromosomal fusions than chains in ETS negative tumors. Adapted with permission from Baca et al [122].
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6. Fig. 5
The Molecular Taxonomy of Primary Prostate Cancer: The Cancer Genome Atlas comprehensive molecular profiling of 333 primary prostate cancer samples revealed seven genomically distinct subtypes, defined (top to bottom) by ERG fusion (46%), ETV1/ETV4/FLI1 fusions or overexpression (8%, 4%, 1%, respectively), or by SPOP (11%), FOXA1 (3%), and IDH1 (1%) mutations. Heatmap shows DNA copy number for all cases, with chromosomes shown from left to right. Regions of loss are indicated by shades of blue, and gains are indicated by shades of red. Adapted with permission from The Cancer Genome Atlas Research Network [124].
cellul.=cellularity; mRNA=messenger RNA; miRNA=microRNA; SCNA=somatic copy-number alterations.
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7. Fig. 6
Alterations in Clinically Relevant Pathways in 333 primary prostate cancer analyzed in The Cancer Genome Atlas. (A) Alterations in DNA repair genes affecting 19% of tumors through mutations or deletions in BRCA2, BRCA1, CDK12, ATM, FANCD2, or RAD51C. (B) Focal deletions of FANCD2 were present in 7% of samples. (C,D,E) RAS or PI-3-kinase pathways alterations were seen in almost one-fourth of tumors, mostly through deletion or mutation of PTEN. (F) BRAF mutations were found in 2% of primary prostate cancers, mostly in known non-V600E hotspots in the kinase domain. Adapted with permission from The Cancer Genome Atlas Research Network [124].
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8. Fig. 7
DNA methylation cityscape plots of lethal metastatic prostate cancer highlight frequent and highly maintained alterations. (A) Genomic cityscapes of somatic hypermethylation and (B) hypomethylation. (C) Each chromosome is folded into neighborhoods along a Hilbert curve. Each structure represents a region showing alteration in TM compared with the normal prostate tissues. The height of each structure indicates number of tumors showing alteration. The color scale represents degree of maintenance of alterations across metastases within individuals normalized to the overall variability (R2). Hypermethylated promoter regions of genes from the National Cancer Institute Cancer Gene Index that fell in top 10th percentile of frequency of alteration or R2 are labeled. The magnified region in (A) illustrates a representative chromosomal segment showing clustering of frequently hypermethylated regions (skyscrapers). The white path shows the Hilbert curve “folding” of this genomic segment. Adapted with permission from Aryee et al [129].
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9. Fig. 8
The Cancer Genome Atlas comprehensive molecular profiling of 333 primary prostate cancer samples: hypermethylation was common across tumors. (A) Primary prostate cancers show diverse methylation changes compared with normal prostate samples (left). Unsupervised clustering was performed on beta values of the 5000 most hypermethylated loci and mapped to the genomic subtypes. ERG-positive tumors had a high diversity of methylation changes, with a distinct subgroup (cluster 1) nearly unique to this group. SPOP and FOXA1 mutant tumors also exhibited global hypermethylation. (B) IDH1 mutant prostate cancers were among the most hypermethylated tumors, as in glioblastoma (GMB) and acute myeloid leukemia (AML). Adapted with permission from The Cancer Genome Atlas Research Network [124].
mRNA=messenger RNA; SCNA=somatic copy-number alterations.
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