Emerging critical role of molecular testing in diagnostic genitourinary pathology

Abstract

Context: The unprecedented advances in cancer genetics and genomics are rapidly affecting clinical management and diagnostics in solid tumor oncology. Molecular diagnostics is now an integral part of routine clinical management in patients with lung, colon, and breast cancer. In sharp contrast, molecular biomarkers have been largely excluded from current management algorithms of urologic malignancies.

Objective: To discuss promising candidate biomarkers that may soon make their transition to the realm of clinical management of genitourologic malignancies. The need for new treatment alternatives that can improve upon the modest outcome so far in patients with several types of urologic cancer is evident. Well-validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management are lacking. Identifying robust predictive biomarkers that will stratify response to emerging targeted therapeutics is another crucially needed development. A compiled review of salient studies addressing the topic could be helpful in focusing future efforts.

Data sources: A PubMed (US National Library of Medicine) search for published studies with the following search terms was conducted: molecular , prognostic , targeted therapy , genomics , theranostics and urinary bladder cancer , prostate adenocarcinoma , and renal cell carcinoma . Articles with large cohorts and multivariate analyses were given preference.

Conclusions: Our recent understanding of the complex molecular alterations involved in the development and progression of urologic malignancies is yielding novel diagnostic and prognostic molecular tools and opening the doors for experimental targeted therapies for these prevalent, frequently lethal solid tumors.

Figure 1

Divergent molecular pathways of oncogenesis in superficial and muscle invasive urothelial carcinoma of urinary bladder. Genetic alterations are depicted in key stages of disease progression. Abbreviations: CIS, carcinoma in situ; EGFR, epidermal growth factor receptor; HG URCa, high-grade urothelial carcinoma; LG URCa, low-grade urothelial carcinoma; mTOR, mammalian target of rapamycin; URCa, urothelial carcinoma; VEGF, vascular endothelial growth factor.

Figure 2

Receptor tyrosine kinase (EGFR/Ras/Mek/ERK) and cell cycle regulator (p14, p16, p53, p21, cyclin D1, cyclin E, and Rb) pathways in urothelial carcinoma. Abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor.

Figure 3

Molecular alterations involved in oncogenesis and progression of prostate cancer. Abbreviations: PCa, prostate adenocarcinoma; PIN, prostatic intraepithelial neoplasia; PTEN, phosphatase and tensin homolog.

Figure 4

Fluorescence in situ hybridization–based evaluation of ERG gene fusion in prostate carcinoma. A, A normal ERG allele will hybridize with the ERG 3′ and the ERG 5′ probes, leading to the formation of juxtaposed green-red signals or a yellow overlap signal. The 2 ERG rearrangements associated with TMPRSS2-ERG fusion lead to either a loss of 5′ (green) signal or to a split of the ERG 5′ (green) and ERG 3′ (red) signals. B, Example of prostate adenocarcinoma showing ERG fusion by deletion.

Figure 5

Overexpression of ERG, as demonstrated by immunohistochemistry, is a simple surrogate method for evaluating TMPRSS2-ERG fusion in prostate adenocarcinoma. Positive expression of ERG in Gleason grades 6 and 8 cases that were also positive for TMPRSS2-ERG fusion by fluorescence in situ hybridization (FISH) are shown in A and B and in C and D, respectively. Lack of ERG expression in a Gleason grade 6 tumor that lacked TMPRSS2-ERG fusion by FISH is shown in E and F (ERG immunostain, original magnifications ×100 [A, C, and E] and ×200 [B, D, and F]).

Figure 6

Clinically distinct groups of prostate cancer are identified by genomic alterations. A, Unsupervised hierarchical clustering of copy number alterations identified 6 groups (clusters) of prostate cancers. B, Statistically significant differences in freedom from biochemical recurrence are found among the 6 groups. Adapted from Taylor et al with permission from Elsevier.

Figure 7

Structure of the PCA3/DD3 gene. The gene, which expresses a noncoding RNA, was mapped to chromosome 9q21–22 and consists of 4 exons. Alternative polyadenylation at 3 different positions in exon 4 (indicated as 4a, 4b, and 4c) gives rise to 3 different-sized transcripts. The most frequently found transcript contains exons 1, 3, 4a, and 4b.