Distinct Mutational Landscape of Inverted Urothelial Papilloma

A recent study has identified gene mutations involving the MAPK/ERK pathway, particularly the HRAS gene, in all inverted urothelial papillomas (IUPs), in the absence of pathway mutations in TERT promoter, FGFR3, and TP53/RB1genes. Neither recurrence nor progression was observed in IUPs. These data support several longstanding hypotheses: (1) IUPs are benign and do not recur or progress; (2) they harbor mutations that are different from those of urothelial carcinoma; and (3) they arise through different molecular mechanisms than low‐ or high‐grade urothelial carcinoma. As the most critical differential diagnosis in this context is inverted‐type urothelial carcinoma, more comprehensive studies are needed to compare and contrast these entities

Differential gene expression between African American and Caucasian American prostate cancer

Background: African-American (AA) men have higher incidence and mortality from prostate cancer compared to Caucasian-American (CA) men. Increasing evidence suggests that genetic and molecular alterations play important roles. We identified a 5 gene panel viz. p-Akt (Ser473), chemokine (C-X-C motif) receptor 4 (CXCR4), fatty acid synthase (FASN), interleukin-6 (IL-6) and matrix metallopeptidase 9 (MMP-9) highly expressed in prostate cancer and analyzed their expression in AA and CA cohorts. Methods: IHC of p-Akt, CXCR4, FASN, IL-6 and MMP-9 were evaluated in RRP specimens (n=20) from each ethnic group exhibiting Gleason scores ranging from 6 through 9. Results: Low to medium staining for p-Akt and weak focal staining for MMP-9 was observed in the cytoplasm of tumor cells (10-20%) in80% of tumor cells in both groups. Expression of IL-6 varied from weak to moderate intensity between (20-100% tumor cells) in 85% cases in CA- and 75% in AA- specimens. A marked difference in CXCR4 expression was noted between AA- and CA- cancer specimens. Weak CXCR4 staining was noted85% of AA- prostate cancer exhibited weak to strong CXCR4 expression in between 10-100% of tumor cells localized in membrane, cytoplasm and nucleus in high-grade tumors. Conclusions: CXCR4 expression appears to be distinctly different in prostate cancers from AA and CA men. Further studies are needed to assess whether this distinction correlates with prognosis between racial groups

Maspin Expression and its Metastasis Suppressing Function in Prostate Cancer

Mammary Serine Protease Inhibitor (Maspin) is a unique member of the serpin family with tumor suppressive properties. Maspin is a secreted protein encoded by a class II tumor suppressor gene, expressed in normal prostate luminal and basal cells but reduced or absent in prostate cancer. Currently, there is a consensus that maspin expression in prostate cancer is an indicator of a better prognosis and is a predictive marker for therapeutic response in prostate cancer. Experimental evidence consistently indicates that maspin suppresses tumor growth, invasion, and metastasis and promotes apoptosis in cancer cells. In this chapter, we discuss regulation of maspin expression, binding partners of maspin, and pathways through which maspin exerts its tumor suppressive properties. In addition, we summarize the progress that investigators have made in clarifying the role of maspin in prostate cancer biology and in assessing its role as a diagnostic marker and therapeutic agent

Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine

Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor.' These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression

Differentially Expressed Genes and Molecular Pathways in an Autochthonous Mouse Prostate Cancer Model

Prostate cancer remains a major public health problem and the second leading cause of cancer-related deaths in men in the United States. The present study aims to understand the molecular pathway(s) of prostate cancer which is essential for early detection and treatment. Dorsolateral prostate from 20 week transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develops prostate cancer and recapitulates human disease and age-matched non-transgenic littermates were utilized for microarray analysis. Mouse genome network and pathway analyses were mapped to the human genome using the Ingenuity Pathway Analysis (IPA) database for annotation, visualization, and integrated discovery. In total, 136 differentially expressed genes, including 32 downregulated genes and 104 upregulated genes were identified in the dorsolateral prostate of TRAMP, compared to non-transgenic mice. A subset of differentially expressed genes were validated by qRT-PCR. Alignment with human genome database identified 18 different classes of proteins, among these, 36% were connected to the nucleic acid binding, including ribosomal proteins, which play important role in protein synthesis—the most enriched pathway in the development of prostate cancer. Furthermore, the results suggest deregulation of signaling molecules (9%) and enzyme modulators (8%) affect various pathways. An imbalance in other protein classes, including transporter proteins (7%), hydrolases (6%), oxidoreductases, and cytoskeleton proteins (5%), contribute to cancer progression. Our study evaluated the underlying pathways and its connection to human prostate cancer, which may further help assess the risk of disease development and progression and identify potential targets for therapeutic intervention

FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations

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TMPRSS2â ERG gene fusion is rare compared to PTEN deletions in stage T1a prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136332/1/mc22535.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136332/2/mc22535_am.pd

Molecular Genetic Evidence for the Independent Origin of Multifocal Papillary Tumors in Patients with Papillary Renal Cell Carcinomas

Abstract Purpose: In patients with papillary renal cell carcinoma, it is not uncommon to find two or more anatomically distinct and histologically similar tumors at radical nephrectomy. Whether these multiple papillary lesions result from intrarenal metastasis or arise independently is unknown. Previous studies have shown that multifocal clear cell renal cell carcinomas express identical allelic loss and shift patterns in the different tumors within the same kidney, consistent with a clonal origin. However, similar clonality assays for multifocal papillary renal cell neoplasia have not been done. Molecular analysis of microsatellite and chromosome alterations and X-chromosome inactivation status in separate tumors in the same patient can be used to study the genetic relationships among the coexisting multiple tumors. Experimental Design: We examined specimens from 21 patients who underwent radical nephrectomy for renal cell carcinoma. All patients had multiple separate papillary lesions (ranging from 2 to 5). Eighteen patients had multiple papillary renal cell carcinomas. Seven had one or more papillary renal cell carcinomas with coexisting papillary adenomas. Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-capture microdissection. Loss of heterozygosity assays were done for six microsatellite polymorphic markers for putative tumor suppressor genes on chromosomes 3p14 (D3S1285), 7q31 (D7S522), 9p21 (D9S171), 16q23 (D16S507), 17q21 (D17S1795), and 17p13 (TP53). X-chromosome inactivation analyses were done on the papillary kidney tumors from three female patients. Fluorescence in situ hybridization analysis was done on the tumors of selected patients showing allelic loss at loci on chromosome 7 and/or chromosome 17. Results: Twenty of 21 (95%) cases showed allelic loss in one or more of the papillary lesions in at least one of the six polymorphic markers analyzed. A concordant allelic loss pattern between each coexisting kidney tumor was seen in only 1 of 21 (5%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the coexisting multiple papillary lesions was seen in two of three female patients. A discordant pattern of X-chromosome inactivation was seen in the tumors of the other female patient. Fluorescence in situ hybridization showed that the majority of tumors analyzed had gains of chromosomes 7 and 17. Two patients had one tumor with chromosomal gain and another separate tumor that did not. Conclusion: Our data suggest that, unlike multifocal clear cell renal cell carcinomas, the multiple tumors in patients with papillary renal cell carcinoma arise independently. Thus, intrarenal metastasis does not seem to play an important role in the spread of papillary renal cell carcinoma, a finding that has surgical, therapeutic, and prognostic implications

Solitary fibrous tumour of the genitourinary tract: a clinicopathological study of 11 cases and their association with the NAB2-STAT6 fusion gene

Aims To characterise clinicopathological features and clinical outcomes of the genitourinary tract solitary fibrous tumours, incorporating NAB2-STAT6 gene fusion status. Methods The presence of the molecular hallmark NAB2-STAT6 gene fusion and for the defining fusion partner product STAT6 was assessed in 11 cases of the genitourinary tract solitary fibrous tumours. NAB2-STAT6 gene fusion analysis was performed using a break-apart fluorescence in situ hybridisation (FISH) probe using a probe cocktail with Bacterial artificial chromosome (BAC) clones for STAT6 and NAB2. Results Eleven solitary fibrous tumours were diagnosed in eight male patients and three female patients with a mean age of 46 years (range: 11–64 years). Four of the tumours had malignant histological features, and three were considered moderate risk for metastasis. With a mean follow-up time of 61 months, 1 recurred locally and 2 presented at distant metastatic sites. Using a break-apart FISH probe cocktail, we found the NAB2-STAT6 gene fusion and nuclear STAT6 expression in 58% and 91% of cases, respectively. However, the NAB2-STAT6 fusion status was not correlated with STAT6 expression or useful in discriminating between malignant histological features or subsequent clinical outcomes in the genitourinary solitary fibrous tumours. Conclusions A subset of solitary fibrous tumours of the genitourinary tract behaved aggressively. Using a break-apart FISH probe cocktail, we found the NAB2-STAT6 gene fusion in 64% of cases. However, the NAB2-STAT6 fusion status was not correlated with STAT6 expression or useful in discriminating between low-risk or high-risk tumours and subsequent clinical outcomes

Multilayered epithelium in a rat model and human Barrett's esophagus: Similar expression patterns of transcription factors and differentiation markers

<p>Abstract</p> <p>Background</p> <p>In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment leads to gastroesophageal reflux disease, multilayered epithelium (MLE, a presumed precursor in intestinal metaplasia), columnar-lined esophagus, dysplasia, and esophageal adenocarcinoma. Previously we have shown that columnar-lined esophagus in EGDA rats resembled human Barrett's esophagus (BE) in its morphology, mucin features and expression of differentiation markers (<it>Lab. Invest. 2004;84:753–765</it>). The purpose of this study was to compare the phenotype of rat MLE with human MLE, in order to gain insight into the nature of MLE and its potential role in the development of BE.</p> <p>Methods</p> <p>Serial sectioning was performed on tissue samples from 32 EGDA rats and 13 patients with established BE. Tissue sections were immunohistochemically stained for a variety of transcription factors and differentiation markers of esophageal squamous epithelium and intestinal columnar epithelium.</p> <p>Results</p> <p>We detected MLE in 56.3% (18/32) of EGDA rats, and in all human samples. As expected, both rat and human squamous epithelium, but not intestinal metaplasia, expressed squamous transcription factors and differentiation markers (p63, Sox2, CK14 and CK4) in all cases. Both rat and human intestinal metaplasia, but not squamous epithelium, expressed intestinal transcription factors and differentiation markers (Cdx2, GATA4, HNF1α, villin and Muc2) in all cases. Rat MLE shared expression patterns of Sox2, CK4, Cdx2, GATA4, villin and Muc2 with human MLE. However, p63 and CK14 were expressed in a higher proportion of rat MLE compared to humans.</p> <p>Conclusion</p> <p>These data indicate that rat MLE shares similar properties to human MLE in its expression pattern of these markers, not withstanding small differences, and support the concept that MLE may be a transitional stage in the metaplastic conversion of squamous to columnar epithelium in BE.</p