Urothelial Cancer With Occult Bone Marrow Metastases and Isolated Thrombocytopenia

AbstractBladder cancer rarely presents clinically with a myelophthisic picture from diffuse bone marrow infiltration especially in the absence of detectable skeletal metastases. A 75-year old man presented with newly diagnosed urothelial cell carcinoma of the bladder. Pathology from transurethral resection of bladder tumor demonstrated muscle-invasive disease. Pre-therapy imaging including CT abdomen/pelvis, CXR and bone scan demonstrated liver lesions concerning for metastatic disease but no skeletal metastases. Labs were notable for isolated thrombocytopenia, hypercalcemia and acute kidney injury prompting hospitalization. Hematologic work-up including bone marrow aspiration and biopsy revealed diffuse infiltration of the bone marrow by urothelial cancer. The case illustrates the importance of fully investigating otherwise unexplained clinical findings in patients with clinically localized urothelial cancer prior to curative intent surgery

Immune associated LncRNAs identify novel prognostic subtypes of renal clear cell carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148402/1/mc22949_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148402/2/mc22949.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148402/3/mc22949-sup-0001-SuppData-S1.pd

Feature Selection and Molecular Classification of Cancer Using Genetic Programming

AbstractDespite important advances in microarray-based molecular classification of tumors, its application in clinical settings remains formidable. This is in part due to the limitation of current analysis programs in discovering robust biomarkers and developing classifiers with a practical set of genes. Genetic programming (GP) is a type of machine learning technique that uses evolutionary algorithm to simulate natural selection as well as population dynamics, hence leading to simple and comprehensible classifiers. Here we applied GP to cancer expression profiling data to select feature genes and build molecular classifiers by mathematical integration of these genes. Analysis of thousands of GP classifiers generated for a prostate cancer data set revealed repetitive use of a set of highly discriminative feature genes, many of which are known to be disease associated. GP classifiers often comprise five or less genes and successfully predict cancer types and subtypes. More importantly, GP classifiers generated in one study are able to predict samples from an independent study, which may have used different microarray platforms. In addition, GP yielded classification accuracy better than or similar to conventional classification methods. Furthermore, the mathematical expression of GP classifiers provides insights into relationships between classifier genes. Taken together, our results demonstrate that GP may be valuable for generating effective classifiers containing a practical set of genes for diagnostic/ prognostic cancer classification

Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty

Testosterone production surges during puberty and orchestrates massive growth and reorganization of the prostate gland, and this glandular architecture is maintained thereafter throughout adulthood. Benign prostatic hyperplasia (BPH) and prostate adenocarcinoma (PCA) are common diseases in adulthood that do not develop in the absence of androgens. Our objective was to gain insight into gene expression changes of the prostate gland at puberty, a crucial juncture in prostate development that is androgen dependent. Understanding the role played by androgens in normal prostate development may provide greater insight into androgen involvement in prostatic diseases. Benign prostate tissues obtained from pubertal and adult age group cadaveric organ donors were harvested and profiled using 20,000 element cDNA microarrays. Statistical analysis of the microarray data identified 375 genes that were differentially expressed in pubertal prostates relative to adult prostates including genes such as Nkx3.1, TMEPAI, TGFBR3, FASN, ANKH, TGFBR2, FAAH, S100P, HoxB13, fibronectin, and TSC2 among others. Comparisons of pubertal and BPH expression profiles revealed a subset of genes that shared the expression pattern between the two groups. In addition, we observed that several genes from this list were previously demonstrated to be regulated by androgen and hence could also be potential in vivo targets of androgen action in the pubertal human prostate. Promoter searches revealed the presence of androgen response elements in a cohort of genes including tumor necrosis factor‐α induced adipose related protein, which was found to be induced by androgen. In summary, this is the first report that provides a comprehensive view of the molecular events that occur during puberty in the human prostate and provides a cohort of genes that could be potential in vivo targets of androgenic action during puberty.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154303/1/fsb2fj042415fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154303/2/fsb2fj042415fje-sup-0001.pd

Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer.

Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer

Plasmacytoid urothelial carcinoma: a rapid autopsy case report with unique clinicopathologic and genomic profile

Abstract Background Rapid (“warm”) autopsies of patients with advanced metastatic cancer provide important insight into the natural history, pathobiology and histomorphology of disease in treatment-resistant tumors. Plasmacytoid urothelial carcinoma (PUC) is a rare variant of urothelial carcinoma characterized by neoplastic cells morphologically resembling plasma cells. PUC is typically aggressive, high-stage at presentation, and associated with poor outcomes. Recurrence is common in PUC, with the majority of recurrences occurring in the peritoneum. Case presentation Here, we report rapid autopsy findings from a patient with recurrent PUC. The patient had persistent pain after cystoprostatectomy, although initial post-operative imaging showed no evidence of disease. Imaging obtained shortly before his death showed only subtle growth along vascular tissue planes; however, extensive disease was seen on autopsy. Plasmacytoid tumor cells formed sheets involving many serosal surfaces. Molecular interrogation confirmed a mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein in the tumor cells. Conclusions The sheet-like growth pattern of PUC makes early phases of disease spread much more difficult to capture on cross-sectional imaging. Alternative forms of surveillance may be required for detection of recurrent PUC, and providers may need to treat based on symptoms and clinical suspicion.https://deepblue.lib.umich.edu/bitstream/2027.42/152229/1/13000_2019_Article_896.pd

The polycomb group protein EZH2 is involved in progression of prostate cancer

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling(1), that the polycomb group protein enhancer of zeste homolog 2 (EZH2)(2,3) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes(4) targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62896/1/nature01075.pd

Immediate Early Inflammatory Gene Responses of Human Umbilical Vein Endothelial Cells to Hemorraghic Venom

This report describes a focused immediate early gene response by human umbilical vein endothelial cells (HUVEC) to Echis carinatus snake venom.Primary cultures of HUVEC were used to assess acute inflammatory gene responses. Crude E. carinatus venom (2.5 A mu g/ml) was used to stimulate HUVEC. HUVEC stimulated for 3 h with E. carinatus venom showed a focused response to the venom, with significant increases in metallothionein (e.g., MT1H, MT2A, MT1X) and cytochrome P450 (e.g., CYP1A1, CYP1B1) gene expressions compared to non-stimulated controls. Several other genes involved in cell growth and matrix attachment were repressed [e.g., thrombospondin 1 (THBS1), connective tissue growth factor (CTGF)]. These data suggest that acute vascular injury induced by hemorrhagic snake venom initiates an anti-oxidant response primarily involving metallothioneins

Isolation and characterization of a transforming growth factor-β\beta Type II receptor cDNA from Xenopus laevis

Transforming Growth Factor-$\beta$ $(TGF-\beta)$ and their receptors have been characterized from many organisms. Two $TGF-\beta$ signaling receptors called Type I and II have been described for various ligands of the superfamily from organisms ranging from Drosophila to humans. In Xenopus laevis, $TGF-\beta 2$ and 5 have been reported and presumably, play important roles during early development. Several Type I and type II receptors for many ligands of the $TGF-\beta$ superfamily except $TGF-\beta$ type II receptor $(T \beta IIR)$, have been characterized in Xenopus laevis. A chemical cross linking experiment using iodinated $TGF-\beta 1$ and -$\beta 5$, revealed four specific binding proteins on XTC cells. In order to understand the $TGF-\beta$ involvement during Xenopus development, a $TGF-\beta$ type II receptor $(XT \beta IIR)$ has been isolated from a XTC cDNA library. $XT \beta IIR$ was a partial cDNA lacking a portion of the signal peptide. The sequence analysis and homology comparison with the human $T\beta IIR$ revealed 67% amino acid similarity in the extra cellular domain, 60% similarity in the transmembrane domain and 87% similarity in the cytoplasmic kinase domain, suggesting that $XT \beta IIR$ is a putative $TGF-\beta$ type II receptor. In addition, the consensus amino acid motif for serine threonine receptor kinases was also present. Further, a dominant negative expression construct lacking the cytoplasmic kinase domain (engineered with the signal peptide from human $TGF-\beta$ type II receptor), was able to abolish $TGF-\beta$ mediated induction of a luciferase reporter plasmid, in a transient cell transfection assay. This substantiates the notion that $XT \beta IIR$ cDNA can act as a receptor for $TGF-\beta$. RT-PCR analysis using RNA isolated from various developmental stages of Xenopus laevis revealed expression of this gene in all the early stages of development and in the adult organs, except in stages 46/48