24 research outputs found

    Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

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    BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063)

    Expression and Regulation of Neuropeptide Y (NPY) in the Islets of Langerhans

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    This thesis deals with the expression, localization and regulation of neuropeptide Y (NPY) in the pancreatic islets of Langerhans under normal and experimental conditions. NPY is widely distributed in the mammalian nervous system and belongs to a family of closely related petides also comprising peptide YY (PYY) and pancreatic polypeptide (PP). NPY exerts a variety of biological effects, such as stimulation of food intake, vasoconstriction, regulation of endocrine functions, and in the pancreas inhibition of insulin secretion. All three peptides occur in the mammalian pancreas; NPY in neuronal elements adrenergic as well as nonadrenergic, and PP and PYY in endocrine cells. Reinnervation of xenografts consisting of purified rat ß-cells and nonß-cells, respectively, transplanted beneath the kidney capsule of nude mouse revealed ingrowth of numerous sympathetic NPY-containing nerves into the ß-cell grafts while reinnervation of nonß-cell grafts was scarce, suggesting a neurotrophic action of the ß-cells. The islet expression and localization of NPY differed between species and was related to the developmental stage in rat. In islets of the hamster, NPY was detected in numerous nerve fibers as well as in somatostatin producing cells, while NPY was confined to nerve fibers within islets of the adult rat. During rat embryogenesis expression of NPY was detected in islet cells and co-localized with insulin. The expression of NPY in fetal rat ß-cells coincides with the known prepartal glucocorticoid surge, which rapidly declines after birth. At the same time the expression of NPY in the ß-cells disappears. Following treatment with the potent glucocorticoid dexamethasone of adult rats, a model for type 2 diabetes, NPY expression was re-induced in the ß-cells. The NPY expression in rat ß-cells rapidly declined after cessation of dexamethasone treatment, indicating that expression of NPY in rat ß-cells is dependent on continuous excessive levels of glucocorticoids. The glucocorticoid-induced expression of NPY in rat ß-cells was found to be markedly reduced by concomitant treatment with insulin or by sympathectomy. Culture of the insulin-producing cell line RINm5F with dexamethasone also induced expression of NPY. Stimulation of RINm5F cells with D-glyceraldehyde and depolarization with KCl increased the release of insulin Ca2+-dependently. However, the release of NPY was not affected by stimulation or removal of extracellular Ca2+, reflecting a constitutive release of NPY in contrast to the regulated release of insulin. Glucocorticoids induce peripheral insulin resistance with increased demands on the functional capacity of the ß-cells to produce and secrete insulin, as in type 2 diabetes. Our findings suggest that the expression of NPY in ß-cells could be part of the ß-cell activation upon the increased secretory demands induced by dexamethasone. Possibly, NPY, being a potent inhibitor of insulin secretion, could act by paracrine or autocrine mechanisms to prevent overwork of the ß-cells

    Beta cell adaptation to dexamethasone-induced insulin resistance in rats involves increased glucose responsiveness but not glucose effectiveness

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    Islet beta cell adaptation to dexamethasone-induced insulin resistance was characterized with respect to glucose-stimulated insulin secretion and islet innervation. Male Sprague-Dawley rats were injected daily with dexamethasone (2 mg/kg for 12 days), which resulted in hyperinsulinemia and hyperglycemia compared with controls (which were injected with sodium chloride). Insulin secretion was characterized in collagenase-isolated islets. Islet innervation was examined by immunocytochemical analysis of tyrosine hydroxylase, neuropeptide Y (sympathetic nerves), and vasoactive intestinal polypeptide (cholinergic nerves). In islets isolated from the insulin-resistant animals, the insulin response to 3.3 or 8.3 mM glucose was three times greater during perifusion compared with controls (p < 0.001). Incubation of islets at 0 to 20 mM glucose revealed a marked leftward shift of the glucose dose-response relation after dexamethasone treatment (potency ratio, 1.78; p < 0.01), with no difference at 0 or 20 mM glucose. Thus, the potency but not the efficacy of glucose was increased. The number of islet nerves did not differ between dexamethasone-treated rats and controls. Dexamethasone-induced insulin resistance leads to adaptively increased glucose responsiveness of the islet beta cells, with increased potency, but not increased efficacy, of glucose to stimulate insulin secretion without any evidence of altered islet innervation

    Somatic Mitochondrial DNA Point Mutations Used as Biomarkers to Demonstrate Genomic Heterogeneity in Primary Prostate Cancer

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    Primary prostate tumor heterogeneity is poorly understood, leaving research efforts with challenges regarding the initiation and advancement of the disease. The growth of tumor cells is accompanied by mutations in nuclear and in mitochondrial genomes. Thus, mitochondrial DNA mutations may be used as tumor cell markers. By the use of laser capture microdissection coupled with assays for mitochondrial point mutation detection, mtDNA mutations were used to trace mutated cells at a histological level. Point mutations in mtDNA were determined in 12 primary prostate cancers. The tumors represent different pathology-prognostic grade groups. Known mutational hotspots of the mtDNA were scanned for heteroplasmy. All specimens with mtDNA heteroplasmy were subsequently subsampled by laser capture microdissection. From a total number of 1728 microsamples, mitochondrial DNA target sequences were amplified and base substitutions detected by cycling temperature capillary electrophoresis. Real-time PCR was used as a quantitative assay to determine the relative mtDNA copy number of 12 tumors studied, represented by two samples from each (N = 24); a high degree (75%) demonstrated tumor specimen heterogeneity. A grid of 96 spots isolated by laser capture microdissection demonstrated interfocal sample heterogeneity and increased the limit of detection. The spots demonstrated a wide range of mutant fractions from 0 to 100% mutant copies. The mitochondrial DNA copy number in the samples was determined by real-time PCR. No correlation between copy number and pathology-prognostic grade groups was observed. Somatic mitochondrial DNA point mutations represent traceable biomarkers demonstrating heterogeneity in primary prostate cancer. Mutations can be detected in areas before changes in tissue histopathology are evident to the pathologist

    Interfocal heterogeneity challenges the clinical usefulness of molecular classification of primary prostate cancer

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    Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier’s performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer

    Dendritic and lymphocytic cell infiltration in prostate carcinoma

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    We examined the distribution of CD1a+ cells and CD8+ and CD4+ T lymphocytes in prostate cancer (PCa) and correlated these with clinicopathological parameters. We also investigated whether the distribution of these cells was related to the expression of the cell membrane protein B7-H3, a putative negative regulator of the immune response expressed on PCa cells. A cohort of 151 PCa patients treated with radical prostatectomy (RP) was followed prospectively from 1985 until 2006 with a median follow-up of 9 years. Whole-mount sections of PCa specimens were immunostained to identify immune cells. A low number of CD1a+ cells was significantly associated with a high Gleason score and high pathological stage of pT3. The number of CD1a+ cells correlated significantly with the number of intratumoral and stromal CD8+ and stromal CD4+ lymphocytes. Kaplan-Meier analysis showed a tendency toward impaired biochemical progression-free survival in patients with few CD1a+ cells within their RP specimens. The expression of B7-H3 correlated inversely with the number of CD1a+ cells and intratumoral CD4+ lymphocytes; there was a trend for a similar inverse relationship between B7-H3 expression and the number of CD8+ lymphocytes. Our findings suggest that high-grade prostate carcinoma cells manipulate the immune system and that these changes contribute to the mechanism underlying tumor escape from immune surveillance

    Multiparametric Magnetic Resonance Imaging of Penile Cancer: A Pictorial Review

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    The role of multiparametric magnetic resonance imaging (mpMRI) in assessing penile cancer is not well defined. However, this modality may be successfully applied for preoperative staging and patient selection; postoperative local and regional surveillance; and assessments of treatment response after oncological therapies. Previous studies have been mostly limited to a few small series evaluating the accuracy of MRI for the preoperative staging of penile cancer. This review discusses the principles of non-erectile mpMRI, including functional techniques and their applications in evaluating the male genital region, along with clinical protocols and technical considerations. The latest clinical classifications and guidelines are reviewed, focusing on imaging recommendations and discussing potential gaps and disadvantages. The development of functional MRI techniques and the extraction of quantitative parameters from these sequences enables the noninvasive assessment of phenotypic and genotypic tumor characteristics. The applications of advanced techniques in penile MRI are yet to be defined. There is a need for prospective trials and feasible multicenter trials due to the rarity of the disease, highlighting the importance of minimum technical requirements for MRI protocols, particularly image resolution, and finally determining the role of mpMRI in the assessment of penile cance

    High expression of SCHLAP1 in primary prostate cancer is an independent predictor of biochemical recurrence, despite substantial heterogeneity

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    In primary prostate cancer, the common multifocality and heterogeneity are major obstacles in finding robust prognostic tissue biomarkers. The long noncoding RNA SCHLAP1 has been suggested, but its prognostic value has not been investigated in the context of tumor heterogeneity. In the present study, expression of SCHLAP1 was investigated using real-time RT-PCR in a multisampled series of 778 tissue samples from radical prostatectomies of 164 prostate cancer patients (median follow-up time 7.4 y). The prognostic value of SCHLAP1 was evaluated with biochemical recurrence as endpoint.In total, 29% of patients were classified as having high expression of SCHLAP1 in at least one malignant sample. Among these, inter- and intrafocal heterogeneity was detected in 72% and 56%, respectively. High expression of SCHLAP1 was shown to be a predictor of biochemical recurrence in both uni- and multivariable cox regression analyses (P < 0.001 and P = 0.02). High expression of SCHLAP1 was also significantly associated with adverse clinicopathological characteristics, including grade group, high pT stage, invasive cribriform growth/intraductal carcinoma of the prostate, and reactive stroma. In conclusion, high expression of SCHLAP1 in at least one malignant sample is a robust prognostic biomarker in primary prostate cancer. For the first time, high SCHLAP1 expression has been associated with the aggressive histopathologic feature reactive stroma. The expression of SCHLAP1 is highly heterogeneous, and analysis of multiple samples is therefore crucial in determination of the SCHLAP1 status of a patient

    In situ expression of ERG protein in the context of tumor heterogeneity identifies prostate cancer patients with inferior prognosis

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    Prognostic biomarkers for prostate cancer are needed to improve prediction of disease course and guide treatment decisions. However, biomarker development is complicated by the common multifocality and heterogeneity of the disease. We aimed to determine the prognostic value of candidate biomarkers transcriptional regulator ERG and related ETS family genes, while considering tumor heterogeneity. In a multisampled, prospective, and treatment-naïve radical prostatectomy cohort from one tertiary center (2010–2012, median follow-up 8.1 years), we analyzed ERG protein (480 patients; 2047 tissue cores), and RNA of several ETS genes in a subcohort (165 patients; 778 fresh-frozen tissue samples). Intra- and interfocal heterogeneity was identified in 29% and 33% (ERG protein) and 39% and 27% (ETS RNA) of patients, respectively. ERG protein and ETS RNA was identified exclusively in a nonindex tumor in 31% and 32% of patients, respectively. ERG protein demonstrated independent prognostic value in predicting biochemical (P = 0.04) and clinical recurrence (P = 0.004) and appeared to have greatest prognostic value for patients with Grade Groups 4–5. In conclusion, when heterogeneity is considered, ERG protein is a robust prognostic biomarker for prostate cancer
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