Discovery and validation of prognostic tissue markers in clinical prostate cancer

Samenvatting Prostaatkanker is divers: in klinische presentatie, in histomorfologische tumor groeipatronen en in overlevingsstatistieken. Momenteel wordt een aantal markers voor prostaatkanker beschreven die het klinisch gedrag van de tumor beter kunnen voorspellen. De meeste markers zijn onderzocht in patiënten die operatief behandeld werden. Om een significant effect te kunnen bewerkstelligen op de therapeutische beslissing is het echter belangrijk dat markers ook getest worden op diagnostische prostaat naaldbiopten. CRISP3 en β-MSP zijn uitgebreid beschreven. β-MSP expressie neemt af en CRISP3 expressie neemt toe in meer hooggradige tumoren. Daarnaast worden zij beschreven als onafhankelijke voorspellers van prostaatkanker recidief na operatie. Wij hebben deze markers getest op een cohort van prostaat naaldbiopten. Beide markers toonden geen voorspellende waarde in de naaldbiopten voor de ernst van prostaatkanker in de totale prostaat van diez

Prognostic Histopathological and Molecular Markers on Prostate Cancer Needle-Biopsies: A Review

Prostate cancer is diverse in clinical presentation, histopathological tumor growth patterns, and survival. Therefore, individual assessment of a tumor's aggressive potential is crucial for clinical decision-making in men with prostate cancer. To date a large number of prognostic markers for prostate cancer have been described, most of them based on radical prostatectomy specimens. However, in order to affect clinical decision-making, validation of respective markers in pretreatment diagnostic needle-biopsies is essential. Here, we discuss established and promising histopathological and molecular parameters in diagnostic needle-biopsies

Gene-expression analysis of gleason grade 3 tumor glands embedded in low- and high-risk prostate cancer

The Gleason score (GS) of prostate cancer on diagnostic biopsies is an important parameter for therapeutic decision-making. Biopsy GS under-estimates the actual GS at radical prostatectomy in a significant number of patients due to sampling artifact. The aim of this study was to identify markers that are differentially expressed in Gleason grade 3 (GG3) tumor glands embedded in GS 4 + 3 = 7 and GS 3 + 3 = 6 prostate cancer using laser capture microdissection and RNA sequencing. GG3 tumor glands embedded in nine GS 3 + 3 = 6 and nine GS 4 + 3 = 7 prostate cancers were isolated by laser capture microdissection of frozen radical prostatectomy specimens. After RNA amplification and RNA sequencing, differentially expressed genes in both GG3 components were identified by a 2log fold change > 1.0 and p-value < 0.05. We applied immunohistochemistry on a tissue micro-array representing 481 radical prostatectomy samples for further validation on protein level. A total of 501 genes were up-regulated and 421 down-regulated in GG3 glands embedded in GS 4 + 3 = 7 as compared to GS 3 + 3 = 6 prostate cancer. We selected HELLS, ZIC2 and ZIC5 genes for further validation. ZIC5 mRNA was up-regulated 17 fold (p = 8.4E–07), ZIC2 8 fold (p = 1.3E–05) and HELLS 2 fold (p = 0.006) in GG3 glands derived from GS 4 + 3 = 7. HELLS expression of ≥ 1% occurred in 10% GS < 7, 17% GS 7 and 43% GS >7 prostate cancer (p < 0.001). Using a cut-off of ≥ 1%, protein expression of ZIC5 was present in 28% GS 7 cancer (p < 0.001). ZIC2 was neither associated with GS nor outcome in our validation set. HELLS was independently predictive for biochemical-recurrence after radical prostatectomy (HR 2.3; CI 1.5–3.6; p < 0.01). In conclusion, HELLS and ZIC5 might be promising candidate markers for selection of biopsy GS 6 prostate cancer being at risk for up-grading at prostatectomy

Specific detection of OCT3/4 isoform A/B/B1 expression in solid (germ cell) tumours and cell lines: confirmation of OCT3/4 specificity for germ cell tumours

BACKGROUND: OCT3/4 (POU5F1) is an established diagnostic immunohistochemical marker for specific histological variants of human malignant germ cell tumours (GCTs), including the seminomatous types and the stem cell component of non-seminomas, known as embryonal carcinoma. OCT3/4 is crucial for the regulation of pluripotency and the self-renewal of normal embryonic stem-and germ cells. Detection of expression of this transcription factor is complicated by the existence of multiple pseudogenes and isoforms. Various claims have been made about OCT3/4 expression in non-GCTs, possibly related to using nonspecific detection methods. False-positive findings undermine the applicability of OCT3/4 as a specific diagnostic tool in a clinical setting. In addition, false-positive findings could result in misinterpretation of pluripotency regulation in solid somatic cancers and their stem cells. Of the three identified isoforms - OCT4A, OCT4B and OCT4B1 - only OCT4A proved to regulate pluripotency. Up until now, no convincing nuclear OCT4A protein expression has been shown in somatic cancers or tissues. METHODS: This study investigates expression of the various OCT3/4 isoforms in GCTs (both differentiated and undifferentiated) and somatic (non-germ cell) cancers, including representative cell lines and xenografts. RESULTS: Using specific methods, OCT4A and OCT4B1 are shown to be preferentially expressed in undifferentiated GCTs. The OCT4B variant shows no difference in expression between GCTs (either differentiated or undifferentiated) and somatic cancers. In spite of the presence of OCT4A mRNA in somatic cancer-derived cell lines, no OCT3/4 protein is detected. Significant positive correlations between all isoforms of OCT3/4 were identified in both tumours with and without a known stem cell component, possibly indicating synergistic roles of these isoforms. CONCLUSION: This study confirms that OCT4A protein only appears in seminomatous GCTs, embryonal carcinoma and representative cell lines. Furthermore, it emphasises that in order to correctly assess the presence of functional OCT3/4, both isoform specific mRNA and protein detection are required. British Journal of Cancer (2011) 105, 854-863. doi: 10.1038/bjc.2011.270 www.bjcancer.com Published online 16 August 2011 (C) 2011 Cancer Research U

Magnetic Resonance Imaging-targeted Prostate Biopsy Compared with Systematic Prostate Biopsy in Biopsy-naïve Patients with Suspected Prostate Cancer

BACKGROUND: It remains uncertain whether transrectal ultrasound (TRUS)-guided systematic biopsies can be omitted and rely solely on multiparametric magnetic resonance imaging–targeted biopsies (MRI-TBx) in biopsy-naïve men suspected of prostate cancer (PCa). OBJECTIVE: To compare PCa detection in biopsy-naïve men between systematic biopsy and MRI-TBx. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted in a Dutch teaching hospital. Consecutive patients with suspected PCa, no history of biopsy, and no clinical suspicion of metastasis underwent both TRUS-guided systematic biopsies and MRI-TBx by multiparametric magnetic resonance imaging (mpMRI)-ultrasound fusion, including sham biopsies in case of negative mpMRI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinically significant PCa (csPCa), defined as group ≥2 on the International Society of Urological Pathology grading, was detected. RESULTS AND LIMITATIONS: The overall prevalence of csPCa, irrespective of biopsy technique, was 37.4% (132/353) in our population. MRI-TBx were performed in 263/353 (74.5%) patients with suspicious mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥3). The detection rates for csPCa were 39.5% for MRI-TBx and 42.9% for systematic biopsies. The added values, defined as the additional percentages of patients with csPCa detected by adding one biopsy technique, were 8.7% for the systematic biopsies and 5.3% for MRI-TBx. In patients with nonsuspicious mpMRI, five cases (6%) of csPCa were found by systematic biopsies. CONCLUSIONS: This study in biopsy-naïve patients suspected for PCa showed that systematic biopsies have added value to MRI-TBx alone in patients with mpMRI PI-RADS >2. PATIENT SUMMARY: We studied magnetic resonance imaging (MRI)-guided prostate biopsy for diagnosing prostate cancer and compared it with the standard method of prostate biopsy. Standard systematic biopsies cannot be omitted in patients with suspicious MRI, as they add to the detection of significant prostate cancer

Genome-wide Investigation of multifocal and unifocal prostate cancer-are they Genetically different?

Prostate cancer is widely observed to be biologically heterogeneous. Its heterogeneity is manifested histologically as multifocal prostate cancer, which is observed more frequently than unifocal prostate cancer. The clinical and prognostic significance of either focal cancer type is not fu

Tissue proteomics outlines AGR2 AND LOX5 as markers for biochemical recurrence of prostate cancer

Although many patients are cured from prostate cancer (PCa) by surgery only, there are still patients who will experience rising prostate-specific antigen (PSA) levels after surgery, a condition known as biochemical recurrence (BCR). Novel protein prognostic markers in PCa tissue might enable finding better treatment for those patients experiencing BCR with a high chance of metastasis. In this study, we aimed to identify altered proteins in prostate cancer tissue, and to evaluate their potential role as prognostic markers. We used two proteomics strategies to analyse 34 prostate tumours (PCa) and 33 normal adjacent prostate (NAP) tissues. An independent cohort of 481 samples was used to evaluate the expression of three proteins: AGR2, FASN and LOX5 as prognostic markers of the disease. Tissue microarray immunohistochemical staining indicated that a low percentage of positive tumour cells for AGR2 (HR (95% CI) = 0.61 (0.43-0.93)), and a low percentage of positive tumour cells for LOX5 expression (HR (95% CI) = 2.53 (1.23-5.22)) are predictors of BCR after RP. In contrast, FASN expression had no prognostic value for PCa

Microcystic stromal tumour of testis

Within the group of gonadal sex cord-stromal tumours, microcystic stromal tumour (MCST) is a rare entity. In the literature, most case series and reviews discussed MCST arising in the ovary, only one case-report concerned a testicular MCST. We present a Caucasian man in his late 30s, who presented with an MCST in his right testis. The tumour was encapsulated and composed of vaguely lobulated cellular nodules and cystic spaces with bland spindle cells and hyalinised fibrous stroma. By immunohistochemistry, the tumour cells expressed cluster designation 10, androgen receptor, steroidogenic factor-1 and nuclear beta-catenine, and there was focal nuclear expression of cyclin D1. Molecular diagnostics confirmed the presence of an exon 3 mutation (c.98C>T) in the CTNNB1 gene. These features are similar to MSCT described in the ovary. Clinical follow-up (more than 1 year) was uneventful.Although the clinical and radiological presentation was that of a possible malignant testicular lesion, this entity is benign