Breast cancer precursors revisited: molecular features and progression pathways

Lopez‐Garcia M A, Geyer F C, Lacroix‐Triki M, Marchió C & Reis‐Filho J S
(2010) Histopathology 57, 171–192
Breast cancer precursors revisited: molecular features and progression pathways Increasingly more coherent data on the molecular characteristics of benign breast lesions and breast cancer precursors have led to the delineation of new multistep pathways of breast cancer progression through genotypic–phenotypic correlations. It has become apparent that oestrogen receptor (ER)‐positive and ‐negative breast lesions are fundamentally distinct diseases. Within the ER‐positive group, histological grade is strongly associated with the number and complexity of genetic abnormalities in breast cancer cells. Genomic analyses of high‐grade ER‐positive breast cancers have revealed that a substantial proportion of these tumours harbour the characteristic genetic aberrations found in low‐grade ER‐positive disease, suggesting that at least a subgroup of high‐grade ER‐positive breast cancers may originate from low‐grade lesions. The ER‐negative group is more complex and heterogeneous, comprising distinct molecular entities, including basal‐like, HER2 and molecular apocrine lesions. Importantly, the type and pattern of genetic aberrations found in ER‐negative cancers differ from those of ER‐positive disease. Here, we review the available molecular data on breast cancer risk indicator and precursor lesions, the putative mechanisms of progression from in situ to invasive disease, and propose a revised model of breast cancer evolution based on the molecular characteristics of distinct subtypes of in situ and invasive breast cancers.     

Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node-positive bladder cancer

Seiler R, von Gunten M, Thalmann G N & Fleischmann A
(2011) Histopathology  58 , 571–578
Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node‐positive bladder cancer Aims: To evaluate risk factors in lymph node‐positive bladder cancer. Methods and results: Lymph node‐positive bladder cancer patients (n = 162), preoperatively staged N0M0, underwent cystectomy and standardized extended lymphadenectomy. Five‐year overall survival of the cohort was 33%. In univariate analysis, tumour stage (P < 0.006), extracapsular extension of lymph node metastases (P < 0.001), total diameter of metastases (P < 0.04) and lymph node stage (P < 0.03) were significantly correlated with overall survival (OS), disease‐specific survival (DSS) and recurrence‐free survival (RFS). On multivariate analysis, only extracapsular extension (OS, P < 0.002; DSS, P < 0.02; RFS, P = 0.058) and primary tumour stage (OS, P = 0.058; DSS, P < 0.02; RFS, P < 0.02) added independent prognostic information. Extracapsular extension of lymph node metastases did not correlate with a specific recurrence pattern; patients with organ‐confined tumours (pT1/2) never had pelvic relapse. Conclusions: Extracapsular extension of lymph node metastases but not lymph node tumour burden adds independent prognostic information in lymph node‐positive bladder cancer. These biological differences in lymph node‐positive bladder cancer are not reflected in the sixth, and challenge future, TNM classification.     

Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder

Sun C‐H, Chang Y‐H & Pan C‐C
(2011) Histopathology 58 , 1054–1063
Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder Aims: Phosphatidylinositol3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of urothelial carcinoma. However, its clinical relevance has not been substantially validated in human samples. The aim of this study was to assess the expression of the pathway in a large cohort of bladder cancers using the tissue microarray technique. Methods and results: Immunohistochemical stains for phosphatase and tensin homologue (PTEN), phosphorylated Akt, mTOR, S6 and 4E‐BP1 were performed for 887 cases, and the results were correlated with clinicopathological characteristics. The high expression of p‐S6 and p‐Akt corresponded significantly with high‐grade and advanced‐stage, while losses of PTEN and p‐4E‐BP1 were observed more often in high‐grade and high‐stage tumours. High expression of p‐Akt and p‐S6 predicted progression and cancer‐specific mortality for non‐muscle‐invasive cancers treated by transurethral resection, and p‐Akt was an independent factor in multivariate analysis. High expression of p‐mTOR and p‐Akt correlated with higher cumulative incidence of cancer‐specific mortality for muscle‐invasive cancer, and p‐mTOR was an independent prognostic factor. Conclusions: We have demonstrated the impact of PI3K/Akt/mTOR alteration on the biological behaviour of bladder tumours. Proper immunohistochemical examination of the PI3K/Akt/mTOR pathway can provide useful prognostic information, and the findings may represent an additional therapeutic avenue in the treatment of bladder cancers.     

Translational genomics: the challenge of developing cancer biomarkers

Early detection and definitive treatment of cancer have been shown to decrease death and suffering in epidemiologic and intervention studies. Application of genomic approaches to many malignancies has produced thousands of candidate biomarkers for detection and prognostication, yet very few have become established in clinical practice. Fundamental issues related to tumor heterogeneity, cancer progression, natural history, and biomarker performance have provided challenges to biomarker development. Technical issues in biomarker assay detection limits, specificity, clinical deployment, and regulation have also slowed progress. The recent emergence of biomarkers and molecular imaging strategies for treatment selection and monitoring demonstrates the promise of cancer biomarkers. Organized efforts by interdisciplinary teams will spur progress in cancer diagnostics.     

High expression of insulin receptor on tumour‐associated blood vessels in invasive bladder cancer predicts poor overall and progression‐free survival

Bladder cancer is a frequently recurring disease with a very poor prognosis once progressed to invasive stages, and tumour‐associated blood vessels play a crucial role in this process. In order to identify novel biomarkers associated with progression, we isolated blood vascular endothelial cells (BECs) from human invasive bladder cancers and matched normal bladder tissue, and found that tumour‐associated BECs greatly up‐regulated the expression of insulin receptor (INSR). High expression of INSR on BECs of invasive bladder cancers was significantly associated with shorter progression‐free and overall survival. Furthermore, increased expression of the INSR ligand IGF‐2 in invasive bladder cancers was associated with reduced overall survival. INSR may therefore represent a novel biomarker to predict cancer progression. Mechanistically, we observed pronounced hypoxia in human bladder cancer tissue, and found a positive correlation between the expression of the hypoxia marker gene GLUT1 and vascular INSR expression, indicating that hypoxia drives INSR expression in tumour‐associated blood vessels. In line with this, exposure of cultured BECs and human bladder cancer cell lines to hypoxia led to increased expression of INSR and IGF‐2, respectively, and IGF‐2 increased BEC migration through the activation of INSR in vitro. Taken together, we identified vascular INSR expression as a potential biomarker for progression in bladder cancer. Furthermore, our data suggest that IGF‐2/INSR mediated paracrine crosstalk between bladder cancer cells and endothelial cells is functionally involved in tumour angiogenesis and may thus represent a new therapeutic target. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients

Fleischmann A, Rocha C, Saxer‐Sekulic N, Zlobec I, Sauter G & Thalmann G N
(2011) Histopathology 58 , 781–789
High‐level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients Aims: To test the prognostic significance of cyclin D1 in nodal‐positive prostate cancer. Methods and results: Nuclear and cytoplasmic cyclin D1 expression was evaluated in 119 nodal‐positive prostate cancer patients undergoing radical prostatectomy and extended lymphadenectomy. Cyclin D1 was correlated with various tumour features and biochemical recurrence‐free survival (bRFS), disease‐specific survival (DSS) and overall survival (OS). In the metastases, high‐level cytoplasmic cyclin D1 expression independently predicted poor outcome (5‐year bRFS, 12.5% versus 26.4%, P = 0.006; 5‐year DSS, 56.3% versus 80.7%, P = 0.007; 5‐year OS, 56.3% versus 78.7%, P = 0.011). These patients had a 2.62‐fold elevated risk of dying from prostate cancer as compared with patients with low‐level cytoplasmic cyclin D1 expression (P = 0.024). All other subcellular compartments of cyclin D1 expression in primary tumours and metastases were prognostically non‐significant. Conclusions: The subcellular location of cyclin D1 expression in prostate cancer is linked to specific clinical courses. Survival stratification according to biomarker expression in metastases indicates an important role for tumour sampling from these tissues.     

Biomarker assessment and molecular testing for prognostication in breast cancer

Current treatment of breast cancer incorporates clinical, pathological and molecular data. Oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) define prognosis and identify tumours for targeted therapy, and remain the sole established single‐molecule biomarkers defining the minimum breast cancer pathology data set. Ki67 remains one of the most promising yet controversial biomarkers in breast cancer, implemented routinely in some, but not all, pathology departments. Beyond the single‐molecule biomarkers, a host of multigene expression tests have been developed to interrogate the driver pathways and biology of individual breast cancers to predict clinical outcome more accurately. A minority of these assays have entered into clinical practice. This review focuses on the established biomarkers of ER, PR and HER2, the controversial but clinically implemented biomarker Ki67 and the currently marketed gene expression signatures.     

YKL‐40 and mast cells are associated with detrusor fibrosis in patients diagnosed with bladder pain syndrome/interstitial cystitis according to the 2008 criteria of the European Society for the Study of Interstitial Cystitis

Richter B, Roslind A, Hesse U, Nordling J, Johansen J S, Horn T & Hansen A B
(2010) Histopathology 57 , 371–383
YKL‐40 and mast cells are associated with detrusor fibrosis in patients diagnosed with bladder pain syndrome/interstitial cystitis according to the 2008 criteria of the European Society for the Study of Interstitial Cystitis Aims: Bladder pain syndrome/interstitial cystitis (BPS/IC), diagnosed according to the new 2008 criteria of the European Society for the Study of Interstitial Cystitis (ESSIC), may lead to detrusor fibrosis. In some inflammatory diseases, fibrosis is related to YKL‐40. The aims were to examine YKL‐40 antigenic expression in bladder tissue and levels in serum and urine in BPS/IC and to evaluate whether YKL‐40 could be a non‐invasive, prognostic biomarker for bladder fibrogenesis and treatment intensity. Methods and results: Immunohistochemistry, immunoelectron microscopy and enzyme‐linked immunosorbent assay (ELISA) analyses in 45 patients showed YKL‐40 expression in detrusor mast cell granules and submucosal macrophages, and elevated YKL‐40 levels in serum and urine compared to healthy individuals (median 72 versus 7 μg/l, P < 0.001). Clinicopathological parameters showed associations of detrusor fibrosis with YKL‐40‐positive cells (P = 0.001), mast cells (P = 0.014) and urine YKL‐40 (P = 0.009). Bladder capacity correlated inversely with YKL‐40‐positive cells (P < 0.001) and mast cells (P = 0.029). Treatment intensity was not associated with YKL‐40. Conclusion: Serum and urine levels of YKL‐40 may be used as non‐invasive biomarkers in BPS/IC for the evaluation of bladder fibrogenesis.     

The role of secreted frizzled-related protein 2 expression in prostate cancer

O’Hurley G, Perry A S, O’Grady A, Loftus B, Smyth P, O’Leary J J, Sheils O, Fitzpatrick J M, Hewitt S M, Lawler M & Kay E W
(2011) Histopathology  59 , 1240–1248
The role of secreted frizzled‐related protein 2 expression in prostate cancer Aims: Improved prostate cancer (PCa)‐specific biomarkers are urgently required to distinguish between indolent and aggressive disease, in order to avoid overtreatment. In this study, we investigated the prostatic tissue expression of secreted frizzled‐related protein (SFRP)‐2. Methods and results: Following immunohistochemical analysis on PCa tissue microarrays with samples from 216 patients, strong/moderate SFRP‐2 expression was observed in epithelial cells of benign prostatic hyperplasia, and negative/weak SFRP‐2 expression was observed in the majority of tumour epithelia. However, among Gleason grade 5 carcinomas, 40% showed strong/moderate SFRP‐2 expression and 60% showed negative SFRP‐2 expression in epithelial cells. Further microscopic evaluation of Gleason grade 5 tumours revealed different morphological patterns, corresponding with differential SFRP‐2 expression. The first subgroup (referred to as Type A) appeared to have a morphologically solid growth pattern, whereas the second subgroup (referred to as Type B) appeared to have a more diffuse pattern. Furthermore, 100% (4/4) of Type A patients experienced biochemical recurrence, as compared with 0% (0/6) of Type B patients. Conclusions: These results imply: (i) that there is a loss of SFRP‐2 expression from benign to malignant prostate glands; and (ii) differential SFRP‐2 expression among two possible subgroups of Gleason grade 5 tumours.     

A neural network-based biomarker association information extraction approach for cancer classification

A number of different approaches based on high-throughput data have been developed for cancer classification. However, these methods often ignore the underlying correlation between the expression levels of different biomarkers which are related to cancer. From a biological viewpoint, the modeling of these abnormal associations between biomarkers will play an important role in cancer classification. In this paper, we propose an approach based on the concept of Biomarker Association Networks (BAN) for cancer classification. The BAN is modeled as a neural network, which can capture the associations between the biomarkers by minimizing an energy function. Based on the BAN, a new cancer classification approach is developed. We validate the proposed approach on four publicly available biomarker expression datasets. The derived Biomarker Association Networks are observed to be significantly different for different cancer classes, which help reveal the underlying deviant biomarker association patterns responsible for different cancer types. Extensive comparisons show the superior performance of the BAN-based classification approach over several conventional classification methods.     

An overview of translational prostate cancer cohorts for prognostic and predictive studies

The aim of this review is to describe the characteristics of patient cohorts commonly used for translational biomarker research in prostate cancer and to outline the most prominent contemporary cohorts which serve as a source of prognostic and predictive biomarkers. A non‐systematic review of the literature was performed to identify and summarise well‐characterized translational prostate cancer cohorts that provide state‐of‐the‐art characterization of (i) primary and (ii) metastatic and castration‐resistant prostate cancer. The main advantages and features of these cohorts are a substantial number of patients, unique patient groups, comprehensive genetic characterisation of tumours using multi‐omics/next‐generation sequencing approaches, high‐quality control standards and fully or partially open data for the research community. This overview includes the contemporary cohorts which serve as a rich source of new targets for prognostic and predictive biomarkers as well as a reference database for validation of known biomarkers, therefore representing the cohorts whose impact extends over the current state of biomarker research into the near future (5–10 years).     

Androgen and oestrogen receptors as potential prognostic markers for patients with ductal carcinoma in situ treated with surgery and radiotherapy

Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has been investigated less extensively than invasive breast cancer. Women with DCIS are mainly treated with conservative surgery almost exclusively followed by radiotherapy. However, as radiation treatment is not always effective, the search for biomarkers capable of identifying DCIS lesions that could progress to invasive cancer is ongoing. Although conventional biomarkers have been thoroughly studied in invasive tumours, little is known about the role played by androgen receptor (AR), widely expressed in DCIS. A series of 42 DCIS patients treated with quadrantectomy and radiotherapy were followed for a period of up to 95 months. Of these, 11 had recurrent DCIS or progressed to invasive cancer. All tumours were analysed for clinical pathological features. Conventional biomarkers and androgen receptor expression were determined by immunohistochemistry. Our results showed that AR was higher in tumours of relapsed patients than non‐relapsed patients (P value: 0.0005). Conversely, oestrogen receptor (ER) was higher, albeit not significantly, in non‐relapsed patients than in relapsed patients. AR/ER ratio was considerably different in the two subgroups (P value: 0.0033). Area under the curve (AUC) values were 0.85 for AR and 0.80 for the AR/ER ratio. These preliminary results highlight the potentially important role of both AR and the AR/ER ratio as prognostic markers in DCIS.     

Immunophenotyping of male breast cancer

Kornegoor R, Verschuur‐Maes A H J, Buerger H, Hogenes M C, de Bruin P C, Oudejans J J, Hinrichs B & van Diest P J
(2012) Histopathology
Immunophenotyping of male breast cancer Aims: Male breast cancer is a rare disease, and knowledge of carcinogenesis is limited. Conflicting results, based on small series, have been reported for clinically relevant biomarkers. Methods and results: One hundred and thirty‐four cases of male breast cancer were immunohistochemically stained on tissue microarrays for oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, human epidermal growth factor receptor 2 (HER2), BRST2, cyclin D1, bcl‐2, p53, p16, p21, Ki67, cytokeratin (CK) 5/6, CK14, and epidermal growth factor receptor. Data were correlated with clinicopathological features and patient outcome. High mitotic count and high grade were correlated with high Ki67, HER2 amplification/overexpression, p53 accumulation, high p21 expression, low PR expression, and low bcl‐2 expression. PR negativity (P = 0.009) and p53 accumulation (P = 0.042) were correlated with decreased 5‐year survival and were independent markers for patient outcome in Cox regression. In unsupervised hierarchical clustering, four groups were identified that were correlated with distinctive clinicopathological features. The hormone negative/ER‐positive/high‐grade cluster was significantly associated with decreased survival (P = 0.011) and was an independent prognostic factor in Cox regression. Conclusions: Several tissue biomarkers are associated with an aggressive phenotype in male breast cancer. PR and p53 are the most promising individual prognostic markers. On the basis of immunophenotype, four distinctive and prognostically relevant male breast cancer groups were identified, indicating that protein expression profiling may be clinically useful in male breast cancer.     

Distinct expression pattern of claudin‐6, a primitive phenotypic tight junction molecule,in germ cell tumours and visceral carcinomas

Ushiku T, Shinozaki‐Ushiku A, Maeda D, Morita S & Fukayama M
(2012) Histopathology
Distinct expression pattern of claudin‐6, a primitive phenotypic tight junction molecule, in germ cell tumours and visceral carcinomas Aims: This study aimed to clarify claudin‐6 expression patterns in cancers. Methods and results: We surveyed claudin‐6 expression by immunohistochemistry using tissue microarray in 860 tumours, including germ cell tumours and major carcinomas. Claudin‐6 was expressed consistently in germ cell tumours (28 of 28, 100%), whereas only 64 (8%) of 832 non‐germ cell tumours demonstrated claudin‐6 expression. Further immunohistochemical study in full tissue sections demonstrated diffuse claudin‐6 staining in all seminomas (n = 14), embryonal carcinomas (n = 10), yolk sac tumours (n = 12) and mononuclear trophoblastic cells of choriocarcinomas (n = 3), and focal staining in immature epithelial components of immature teratomas (n = 6). Additionally, because alpha‐fetoprotein (AFP)‐producing gastric adenocarcinomas and pulmonary high‐grade fetal adenocarcinomas were among the claudin‐6 expressing non‐germ cell tumours in the microarray studies, we predicted that claudin‐6 may be a biomarker for them and studied additional tumours in full sections, which showed claudin‐6 expression in AFP‐producing gastric adenocarcinomas (18 of 20, 90%) and pulmonary high‐grade fetal adenocarcinomas (four of five, 80%). Only one of 11 hepatoblastomas demonstrated focal claudin‐6 staining. Conclusions: This study demonstrated that claudin‐6 is a novel diagnostic marker for primitive germ cell tumours and is also expressed frequently in some cancers with a primitive phenotype.     

Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance

Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET–PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular‐patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen‐activated protein kinase and phosphoinositide 3‐kinase–PTEN–AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance.     

Expression of transient receptor potential vanilloid-1 (TRPV1) in urothelial cancers of human bladder: relation to clinicopathological and molecular parameters

Kalogris C, Caprodossi S, Amantini C, Lambertucci F, Nabissi M, Morelli M B, Farfariello V, Filosa A, Emiliozzi M C, Mammana G & Santoni G
(2010) Histopathology 57 , 744–752
Expression of transient receptor potential vanilloid‐1 (TRPV1) in urothelial cancers of human bladder: relation to clinicopathological and molecular parameters Aims: To evaluate the expression of transient receptor potential vanilloid type‐1 channel protein (TRPV1) in normal and neoplastic urothelial tissues and to correlate TRPV1 expression with clinicopathological parameters and disease‐specific survival. Methods and results: TRPV1 expression was analysed in normal and neoplastic urothelial samples at both mRNA and protein levels by quantitative real time polymerase chain reaction (qPCR) and immunohistochemistry, respectively. TRPV1 downregulation was found in urothelial cancer (UC) specimens, which correlated with tumour progression. Moreover, TRPV1 mRNA levels were associated with clinicopathological parameters to assess the role of TRPV1 downregulation as a negative prognostic factor for survival. Kaplan–Meier survival analysis demonstrated a significantly shorter survival in patients showing TRPV1 mRNA downregulation. Multivariate Cox regression analysis indicated further that TRPV1 mRNA expression retained its significance as an independent risk factor. Conclusions: The progression of UC of human bladder is associated with a marked decrease in TRPV1 expression, with a progressive loss in high‐grade muscle invasive UC. Downregulation of TRPV1 mRNA expression may represent an independent negative prognostic factor for bladder cancer patients.     

Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling

Tzelepi V, Karlou M, Wen S, Hoang A, Logothetis C, Troncoso P & Efstathiou E
(2011) Histopathology 58, 1037–1047
Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling Aims: The hedgehog (Hh) signalling pathway has been implicated in the pathogenesis and aggressiveness of prostate cancer through epithelial–mesenchymal interactions. The aim of this study was to elucidate the cell‐type partitioned expression of the Hh pathway biomarkers in the non‐neoplastic and tumour microenvironments and to correlate it with the grade and stage of prostate cancer. Methods and results: Expression of the Hh pathway components (Shh, Smo, Ptch, Gli1) in the microenvironment of non‐neoplastic peripheral zone (n = 119), hormone‐naive primary prostate carcinoma (n = 141) and castrate‐resistant bone marrow metastases (n = 53) was analysed using immunohistochemistry in tissue microarrays and bone marrow sections. Results showed that epithelial Shh, Smo and Ptch expression was up‐regulated, whereas stromal Smo, Ptch, and Gli1 expression was down‐regulated in prostate carcinomas compared to non‐neoplastic peripheral zone tissue. Ptch expression was modulated further in high‐grade and high‐stage primary tumours and in bone marrow metastases. Hh signalling correlated with ki67 and vascular endothelial growth factor (VEGF) but not with CD31 expression. Conclusion: Our results highlight the importance of Hh‐mediated epithelial–mesenchymal interactions in the non‐neoplastic prostate and imply that shifting the balance from paracrine towards autocrine signalling is important in the pathogenesis and progression of prostate carcinoma.     

CARLo‐7—A plausible biomarker for bladder cancer

Cancer is defined as undifferentiated and unchecked growth of cells damaging the surrounding tissue. Cancers manifest altered gene expression. Gene expression is regulated by a diverse array of non‐protein‐coding RNA. Aberrant expression of long non‐coding RNAs (lncRNAs) has been recently found to have functional consequences in cancers. In the current study, we report CARLo‐7 as the only bladder cancer–specific lncRNA from the CARLos cluster. The expression of this lncRNA correlates with bladder cancer grade. We propose that CARLo‐7 has an oncogenic potential and might be regulator of cell proliferation. Furthermore, by comparison the expression of proto‐oncogene MYC, which is the only well‐annotated gene close to the cancer ‐ associated linkage disequilibrium blocks of this region, does not show a pronounced change in expression between the low‐ and high‐grade tumours. Our results indicate that CARlo‐7 can act as a prognostic marker for bladder cancer.