Prognostic Impact of a 12-gene Progression Score in Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study

Dyrskjøt, Lars; Reinert, Thomas; Algaba, Ferrán; Christensen, Emil; Nieboer, Daan; Hermann, Gregers G.; Mogensen, Karin; Beukers, Willemien; Márquez, Mirari; Segersten, Ulrika; Høyer, Søren; Ulhøi, Benedicte Parm; Hartmann, Arndt; Stöhr, Robert; Wach, Sven; Nawroth, Roman; Schwamborn, Kristina; Tulić, C.; Simić, Tatjana; Junker, Kerstin; Harving, Niels; Petersen, Astrid; Jensen, Jørgen Bjerggaard; Keck, Bastian; Grimm, Marc‐Oliver; Horstmann, Marcus; Maurer, Tobias; Steyerberg, Ewout W.; Zwarthoff, Ellen C.; Real, Francisco X.; Malats, Núria; Malmström, Per‐Uno; Ørntoft, Torben F.

doi:10.1016/j.eururo.2017.05.040

Cited by 84 publications

(74 citation statements)

References 30 publications

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“…This is in accordance with the high spearman correlation between FOXM1 and MKI67 of the UROMOL, Chungbuk and Lund cohorts (Spearman coefficient: 0.88 / 0.86 / 0.77, respectively, p < 0.001). The 12-gene risk score developed for predicting progression (Dyrskjøt et al 2017) positively correlated with the FOXM1 expression ( p < 0.001, Fig. 1a).…”

Section: Resultsmentioning

confidence: 93%

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

Rinaldetti

Wirtz²,

Worst

et al. 2018

J Cancer Res Clin Oncol

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PurposeThe proto-oncogene forkhead box M1 (FOXM1) is associated with poor survival in many cancers. The impact of FOXM1 expression on progression-free survival (PFS) of non-muscle invasive bladder cancer (NMIBC) has not yet been investigated. The differential expression of FOXM1 between the different molecular NMIBC subtypes has further been assessed.MethodsTranscript levels of FOXM1 and MKI67 were determined in 460 NMIBC patients (UROMOL cohort) by RNA-Seq and validated in silico by the Chungbuk and Lund cohort (n = 277). FOXM1 and MKI67 cutoffs were identified by the minimal p value method. Variables were evaluated by multivariable Cox regression analyses in order to identify independent predictors.ResultsFOXM1 is an independent predictor for PFS superior to current histological, clinical and molecular staging methods. Patients with high FOXM1 expression have a 6- to 8-fold higher risk of progression in multivariable analysis (p < 0.03). Highest transcript levels were found in the Class 2 and genomically unstable molecular NMIBC subtype (p < 0.03). The proto-oncogene further positively correlated with tumor grade and stage. NMIBCs with high FOXM1 expression showed a PFS advantage when treated with intravesical BCG instillation.ConclusionFOXM1 is a highly prognostic marker for disease progression of NMIBC superior to current histological, clinical and molecular staging methods and MKI67. It is mainly expressed in the Class 2 and genomically unstable molecular bladder cancer subtypes. Its role in drug resistance development makes FOXM1 valuable biomarker for NMIBC risk stratification.

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Section: Resultsmentioning

confidence: 93%

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

Rinaldetti

Wirtz²,

Worst

et al. 2018

J Cancer Res Clin Oncol

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“…Among the differentially expressed proteins in each case (ranging from 370 to 520 proteins), multiple previously described BC subtype markers were found. As shown in Figure 1b, some basal and cancer stem cell markers, 3,5,8,28 including MSN, COL18A1, RPSA, ALDH1A1, TGM2 and BAX were of higher abundance in NPS1 and NPS2, with the basal-layer antigen CD47 29 being overrepresented in NPS1. Molecules that guide cell adhesion during wound healing (FN1, VTN) 30,31 and several lamina propria laminins, were found upregulated in NPS1 and NPS2.…”

Section: Segregation Of the Existing Subtype Markers To The Proteome-mentioning

confidence: 94%

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Stroggilos

Mokou

Latosinska

et al. 2019

Intl Journal of Cancer

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DNA/RNA‐based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high‐resolution proteomics analysis by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype‐specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low‐risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross‐omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

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“…High‐risk NMIBC patients are treated with intravesical Bacillus Calmette‐Guerin (BCG) or even radical cystectomy (RC). Predictors of increased risk include pathological stage T1, high pathological grade, molecular risk scores and an aggressive, Genomically Unstable or Basal/Squamous, molecular subtype . Recurrent as well as progressive disease has also been studied longitudinally in clinical and molecular studies .…”

Section: Introductionmentioning

confidence: 99%

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

Sjödahl

Eriksson

Patschan

et al. 2019

Intl Journal of Cancer

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Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient‐derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression patterns at regions harboring frequent copy number alterations. We show that early driver mutations were largely preserved in UBC recurrences. Changes in FGFR3, PIK3CA or TERT mutation status were not linked to changes in molecular subtype and aggressive behavior. Instead, changes into a more aggressive molecular subtype seem to be associated with p53 alterations. We analyze changes in gene expression from primary tumors, to recurrences and progression tumors, and identify two modes of progression: Patients for whom progression is preceded by or coincides with a radical subtype shift, and patients who progress without any systematic molecular changes. For the latter group of patients, progression may be either stochastic or depending on factors already present at primary tumor initiation.

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Prognostic Impact of a 12-gene Progression Score in Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study

Cited by 84 publications

References 30 publications

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

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