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Diagnostic and prognostic implications of a three-antibody molecular subtyping algorithm for non-muscle invasive bladder cancer.

ABSTRACT: Intrinsic molecular subtypes may explain marked variation between bladder cancer patients in prognosis and response to therapy. Complex testing algorithms and little attention to more prevalent, early-stage (non-muscle invasive) bladder cancers (NMIBCs) have hindered implementation of subtyping in clinical practice. Here, using a three-antibody immunohistochemistry (IHC) algorithm, we identify the diagnostic and prognostic associations of well-validated proteomic features of basal and luminal subtypes in NMIBC. By IHC, we divided 481 NMIBCs into basal (GATA3^- /KRT5⁺ ) and luminal (GATA3⁺ /KRT5 variable) subtypes. We further divided the luminal subtype into URO (p16 low), URO-KRT5⁺ (KRT5⁺ ), and genomically unstable (GU) (p16 high) subtypes. Expression thresholds were confirmed using unsupervised hierarchical clustering. Subtypes were correlated with pathology and outcomes. All NMIBC cases clustered into the basal/squamous (basal) or one of the three luminal (URO, URO-KRT5⁺ , and GU) subtypes. Although uncommon in this NMIBC cohort, basal tumors (3%, n = 16) had dramatically higher grade (100%, n = 16, odds ratio [OR] = 13, relative risk = 3.25) and stage, and rapid progression to muscle invasion (median progression-free survival = 35.4 months, p = 0.0001). URO, the most common subtype (46%, n = 220), showed rapid recurrence (median recurrence-free survival [RFS] = 11.5 months, p = 0.039) compared to its GU counterpart (29%, n = 137, median RFS = 16.9 months), even in patients who received intravesical immunotherapy (p = 0.049). URO-KRT5⁺ tumors (22%, n = 108) were typically low grade (66%, n = 71, OR = 3.7) and recurred slowly (median RFS = 38.7 months). Therefore, a simple immunohistochemical algorithm can identify clinically relevant molecular subtypes of NMIBC. In routine clinical practice, this three-antibody algorithm may help clarify diagnostic dilemmas and optimize surveillance and treatment strategies for patients.

SUBMITTER: Jackson CL

PROVIDER: S-EPMC8822375 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Diagnostic and prognostic implications of a three-antibody molecular subtyping algorithm for non-muscle invasive bladder cancer.

Jackson Chelsea L CL Chen Lina L Hardy Céline Sc CS Ren Kevin Ym KY Visram Kash K Bratti Vanessa F VF Johnstone Jeannette J Sjödahl Gottfrid G Siemens David Robert DR Gooding Robert J RJ Berman David M DM

The journal of pathology. Clinical research 20211026 2

Intrinsic molecular subtypes may explain marked variation between bladder cancer patients in prognosis and response to therapy. Complex testing algorithms and little attention to more prevalent, early-stage (non-muscle invasive) bladder cancers (NMIBCs) have hindered implementation of subtyping in clinical practice. Here, using a three-antibody immunohistochemistry (IHC) algorithm, we identify the diagnostic and prognostic associations of well-validated proteomic features of basal and luminal su ...[more]

PMID: 34697907

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Project description:PurposeRecently discovered molecular classifications for urothelial bladder cancer appeared to be promising prognostic and predictive biomarkers. The present study was conducted to evaluate the prognostic impact of molecular subtypes assessed by two different methodologies (gene and protein expression), to compare these two approaches and to correlate molecular with histological subtypes in a consecutively collected, mono-institutional muscle-invasive bladder cancer (MIBC) cohort.Methods193 MIBC were pathologically re-evaluated and molecular subtypes were assessed on mRNA (NanoString technology, modified 21-gene-containing MDACC approach) and protein levels (immuno-histochemical [IHC] analysis of CK5, CK14, CD44, CK20, GATA3 and FOXA1). Descriptive statistical methods and uni-/multi-variable survival models were employed to analyze derived data.ResultsNeither gene expression nor protein-based subtyping showed significant associations with disease-specific (DSS) or recurrence-free survival (RFS). Agreement between mRNA (reference) and protein-based subtyping amounted 68.6% for basal, 76.1% for luminal and 50.0% for double-negative tumors. Histological subtypes associated with RFS in uni-variable (P = 0.03), but not in multivariable survival analyses. Tumors with variant histology predominantly showed luminal subtypes (gene expression subtyping: 36/55 cases, 65.5%; protein subtyping: 44/55 cases, 80.0%). Squamous differentiation significantly associated with basal subtypes (gene expression subtyping: 44/45 squamous cases, 97.8%; protein subtyping: 36/45 cases, 80.0%).ConclusionIn our consecutive cystectomy cohort, neither gene, protein expression-based subtyping, nor histological subtypes associated with DSS or RFS in multi-variably adjusted survival analyses. Application of a limited IHC subtyping marker panel showed high concordance of 83.9% with gene expression-based subtyping, thus underlining the utility for subtyping in pathological routine diagnostics. In addition, histological MIBC subtypes are strong indicators for intrinsic subtypes.

Project description:BackgroundBladder cancer is one of the most lethal malignancy in urological system, and 20-25% of bladder cancer patients are muscle invasive with unfavorable prognosis. However, the role of alternative splicing (AS) in muscle-invasive bladder cancer (MIBC) remains to be elucidated.MethodsPercent spliced in (PSI) data obtained from the Cancer Genome Atlas (TCGA) SpliceSeq database (n = 394) were utilized to evaluate the AS events in MIBC. Prognosis-associated AS events were screened out by univariate Cox regression. LASSO Cox regression was used to identify reliable prognostic patterns in a training set and further validated in a test set. Splicing regulatory networks were constructed by correlations between PSI of AS events and RNA expression of splicing factors.ResultsAs a result, a total of 2589 prognosis-related AS events in MIBC were identified. Pathways of spliceosomal complex (FDR = 0.017), DNA-directed RNA polymerase II, core complex (FDR = 0.032), and base excision repair (FDR = 0.038) were observed to be significantly enriched. Additionally, we noticed that most of the prognosis-related AS events were favorable factors. According to the LASSO and multivariate Cox regression analyses, 15-AS-based signature was established with the area under curve (AUC) of 0.709, 0.823, and 0.857 at 1-, 3-, and 5- years, respectively. The MIBC patients were further divided into high- and low-risk groups based on median risk sores. Interestingly, we observed that the prevalence of FGFR3 with mutations and focal amplification was significantly higher in low-risk group. Functional and immune infiltration analysis suggested potential signaling pathways and distinct immune states between these two groups. Moreover, splicing correlation network displayed a regulatory mode of prognostic splicing factors (SF) in MIBC patients.ConclusionsThis study not only provided novel insights into deciphering the possible mechanism of tumorgenesis and pathogenesis but also help refine risk stratification systems and potential treatment of decision-making for MIBC.

Dataset Information

Diagnostic and prognostic implications of a three-antibody molecular subtyping algorithm for non-muscle invasive bladder cancer.

Publications

Diagnostic and prognostic implications of a three-antibody molecular subtyping algorithm for non-muscle invasive bladder cancer.

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