Predicting outcomes in non-muscle invasive (Ta/T1) bladder cancer: the role of molecular grade based on luminal/basal phenotype

Rebola, Jorge; Aguiar, Pedro; Blanca, Ana; Montironi, Rodolfo; Cimadamore, Alessia; Cheng, Liang; Henriques, Vanessa; Lobato-Faria, Paula; López-Beltrán, Antonio

doi:10.1007/s00428-019-02593-x

Cited by 41 publications

(41 citation statements)

References 42 publications

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“…Several biologic characteristics shared in both the K20-only group and the K20-only_Lund group underscore the high-risk characteristics of NMIBC with a luminal phenotype, concurring other studies where aggressive subtypes of NMIBC have high K20 and low K5/6 expression [ 5 , 6 , 11 , 17 ]. High levels of genes related to cell proliferation and DNA repair have been commonly found in high-risk subtypes of early urothelial carcinoma [ 6 , 7 , 13 , 21 ].…”

Section: Discussionsupporting

confidence: 85%

“…On the contrary, early cell cycle genes were mostly enriched in low-risk transcriptional subtypes of NMIBC in previous studies [ 6 , 7 ]. Considering that there are architectural and grade disparities between our study (papillary high-grade) and previous studies (various growth patterns and grades) and that basal/luminal proteins might be expressed discretely by tumor grade [ 6 , 7 , 11 ], we speculate that regulation of the tumor cell cycle might be affected by different pathological traits. In addition, enrichment of the ERBB2 signature and relative overexpression of IHC staining for HER2 in the K20-only group coincides with the “HER2-like” subtype, another major high-risk subset of NMIBC, which suggests that HER2 blockade could be explored as a treatment option for K20-only group tumors [ 21 ].…”

Section: Discussionmentioning

confidence: 54%

“…A pan-FGFR inhibitor, erdafitinib, displayed a meaningful tumor response rate in patients with urothelial carcinoma, indicating that it could be especially beneficial to those with FGFR3 -activated tumors, suggesting a promising targetable axis of the double-high group [ 21 , 26 ]. In addition, previous studies showed that K5/6 and K20 dual positivity marked well-differentiated tumors that maintained tissue architectural hierarchy, which was demonstrated to be a favorable prognostic factor for early urothelial carcinoma [ 11 , 12 , 13 ]. We also found that upregulated genes in the double-high group, consistent with Lindgren’s cluster 1, were involved in numerous themes of protein synthesis and metabolism [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…The aggressiveness of luminal-like NMIBC is known to stem from the enrichment of the cell cycle, changes in junctional complexes, or high copy number alteration [ 6 , 7 , 8 ]. K5/6 and K20 have been widely used as surrogate markers of intrinsic subtypes of NMIBC, and their expression is significantly associated with the clinical outcomes of NMIBC [ 9 , 10 , 11 ]. In addition, it was demonstrated that immunohistochemical (IHC) expression of K5/6 and K20 was associated with the molecular biology of non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC), including proliferation, cell adhesion, and the mitogen-activated protein kinase (MAPK) pathway [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression

Jung

Jang

Kim

et al. 2020

IJMS

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Non-muscle-invasive bladder cancer (NMIBC) consists of transcriptional subtypes that are distinguishable from those of muscle-invasive cancer. We aimed to identify genetic signatures of NMIBC related to basal (K5/6) and luminal (K20) keratin expression. Based on immunohistochemical staining, papillary high-grade NMIBC was classified into K5/6-only (K5/6High-K20Low), K20-only (K5/6Low-K20High), double-high (K5/6High-K20High), and double-low (K5/6Low-K20Low) groups (n = 4 per group). Differentially expressed genes identified between each group using RNA sequencing were subjected to functional enrichment analyses. A public dataset was used for validation. Machine learning algorithms were implemented to predict our samples against UROMOL subtypes. Transcriptional investigation demonstrated that the K20-only group was enriched in the cell cycle, proliferation, and progression gene sets, and this result was also observed in the public dataset. The K5/6-only group was closely regulated by basal-type gene sets and showed activated invasive or adhesive functions. The double-high group was enriched in cell cycle arrest, macromolecule biosynthesis, and FGFR3 signaling. The double-low group moderately expressed genes related to cell cycle and macromolecule biosynthesis. All K20-only group tumors were classified as UROMOL “class 2” by the machine learning algorithms. K5/6 and K20 expression levels indicate the transcriptional subtypes of NMIBC. The K5/6Low-K20High expression is a marker of high-risk NMIBC.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression

Jung

Jang

Kim

et al. 2020

IJMS

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“…Far less is known about the impact of these molecular subtypes in NMIBC patients. In contrast to MIBC, first data in NMIBC and non-muscle-invasive urothelial cancer of the upper urinary tract indicate that especially luminal-like tumors are associated with an unfavorable outcome [12,13,[28][29][30]. The use of a minimal set of immunohistochemical markers (including KRT20 and KRT5/6) has been demonstrated to be a feasible and reliable approach to reflect intrinsic molecular subtypes (at least) in MIBC samples [11].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity of surrogate molecular subtypes in urothelial carcinoma in situ of the urinary bladder: implications for prognostic stratification of high-risk non-muscle-invasive bladder cancer

et al. 2021

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Reliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213–231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation.

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

Jackson

Chen

Hardy

et al. 2021

The Journal of Pathology CR

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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 À /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.

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Predicting outcomes in non-muscle invasive (Ta/T1) bladder cancer: the role of molecular grade based on luminal/basal phenotype

Cited by 41 publications

References 42 publications

Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression

Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression

Intratumoral heterogeneity of surrogate molecular subtypes in urothelial carcinoma in situ of the urinary bladder: implications for prognostic stratification of high-risk non-muscle-invasive bladder cancer

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

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