When the Molecular Subtype Is Hidden Behind a Veil of Stroma

Sjödahl, Gottfrid; Höglund, Mattias; Eriksson, Pontus

doi:10.1016/j.eururo.2021.04.014

Cited by 5 publications

(3 citation statements)

References 7 publications

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“…Each line, is the regression line assessed in the correlation test performed by subtypes and they are colored by them. stroma-rich due to chance or sampling at the tumor margin (40). Hence, it is necessary be careful in conclusions about this subtype.…”

Section: A B Cmentioning

confidence: 99%

Characterization of the tumor-infiltrating immune repertoire in muscle invasive bladder cancer

Benítez

Yu²,

Sirota³

et al. 2023

Front. Immunol.

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IntroductionMuscle-invasive bladder cancer (MIBC) is a heterogeneous disease with several taxonomic molecular subtypes showing different genetic, clinical, and epidemiological profiles. It has been suggested that MIBC-subtypes follow different tumorigenesis pathways playing decisive roles at different stages of tumor development, resulting in distinct tumor microenvironment containing both innate and adaptive immune cells (T and B lymphocytes). We aim to characterize the MIBC tumor microenvironment by analyzing the tumor-infiltrating B and T cell repertoire according to the taxonomic molecular subtypes.MethodsRNAseq data from 396 MIBC samples included in TCGA were considered. The subtype information was collected from the international consensus taxonomic classification describing six subtypes: Basal/Squamous-like (Ba/Sq), Luminal papillary (LumP), Luminal non-Specify (LumNS), Luminal unstable (LumU), Stroma-rich, and Neuroendocrine-like (NE-like). Using MiXCR, we mapped the RNA read sequences to their respective B-cell receptor (BCR) and T-cell receptor (TCR) clonotypes. To evaluate the BCR and TCR differences among subtypes, we compared diversity measures (richness and diversity) using a Wilcoxon test and we performed a network analysis to characterize the clonal expansion. For the survival analysis stratified by subtypes, Cox regression models adjusted for age, region, and pathological stage were performed.ResultsOverall, we found different patterns of tumor-infiltrating immune repertoire among the different MIBC subtypes. Stroma-rich and Ba/Sq tumors showed the highest BCR and TCR infiltration while LumP showed the lowest. In addition, we observed that the Ba/Sq and Stroma-rich tumors were more clonally expanded than the Luminal subtypes. Moreover, higher TCR richness and diversity were significantly associated with better survival in the Stroma-rich and Ba/Sq subtypes.DiscussionThis study provides evidence that MIBC subtypes present differences in the tumor microenvironment, in particular, the Ba/Sq and the Stroma-rich are related with a higher tumoral-infiltrating immune repertoire, which seems to be translated into better survival. Determining the causes of the different tumoral-infiltrating immune repertoire according to the MIBC molecular subtypes will help to improve our understanding of the disease and the distinct responses to immunotherapy of MIBC.

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Section: A B Cmentioning

confidence: 99%

Characterization of the tumor-infiltrating immune repertoire in muscle invasive bladder cancer

Benítez

Yu²,

Sirota³

et al. 2023

Front. Immunol.

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“…The subtype determined from the isolated RNA might not be the only and/or predominant subtype of a tumor, which is known to be heterogenous, especially in bladder cancer [ 17 , 33 ]. Furthermore, the subtype assigned depends on the cellular components, of which the RNA is extracted and the proportion of stromal content will influence, if a tumor is called as stroma-rich or infiltrated [ 17 , 31 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Optimizing identification of consensus molecular subtypes in muscle-invasive bladder cancer: a comparison of two sequencing methods and gene sets using FFPE specimens

et al. 2023

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Background Molecular subtypes predict prognosis in muscle-invasive bladder cancer (MIBC) and are explored as predictive markers. To provide a common base for molecular subtyping and facilitate clinical applications, a consensus classification has been developed. However, methods to determine consensus molecular subtypes require validation, particularly when FFPE specimens are used. Here, we aimed to evaluate two gene expression analysis methods on FFPE samples and to compare reduced gene sets to classify tumors into molecular subtypes. Methods RNA was isolated from FFPE blocks of 15 MIBC patients. Massive analysis of 3’ cDNA ends (MACE) and the HTG transcriptome panel (HTP) were used to retrieve gene expression. We used normalized, log2-transformed data to call consensus and TCGA subtypes with the consensusMIBC package for R using all available genes, a 68-gene panel (ESSEN1), and a 48-gene panel (ESSEN2). Results Fifteen MACE-samples and 14 HTP-samples were available for molecular subtyping. The 14 samples were classified as Ba/Sq in 7 (50%), LumP in 2 (14.3%), LumU in 1 (7.1%), LumNS in 1 (7.1%), stroma-rich in 2 (14.3%) and NE-like in 1 (7.1%) case based on MACE- or HTP-derived transcriptome data. Consensus subtypes were concordant in 71% (10/14) of cases when comparing MACE with HTP data. Four cases with aberrant subtypes had a stroma-rich molecular subtype with either method. The overlap of the molecular consensus subtypes with the reduced ESSEN1 and ESSEN2 panels were 86% and 100%, respectively, with HTP data and 86% with MACE data. Conclusion Determination of consensus molecular subtypes of MIBC from FFPE samples is feasible using various RNA sequencing methods. Inconsistent classification mainly involves the stroma-rich molecular subtype, which may be the consequence of sample heterogeneity with (stroma)-cell sampling bias and highlights the limitations of bulk RNA-based subclassification. Classification is still reliable when analysis is reduced to selected genes.

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“…Each line, is the regression line assessed in the correlation test performed by subtypes and they are colored by them. stroma-rich due to chance or sampling at the tumor margin (40). Hence, it is necessary to be careful in drawing conclusions about this subtype.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the tumor-infiltrating immune repertoire in Muscle Invasive Bladder Cancer

Dorta¹,

Yu²,

Sirota³

et al. 2021

European Urology

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When the Molecular Subtype Is Hidden Behind a Veil of Stroma

Cited by 5 publications

References 7 publications

Characterization of the tumor-infiltrating immune repertoire in muscle invasive bladder cancer

Characterization of the tumor-infiltrating immune repertoire in muscle invasive bladder cancer

Optimizing identification of consensus molecular subtypes in muscle-invasive bladder cancer: a comparison of two sequencing methods and gene sets using FFPE specimens

Characterization of the tumor-infiltrating immune repertoire in Muscle Invasive Bladder Cancer

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