Dataset Information

Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed.

ABSTRACT:

Background

Improved therapies are needed for patients with invasive urothelial carcinoma (InvUC). Tailoring treatment to molecular subtypes holds promise, but requires further study, including studies in pre-clinical animal models. Naturally-occurring canine InvUC harbors luminal and basal subtypes, mimicking those observed in humans, and could offer a relevant model for the disease in people.

Objective

To further validate the canine InvUC model, clinical and tumor characteristics associated with luminal and basal subtypes in dogs were determined, with comparison to findings from humans.

Methods

RNA sequencing (RNA-seq) analyses were performed on 56 canine InvUC tissues and bladder mucosa from four normal dogs. Data were aligned to CanFam 3.1, and differentially expressed genes identified. Data were interrogated with panels of genes defining luminal and basal subtypes, immune signatures, and other tumor features. Subject and tumor characteristics, and outcome data were obtained from medical records.

Results

Twenty-nine tumors were classified as luminal and 27 tumors as basal subtype. Basal tumors were strongly associated with immune infiltration (OR 52.22, 95%CI 4.68-582.38, P = 0.001) and cancer progression signatures in RNA-seq analyses, more advanced clinical stage, and earlier onset of distant metastases in exploratory analyses (P = 0.0113). Luminal tumors were strongly associated with breeds at high risk for InvUC (OR 0.06, 95%CI 0.01 -0.37, P = 0.002), non-immune infiltrative signatures, and less advanced clinical stage.

Conclusions

Dogs with InvUC could provide a valuable model for testing new treatment strategies in the context of molecular subtype and immune status, and the search for germline variants impacting InvUC onset and subtype.

SUBMITTER: Sommer BC

PROVIDER: S-EPMC11181872 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed.

Sommer Breann C BC Dhawan Deepika D Ruple Audrey A Ramos-Vara José A JA Hahn Noah M NM Utturkar Sagar M SM Ostrander Elaine A EA Parker Heidi G HG Fulkerson Christopher M CM Childress Michael O MO Fourez Lindsey M LM Enstrom Alexander W AW Knapp Deborah W DW

Bladder cancer (Amsterdam, Netherlands) 20210831 3

<h4>Background</h4>Improved therapies are needed for patients with invasive urothelial carcinoma (InvUC). Tailoring treatment to molecular subtypes holds promise, but requires further study, including studies in pre-clinical animal models. Naturally-occurring canine InvUC harbors luminal and basal subtypes, mimicking those observed in humans, and could offer a relevant model for the disease in people.<h4>Objective</h4>To further validate the canine InvUC model, clinical and tumor characteristics ...[more]

PMID: 38993617

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Project description:There is growing evidence that molecular subtypes (e.g. luminal and basal subtypes) affect the prognosis and treatment response in patients with muscle invasive urinary bladder cancer (invasive urothelial carcinoma, iUC). Modeling these subtypes in pre-clinical animal studies is essential, but it is challenging to produce these subtypes, along with other critical host and tumor features, in experimentally-induced animal models. This study was conducted to determine if luminal and basal molecular subtypes are present in naturally-occurring canine iUC, a cancer that mimics the human condition in other key aspects. RNA sequencing was performed on 29 canine treatment naive iUC tissue samples and on four normal canine bladder mucosal samples. Data were aligned to CanFam 3.1, and differentially expressed genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups (n = 13, n = 16). When genes that distinguish basal and luminal subtypes in human cancer (n = 2015) were used to probe genes differentially expressed between normal canine bladder and iUC, 829 enriched signature genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups comprised of 18 luminal subtype tumors and 11 basal subtype tumors. The enriched genes included MMP9, SERPINE2, CAV1, KRT14, and RASA3 in basal tumors, and PPARG, LY6E, CTSE, CDK3, and TBX2 in luminal tumors. In supervised clustering, additional genes of importance in human iUC were identified in canine iUC associated with claudin-low and infiltrated tumors. A smaller panel of genes (n = 60) was identified that distinguished canine luminal and basal iUC with overall 93.1% accuracy. Immune signature patterns similar to those in human iUC were also identified with the greatest enrichment of immune genes being in the basal subtype tumors. These findings provide additional compelling evidence that naturally-occurring canine iUC is a highly relevant and much needed model of human iUC for translational research.

Dataset Information

Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed.

Background

Objective

Methods

Results

Conclusions

Publications

Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed.

Similar Datasets

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