TY - JOUR
T1 - Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed
AU - Sommer, Breann C.
AU - Dhawan, Deepika
AU - Ruple, Audrey
AU - Ramos-Vara, José A.
AU - Hahn, Noah M.
AU - Utturkar, Sagar M.
AU - Ostrander, Elaine A.
AU - Parker, Heidi G.
AU - Fulkerson, Christopher M.
AU - Childress, Michael O.
AU - Fourez, Lindsey M.
AU - Enstrom, Alexander W.
AU - Knapp, Deborah W.
N1 - Funding Information:
Breann C. Sommer, Deepika Dhawan, Audrey Ruple, José A. Ramos-Vara, Sagar M. Utturkar, Elaine A Ostrander, Heidi G. Parker, Christopher M. Fulkerson, Michael O. Childress, Lindsey M. Fourez, Alexander W. Enstrom, and Deborah W. Knapp have nothing to disclose. Dr. Hahn reports personal fees and non-financial support from Genen-tech, personal fees and non-financial support from Merck, non-financial support from BMS, personal fees and non-financial support from Seattle Genetics, personal fees and non-financial support from Incyte, non-financial support from Inovio, personal fees and non-financial support from Janssen, personal fees and non-financial support from Pieris, personal fees from Boehringer Ingelheim, personal fees from Glaxo Smith Kline, personal fees from Bladder Cancer Academy, personal fees from Ferring, nonfinancial support from AstraZeneca, non-financial support from HTG Molecular, personal fees from Pfizer, outside the submitted work.
Publisher Copyright:
© 2021 - IOS Press. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Muscle invasive bladder cancer
KW - RNA-seq
KW - T-cell-inflamed
KW - animal model
KW - breed
KW - subtype
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U2 - 10.3233/BLC-201523
DO - 10.3233/BLC-201523
M3 - Article
AN - SCOPUS:85114475628
VL - 7
SP - 317
EP - 333
JO - Bladder Cancer
JF - Bladder Cancer
SN - 2352-3727
IS - 3
ER -