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Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

ABSTRACT: Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

SUBMITTER: Kim K

PROVIDER: S-EPMC7181640 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Kim Kwanghee K Hu Wenhuo W Audenet François F Almassi Nima N Hanrahan Aphrothiti J AJ Murray Katie K Bagrodia Aditya A Wong Nathan N Clinton Timothy N TN Dason Shawn S Mohan Vishnu V Jebiwott Sylvia S Nagar Karan K Gao Jianjiong J Penson Alex A Hughes Chris C Gordon Benjamin B Chen Ziyu Z Dong Yiyu Y Watson Philip A PA Alvim Ricardo R Elzein Arijh A Gao Sizhi P SP Cocco Emiliano E Santin Alessandro D AD Ostrovnaya Irina I Hsieh James J JJ Sagi Irit I Pietzak Eugene J EJ Hakimi A Ari AA Rosenberg Jonathan E JE Iyer Gopa G Vargas Herbert A HA Scaltriti Maurizio M Al-Ahmadie Hikmat H Solit David B DB Coleman Jonathan A JA

Nature communications 20200424 1

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with t ...[more]

PMID: 32332851

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Project description:BackgroundDespite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.ObjectiveTo investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Design, setting, and participantsTumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.Outcome measurements and statistical analysisWe described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Results and limitationsComparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.ConclusionsHigh-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Patient summaryComparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Dataset Information

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Publications

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Similar Datasets

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