Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling

Robinson, Brian D.; Vlachostergios, Panagiotis J.; Bhinder, Bhavneet; Liu, Weisi; Li, Kailyn; Moss, Tyler J.; Bareja, Rohan; Park, Kyung; Tavassoli, Peyman; Cyrta, Joanna; Tagawa, Scott T.; Nanus, David M.; Beltran, Himisha; Molina, Ana M.; Khani, Francesca; Mosquera, Juan Miguel; Xylinas, Évanguelos; Shariat, Shahrokh F.; Scherr, Douglas S.; Rubin, Mark A.; Lerner, Seth P.; Matin, Surena F.; Elemento, Olivier; Faltas, Bishoy

doi:10.1038/s41467-019-10873-y

Cited by 168 publications

(188 citation statements)

References 47 publications

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“…1b) 16 . These data are consistent with those of Robinson et al 5 and suggest that the luminal-papillary sub-type is enriched in UTUC as compared to bladder cancer where only 24% of tumors were luminal-papillary sub-type 16 .…”

Section: Discussionsupporting

confidence: 92%

“…Recent genomic analyses of UTUC [2][3][4][5] have identified a high incidence of potentially actionable genomic alterations including recurrent activating mutations in receptor tyrosine kinases (FGFR3, ERBB2), HRAS, PIK3CA and TSC1. These molecular profiling studies have also, however, identified significant genetic diversity among UTUC patients and a large number of genomic variants of unknown significance 6,7 .…”

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confidence: 99%

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

Kim

Audenet

et al. 2020

Nat Commun

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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 diseasespecific 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.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

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

Kim

Audenet

et al. 2020

Nat Commun

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“…We identi ed FGFRs gene alteration in 26.85% of UC patients, which was close to the corresponding ratio in the TCGA database [4]. Though may have an increased sensitivity to FGFR inhibitor, UC patients with FGFRs alterations may have a lower response rate to the ICIs therapy because of the suppressed in ltration of tumor immune cells in the tumor environment [11,12]. Meanwhile, alterations in ERBB pathway, especially in ERBB2, raised increasing interest in UC recently, as 12.4% and 11% UCB patients had ERBB2 overexpressing (as tested by HER2 immunohistochemistry (IHC) staining) and mutations, respectively [13].…”

Section: Discussionsupporting

confidence: 54%

Genomic Profiling of Chinese Urothelial Carcinoma Patients

Yang

Zhao

Wang³

et al. 2020

Preprint

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Background Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we studied the genomic features in Chinese UC patients, and investigated the concordance of genetic alterations between serum circulating tumor free DNA (ctDNA) and matched tumor tissue. Methods A total of 112 UC patients were enrolled, and 31 of which were upper tract UC (UTUC) and 81 were UC of bladder (UCB), respectively. Utilizing target next-generation sequencing, we analyzed genomic alterations of 92 selected genes. Results 94.64%, 86.61% and 62.50% of patients in our cohort were identified as having valid, oncogenic or actionable somatic alterations, respectively, and the most altered genes were TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) were more altered in UTUC than in UCB in our cohort. Comparisons of somatic alterations of UCB and UTUC between our cohort and western cohorts revealed significant differences in gene prevalence. Notably, 28.57%, 17.86% and 47.32% of cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of patients carried non-benign germline variants, but only two (1.79%) were pathogenic. By comparison of ctDNA and matched tumor tissue, the overall concordance for genomic alterations was 42.97% (0-100%). 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 25.58% of which were oncogenic. Conclusions We found a unique genomic feature of Chinese UC patients. A good concordance of genomic features between ctDNA and tissue samples were identified.

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“…The poorer outcomes of this cohort of patients speak to an unmet need for unique, upper tract-specific therapeutic strategies with good scientific rationale. Robinson et al undertook comprehensive genomic and transcriptomic analysis of 37 upper tract urothelial primary tumours in an attempt to define their key biological differences from urothelial carcinoma of the bladder 12. Among the discoveries made were upregulation of FGFR3 , a T-cell-depleted immune milieu, and a luminal-papillary signature in the majority of tumours 12.…”

Section: Molecularly Matched Treatment: Targeting Driver Mutationsmentioning

confidence: 99%

Precision oncology in urothelial cancer

Liow

2020

ESMO Open

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Genomics-driven, precision medicine has been adopted in virtually every tumour type and underlies the significant advances in cancer management to date. The paradigm shift from the indiscriminate use of chemotherapeutics, to strategies that harness our mechanistic knowledge of cancer biology has led to profound clinical benefit for patients, and will continue to mould present and future treatment approaches. In the realm of urothelial cancer, the present status of precision medicine includes a rich landscape that encompasses molecularly-matched therapy, predictive biomarkers that could help inform response to chemotherapy and immunotherapy, as well as novel strategies such as antibody drug conjugates that exploit the use of target proteins for enhanced tumour killing. Here, we present an overview on these clinically-impactful discoveries in urothelial cancer, discuss the limitations and challenges in the implementation of precision oncology, and offer our vision for its future.

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Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling

Cited by 168 publications

References 47 publications

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

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

Genomic Profiling of Chinese Urothelial Carcinoma Patients

Precision oncology in urothelial cancer

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