Urothelial CancerComprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma
Introduction
Upper tract urothelial carcinoma (UTUC) is histologically similar to urothelial bladder cancer yet several clinical, biological and molecular features are unique to UTUC, prompting the term disparate twins when considering the similarities and differences between bladder urothelial cancer and UTUC [1]. Major knowledge gaps remain in our understanding of the biology and genomic landscape of UTUC, a rare disease in Western countries but of potentially epidemic proportions in the Far East [2]. Biologically interesting features along the environmental-genetic spectrum include the strong association between known exposure to agents such as tobacco [3] and aristolochic acid [2] and genetic predisposition in patients with Lynch syndrome [4].
The Cancer Genome Atlas (TGCA) reported the mutation landscape in muscle-invasive bladder cancer, which has a high somatic mutation frequency among adult solid tumors, similar to melanoma and lung adenomas and squamous carcinomas [5]. The most common mutation was TP53, with frequent alterations in chromatin modifier genes (MLL2, ARID1A, KDM6A) [6], [7]. Four expression-based subtypes were described, and were shown to be associated with overall survival and response to immune checkpoint inhibition and potentially cisplatin-based chemotherapy [8], [9], [10].
The largest targeted genomic study of UTUC to date evaluated 300 cancer-associated genes in 83 patients using next-generation sequencing [11]. Mutations of FGFR3, CREBBP, and STAG2 were commonly found in low-grade tumors, while TP53 mutations were more common in high-grade tumors. FGFR3 mutations were observed at a similar rate in high- and low-grade tumors [6].
In this study we report the first integrated comprehensive genomic analysis of UTUC using whole exome sequencing (WES), gene expression profiling, and protein expression analysis to further characterize the genomic landscape of UTUC and provide deeper insights into the biology of this rare cancer.
Section snippets
Materials and methods
UTUC samples were obtained from 31 patients under protocols approved by institutional review boards using endoscopic biopsy or surgical resection, and were stored frozen at −80 °C. Ten samples were primary ureter and 21 were renal pelvis in origin. Histology slides were reviewed by genitourinary pathology experts at each respective institution (M.I., C.G.). All tumors were composed of conventional urothelial carcinoma, and no variant histology was present. Microdissection was not performed, as
Patient demographic and clinical data
Patient demographic and clinical data are shown in Table 1. The male/female ratio of 2:1 is similar to that in previous reports for UTUC [21]. The majority of patients were white and former or current smokers. The majority had high-grade tumors and 32.3% had muscle-invasive or higher-stage disease (pT2+). Recurrences that were local, distant, or in the bladder were detected in approximately half of patients during median follow-up of 20 mo (range 3–66) for living patients. Median overall
Discussion
This is the first comprehensive, integrated genomic analysis of UTUC. Procurement of sufficient banked samples of this rare disease required pooling from two different institutions, and harmonization of clinical and genomic data. From the merged WES data set we identified 2784 mutations, with FGFR3 the most commonly mutated gene (74%) in both low-grade (92%) and high-grade (60%) tumors. The relatively high rate of FGFR3 mutations in high-grade tumors is nearly double the rate previously
Conclusions
Comprehensive genomic characterization of UTUC revealed novel mutations and mutation frequencies in comparison to bladder cancer, and identified four expression subtypes with unique molecular profiles and clinical correlates. WES analyses demonstrated that DNA repair and chromatin-modifying genes play a critical role in this disease. Expression analyses confirmed the additional critical role of FGFR3 in both low- and high-grade tumors, and validate this as a rational therapeutic target, along
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