Somatic FGFR3 Mutations Distinguish a Subgroup of Muscle-Invasive Bladder Cancers with Response to Neoadjuvant Chemotherapy

Zhao Yang, Ruiyun Zhang, Yunxia Ge, Xuying Qin, Xing Kang, Yue Wang, Xu Zhang, Chengli Song, Xiaofang Quan, Haifeng Wang, Haige Chen, Chong Li, Zhao Yang, Ruiyun Zhang, Yunxia Ge, Xuying Qin, Xing Kang, Yue Wang, Xu Zhang, Chengli Song, Xiaofang Quan, Haifeng Wang, Haige Chen, Chong Li

Abstract

The administration of neoadjuvant chemotherapy (NAC) preceding radical cystectomy benefits overall survival for patients with muscle-invasive bladder cancer (MIBC). However, the relationship between the genetic profiling of MIBC and NAC response remains unclear. Here, a mutation panel of six cancer-associated genes (TSC1, FGFR3, TERT, TP53, PIK3CA and ERBB2) and an immunohistochemistry (IHC) panel containing eight bladder cancer (BC) biomarkers (EGFR, RRM1, PD-L1, BRCA1, TUBB3, ERCC, ERCC1, aberrantly glycosylated integrin α3β1 (AG) and CK5/6) were developed. BC samples from patients who showed a pathologic response (n = 39) and non-response (n = 13) were applied to the panel analysis. ERBB2, FGFR3 and PIK3CA exclusively altered in the responders group (19/39, 48.7%), in which FGFR3 mutations were significantly enriched in patients with a response in the cohort (14/39, 35.9%; P = 0.01). Additionally, strong expression of ERCC1 was associated with a pathologic response (P = 0.01). However, positive lymph node metastasis (P < 0.01) and lymph-vascular invasion (LVI) (P = 0.03) were correlated with a non-response. Overall, the data show that FGFR3 mutations and elevated expression of ERCC1 in MIBCs are potential predictive biomarkers of the response to NAC.

Keywords: Bladder cancer; ERCC1; FGFR3; Neoadjuvant chemotherapy.

Copyright © 2018. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
Study design and mutation rates of key genes in fifty-two muscle-invasive bladder cancer patients. a. Fifty-two patients were split into responders and nonresponders based on their pathologic response to neoadjuvant chemotherapy. TURBT, transurethral resection of bladder tumor. b. The alteration landscape of the aggregate cohort (n = 52 patients) are displayed in the center. Each column represents a tumor, and each row represents a gene. TERT, FGFR3, TP53, PIK3CA, ERBB2 and TSC1 are listed on the left and the center panel is divided into responders (left and green) and nonresponders (right and orange). The mutation rates (top) and mutational frequency (left) are also summarized.
Fig. 2
Fig. 2
FGFR3 significantly altered in the responder group of muscle-invasive bladder cancer patients. a and b. FGFR3, ERBB2 and PIK3CA somatic mutations exclusively occurred in the responder group. Only FGFR3 demonstrated significant enrichment in patients with a response in the cohort. c. FGFR3 somatic mutations were significantly enriched in the responder cohort compared with the unselected TCGA, Kim et al. and Guo et al. urothelial carcinoma cohorts.
Fig. 3
Fig. 3
FGFR3 mutation mapping and distribution across tumor types. a. A stick plot of FGFR3 showing the locations of mutations in the responders. Red, somatic mutations. Blue, synonymous mutation. b. Structure of the immunoglobulin domain of FGFR3 (PDB code, 1RY7) with mutations identified in the responder cohort. c. The somatic FGFR3 mutation frequency in multiple tumor types from COSMIC. d. Kaplan-Meier curves comparing OS between BC patients expressing high or low levels of FGFR3 using the log-rank test. n, patient number.

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