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

doi:10.1016/j.ebiom.2018.06.011

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

EBioMedicine. 2018 Sep:35:198-203. doi: 10.1016/j.ebiom.2018.06.011. Epub 2018 Jun 22.

Authors

Zhao Yang¹, Ruiyun Zhang², Yunxia Ge³, Xuying Qin⁴, Xing Kang⁵, Yue Wang³, Xu Zhang⁵, Chengli Song³, Xiaofang Quan⁵, Haifeng Wang⁶, Haige Chen⁷, Chong Li⁸

Affiliations

¹ Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Laboratory of Biomanufacturing and Food Engineering, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
² Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
³ Novogene Bioinformatics Technology Co., Ltd, Beijing 100083, China.
⁴ Beijing Taipu-Shunkang Institute For Laboratory Medicine, Beijing 100076, China.
⁵ Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Department of Urology, The Second Affliated Hospital of Kunming Medical University, Kunming 650101, China.
⁷ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: chenhaige011435@renji.com.
⁸ Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Department of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China; Beijing Jianlan Institute of Medicine, Beijing 100190, China. Electronic address: lichong@moon.ibp.ac.cn.

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.

MeSH terms

Cisplatin / pharmacology
Cisplatin / therapeutic use
DNA Mutational Analysis
Female
Genes, Neoplasm
Humans
Lymphatic Metastasis
Lymphatic Vessels / pathology
Male
Middle Aged
Muscles / pathology*
Mutation / genetics*
Mutation Rate
Neoadjuvant Therapy*
Neoplasm Invasiveness
Receptor, Fibroblast Growth Factor, Type 3 / genetics*
Urinary Bladder Neoplasms / drug therapy*
Urinary Bladder Neoplasms / genetics*

Substances

FGFR3 protein, human
Receptor, Fibroblast Growth Factor, Type 3
Cisplatin