Abstract P5-04-25: Characterization of FGFR1/2 genetic alterations reveals novel fusions of FGFR1 in Chinese breast cancer
Authors: Y Wang, L Guo, L Cao, M Jia, L Wen, C Ren, G Zhang, N Liao
Journal: Cancer Research (2019)

Abstract Background: Deregulation of fibroblast growth factor receptor 1 (FGFR1) signalling has been extensively studied in various tumor types, and has been implicated in driving endocrine resistance in breast cancer. Genetic alterations of FGFR1, especially FGFR1 amplification, is one of particularly important mechanisms leading to enhanced FGFR signaling in breast cancer. However, the prevalence of FGFR1/2 genetic variations in Chinese breast cancer patients has not been well explored. Methods: To investigate the characteristics of FGFR1 and FGFR2 genetic variations in Chinese breast cancer, we employed customized next-generation sequencing panel to screen the somatic mutation or copy number variations of FGFR1/2 in primary breast cancer tissues by using two ongoing breast cancer Cohorts, in which we have recruited 289 of early breast cancer patients (EBC Cohort) and 74 of advanced breast cancer patients (ABC Cohort). Results: In EBC Cohort, we found FGFR1 amplification in 9.0% (26/289) patients and FGFR2 amplification in 2.1% (6/289) patients, and also found 3 of somatic FGFR1 mutations (FGFR1 p.W4C; p.E334K; p.V396I ) and 2 of FGFR2 mutations (FGFR2 p.S702L; p.Y779*). Unlike the comparable prevalence of FGFR2 genetic variations in 2.8% (8/289) of EBC Cohort and 2.7% (2/74; one amplification event and one FGFR2 p.E499D mutation) of ABC Cohort, there were more FGFR1 genetic alterations in ABC Cohort (27%; 20/74 patients; p&amp;lt;0.001), including 19 events of FGFR1 amplification and 1 of FGFR1 c.2186+20G&amp;gt;A intron mutation. More importantly, we identified 5 novel FGFR1 fusion genes in our cohorts, including TACC1-FGFR1, FGFR1-KCNU1, FGFR1-MIR1268A, FGFR1-LZTS1-AS1 and FGFR1-RNF5P1. Although FGFR1-TACC1 fusion gene has been previously reported in breast cancer and TACC1 is fused to the C-terminal of FGFR1 protein leading to aberrant activation of FGFR1, we found TACC1 was fused to the N-terminal of FGFR1 at exon 6 of FGFR1 in our study. In addition, we identified and verified FGFR1-MIR1268A fusion gene at mRNA level using RNA-seq analysis, and further found this fusion gene might result in the truncation of FGFR1. Conclusions: Collectively, we characterized the prevalence of FGFR1/2 genetic alterations in Chinese breast cancer, and identified 5 of novel FGFR1 fusion genes. The potential roles for novel FGFR1 fusion genes in regulating breast cancer cellular biology and in affecting the efficacy of endocrine therapy have been under the investigation in our laboratory, and the result from which will help us better elucidate the molecular mechanism of FGFR1 in driving the resistance of endocrine therapy. This study was supported by funding from National Natural Science Foundation of China (Grant No. 81602645), Guangdong Provincial Natural Science Foundation (Grant No. 2016A030313768) and Research Funds from Guangzhou Science and Technology Bureau (Grant No. 201707010418 and 201804010430). Citation Format: Wang Y, Guo L, Cao L, Jia M, Wen L, Ren C, Zhang G, Liao N. Characterization of FGFR1/2 genetic alterations reveals novel fusions of FGFR1 in Chinese breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-25.