An mRNA Gene Expression–Based Signature to Identify FGFR1-Amplified Estrogen Receptor–Positive Breast Tumors

Luo, Jingqin; Liu, Shuzhen; Leung, Samuel; Gru, Alejandro A.; Tao, Yu; Hoog, Jeremy; Ho, Julie; Davies, Sherri R.; Allred, D. Craig; Salavaggione, Andrea L.; Snider, Jacqueline; Mardis, Elaine R.; Nielsen, Torsten O.; Ellis, Matthew J.

doi:10.1016/j.jmoldx.2016.09.007

Cited by 11 publications

(9 citation statements)

References 61 publications

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“…Oncogenic gene alternations are present in all FGFR family members in human cancers. For example, FGFR1 amplification occurs in breast, lung, gastric and bladder cancers 7–10 . FGFR2 amplification, mutations and fusions occur in breast, liver, uterine, lung, gastric cancer 11–13 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

Futami

Kawase

Mori

et al. 2019

Sci Rep

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Gastric cancer remains one of the leading causes of cancer death worldwide. Despite intensive investigations of treatments over the past three decades, the poor prognosis of patients with unresectable advanced or recurrent gastric cancer has not significantly changed, and improved therapies are required. Here, we report the identification of an oncogenic mutation in FGFR4 in a human gastric tumour that leads to constitutive activation of its product, FGFR4. The G636C-FGFR4 tyrosine kinase domain mutation was found in 1 of 83 primary human gastric tumours. The G636C mutation increased FGFR4 autophosphorylation, and activated FGFR4 downstream signalling molecules and enhanced anchorage-independent cell growth when expressed in NIH/3T3 cells. 3D-structural analysis and modelling of FGFR4 suggest that G636C destabilizes an auto-inhibitory conformation and stabilizes an active conformation, leading to increased kinase activation. Ba/F3 cell lines expressing the G636C-FGFR4 mutant were significantly more sensitive to ASP5878, a selective FGFR inhibitor, than the control. Oral administration of ASP5878 significantly inhibited the growth of tumours in mice engrafted with G636C-FGFR4/3T3 cells. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncoprotein. These findings support the therapeutic targeting of FGFR4 in gastric cancer.

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Section: Introductionmentioning

confidence: 99%

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

Futami

Kawase

Mori

et al. 2019

Sci Rep

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“…FGFR1 amplification is associated with increased expression [ 33 , 61 ]. However, it needs to be borne in mind that increased copy numbers may not always predict high levels of FGFR1 protein expression [ 48 ], so that inhibition might fail if treatment were to be selected on the basis of FGFR1 amplification.…”

Section: Discussionmentioning

confidence: 99%

Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients

Erber

Rübner

Davenport

et al. 2020

Breast Cancer Res Treat

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Purpose Various aberrations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3 are found in different cancers, including breast cancer (BC). This study analyzed the impact of FGFR amplification on the BC prognosis. Methods The study included 894 BC patients. The amplification rates of FGFR1, FGFR2, and FGFR3 were evaluated on tissue microarrays using fluorescence in situ hybridization (FISH). Associations between these parameters and prognosis were analyzed using multivariate Cox regression analyses. Results FGFR1 FISH was assessable in 503 samples, FGFR2 FISH in 447, and FGFR3 FISH in 562. The FGFR1 amplification rate was 6.6% (n = 33). Increased FGFR2 copy numbers were seen in 0.9% (n = 4); only one patient had FGFR3 amplification (0.2%). Most patients with FGFR1 amplification had luminal B-like tumors (69.7%, n = 23); only 32.6% (n = 153) of patients without FGFR1 amplification had luminal B-like BC. Other patient and tumor characteristics appeared similar between these two groups. Observed outcome differences between BC patients with and without FGFR1 amplification did not achieve statistical significance; however, there was a trend toward poorer distant metastasis-free survival in BC patients with FGFR1 amplification (HR = 2.08; 95% CI 0.98 to 4.39, P = 0.05). Conclusion FGFR1 amplification occurs most frequently in patients with luminal B-like BC. The study showed a nonsignificant correlation with the prognosis, probably due to the small sample size. Further research is therefore needed to address the role of FGFR1 amplifications in early BC patients. FGFR2 and FGFR3 amplifications are rare in patients with primary BC.

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“…The mRNA-based approach for selecting amplicons has been applied by Luo et al, who used a multigene mRNA expression signature to identify FGFR1-amplified estrogen receptor-positive (ERfl) breast tumors [17]. While this study and other research have mainly focused on amplicons in breast and gastric cancer, limited knowledge exists for bladder cancer [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

A comprehensive molecular characterization of the 8q22.2 region reveals the prognostic relevance of OSR2 mRNA in muscle invasive bladder cancer

et al. 2021

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Technological advances in molecular profiling have enabled the comprehensive identification of common regions of gene amplification on chromosomes (amplicons) in muscle invasive bladder cancer (MIBC). One such region is 8q22.2, which is largely unexplored in MIBC and could harbor genes with potential for outcome prediction or targeted therapy. To investigate the prognostic role of 8q22.2 and to compare different amplicon definitions, an in-silico analysis of 357 patients from The Cancer Genome Atlas, who underwent radical cystectomy for MIBC, was performed. Amplicons were generated using the GISTIC2.0 algorithm for copy number alterations (DNA_Amplicon) and z-score normalization for mRNA gene overexpression (RNA_Amplicon). Kaplan-Meier survival analysis, univariable, and multivariable Cox proportional hazard ratios were used to relate amplicons, genes, and clinical parameters to overall (OS) and disease-free survival (DFS). Analyses of the biological functions of 8q22.2 genes and genomic events in MIBC were performed to identify potential targets. Genes with prognostic significance from the in silico analysis were validated using RT-qPCR of MIBC tumor samples (n = 46). High 8q22.2 mRNA expression (RNA-AMP) was associated with lymph node metastases. Furthermore, 8q22.2 DNA and RNA amplified patients were more likely to show a luminal subtype (DNA_Amplicon_core: p = 0.029; RNA_Amplicon_core: p = 0.01). Overexpression of the 8q22.2 gene OSR2 predicted shortened DFS in univariable (HR [CI] 1.97 [1.2; 3.22]; p = 0.01) and multivariable in silico analysis (HR [CI] 1.91 [1.15; 3.16]; p = 0.01) and decreased OS (HR [CI] 6.25 [1.37; 28.38]; p = 0.0177) in RT-qPCR data analysis. Alterations in different levels of the 8q22.2 region are associated with manifestation of different clinical characteristics in MIBC. An in-depth comprehensive molecular characterization of genomic regions involved in cancer should include multiple genetic levels, such as DNA copy number alterations and mRNA gene expression, and could lead to a better molecular understanding. In this study, OSR2 is identified as a potential biomarker for survival prognosis.

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An mRNA Gene Expression–Based Signature to Identify FGFR1-Amplified Estrogen Receptor–Positive Breast Tumors

Cited by 11 publications

References 61 publications

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients

A comprehensive molecular characterization of the 8q22.2 region reveals the prognostic relevance of OSR2 mRNA in muscle invasive bladder cancer

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