FGFR3 mutant receptor activation

Stable Identifier
R-HSA-2033514
Type
Pathway
Species
Homo sapiens
Compartment
plasma membrane, cytosol, extracellular region
ReviewStatus
5/5
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FGFR3 mutant receptor activation
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The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Wesche et al, 2011). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3 (Otsuki et al, 1999). In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997; Onwuazor et al, 2003; Ronchetti et al, 2001).
Finally, FGFR3 is subject to fusion events in a number of cancers, including lung, bladder and glioblastoma (Singh et al, 2012; Parker et al, 2013; Williams et al, 2013; Wu et al, 2013; Capelletti et al, 2014; Yuan et al, 2014; Wang et al, 2014; Carneiro et al, 2015; reviewed in Parker et al, 2014). These fusions are constitutively active based on dimerization domains provided by the fusion partners and support transformation and proliferation through downstream signaling pathways such as ERK and AKT (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; reviewed in Parker et al, 2014).
Literature References
PubMed ID Title Journal Year
9207791 Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3

Chesi, M, Nardini, E, Brents, LA, Schröck, E, Ried, T, Kuehl, WM, Bergsagel, PL

Nat Genet 1997
12835230 Mutation, SNP, and isoform analysis of fibroblast growth factor receptor 3 (FGFR3) in 150 newly diagnosed multiple myeloma patients

Onwuazor, ON, Wen, XY, Wang, DY, Zhuang, L, Masih-Khan, E, Claudio, J, Barlogie, B, Shaughnessy JD, Jr, Stewart, AK

Blood 2003
23175443 Oncogenic FGFR3 gene fusions in bladder cancer

Williams, SV, Hurst, CD, Knowles, MA

Hum. Mol. Genet. 2013
25535896 Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma

Yuan, L, Liu, ZH, Lin, ZR, Xu, LH, Zhong, Q, Zeng, MS

Cancer Biol. Ther. 2014
22837387 Transforming fusions of FGFR and TACC genes in human glioblastoma

Singh, D, Chan, JM, Zoppoli, P, Niola, F, Sullivan, R, Castano, A, Liu, EM, Reichel, J, Porrati, P, Pellegatta, S, Qiu, K, Gao, Z, Ceccarelli, M, Riccardi, R, Brat, DJ, Guha, A, Aldape, K, Golfinos, JG, Zagzag, D, Mikkelsen, T, Finocchiaro, G, Lasorella, A, Rabadan, R, Iavarone, A

Science 2012
9154000 FGFR activation in skeletal disorders: too much of a good thing

Webster, MK, Donoghue, DJ

Trends Genet 1997
24850843 FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer

Wang, R, Wang, L, Li, Y, Hu, H, Shen, L, Shen, X, Pan, Y, Ye, T, Zhang, Y, Luo, X, Zhang, Y, Pan, B, Li, B, Li, H, Zhang, J, Pao, W, Ji, H, Sun, Y, Chen, H

Clin. Cancer Res. 2014
9538690 Fibroblast growth factor receptors: lessons from the genes

Burke, D, Wilkes, D, Blundell, TL, Malcolm, S

Trends Biochem Sci 1998
21711248 Fibroblast growth factors and their receptors in cancer

Wesche, J, Haglund, K, Haugsten, EM

Biochem J 2011
24588013 Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours

Parker, BC, Engels, M, Annala, M, Zhang, W

J. Pathol. 2014
23298836 The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma

Parker, BC, Annala, MJ, Cogdell, DE, Granberg, KJ, Sun, Y, Ji, P, Li, X, Gumin, J, Zheng, H, Hu, L, Yli-Harja, O, Haapasalo, H, Visakorpi, T, Liu, X, Liu, CG, Sawaya, R, Fuller, GN, Chen, K, Lang, FF, Nykter, M, Zhang, W

J. Clin. Invest. 2013
23558953 Identification of targetable FGFR gene fusions in diverse cancers

Wu, YM, Su, F, Kalyana-Sundaram, S, Khazanov, N, Ateeq, B, Cao, X, Lonigro, RJ, Vats, P, Wang, R, Lin, SF, Cheng, AJ, Kunju, LP, Siddiqui, J, Tomlins, SA, Wyngaard, P, Sadis, S, Roychowdhury, S, Hussain, MH, Feng, FY, Zalupski, MM, Talpaz, M, Pienta, KJ, Rhodes, DR, Robinson, DR, Chinnaiyan, AM

Cancer Discov 2013
10568829 Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation

Otsuki, T, Yamada, O, Yata, K, Sakaguchi, H, Kurebayashi, J, Nakazawa, N, Taniwaki, M, Yawata, Y, Ueki, A

Int J Oncol 1999
25294908 Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma

Capelletti, M, Dodge, ME, Ercan, D, Hammerman, PS, Park, SI, Kim, J, Sasaki, H, Jablons, DM, Lipson, D, Young, L, Stephens, PJ, Miller, VA, Lindeman, NI, Munir, KJ, Richards, WG, Jänne, PA

Clin. Cancer Res. 2014
11429702 Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations

Ronchetti, D, Greco, A, Compasso, S, Colombo, G, Dell'Era, P, Otsuki, T, Lombardi, L, Neri, A

Oncogene 2001
9865713 High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies

Avet-Loiseau, H, Li, JY, Facon, T, Brigaudeau, C, Morineau, N, Maloisel, F, Rapp, MJ, Talmant, P, Trimoreau, F, Jaccard, A, Harousseau, JL, Bataille, R

Cancer Res 1998
26425723 FGFR3-TACC3: A novel gene fusion in cervical cancer

Carneiro, BA, Elvin, JA, Kamath, SD, Ali, SM, Paintal, AS, Restrepo, A, Berry, E, Giles, FJ, Johnson, ML

Gynecol Oncol Rep 2015
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
bone development disease DOID:0080006
Cross References
Mondo
Authored
Rothfels, K  (2012-02-10)
Reviewed
Ezzat, S  (2012-05-15)
Grose, RP  (2016-01-25)
Created
Rothfels, K  (2012-01-09)
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