Difference between revisions of "FGFR1"
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==Primary Author(s)*== | ==Primary Author(s)*== | ||
| − | + | Brian Davis PhD | |
__TOC__ | __TOC__ | ||
| Line 7: | Line 7: | ||
==Synonyms== | ==Synonyms== | ||
| − | "FLT2 | + | "Fibroblast Growth Factor Receptor 1"; "Basic Fibroblast Growth Factor Receptor 1"; BFGFR; "Heparin-Binding Growth Factor Receptor "; HBGFR; "Fms-Related Tyrosine Kinase 2"; "Fms-Like Tyrosine Kinase 2"; FLT2; CEK; FLG; CD331; ECCL; KAL2 |
==Genomic Location== | ==Genomic Location== | ||
| − | '''Cytoband:''' | + | '''Cytoband:''' 8p11.23 |
'''Genomic Coordinates:''' | '''Genomic Coordinates:''' | ||
| − | + | chr8:38,411,138-38,468,834 [hg38] | |
| + | |||
| + | chr8:38,268,656-38,326,352 [hg19] | ||
| + | |||
| + | ==Cancer Category/Type== | ||
| + | |||
| + | Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 | ||
| + | |||
| + | According to "WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues", | ||
| + | "...clinical and morphologic presentations associated with FGFR1 rearrangement are variable, and include not only presentation as a myeloproliferative neoplasm with eosinophilia, but also as AML and they may even present as, or evolve to, precursor T or B lymphoblastic leukaemia/lymphoma with prominent eosinphils." (p.28). | ||
| − | + | FGFR1 rearrangements are used to rule out diagnoses of Chronic Eosinophilic Leukaemia (p.54) and Myeloproliferative neoplasm,unclassifiable (p.66). | |
| − | + | In the case of FGFR1-related disease, | |
| + | a lymphomatous presentation is common, | ||
| + | particularly T-LBL with accompanying eosinophilia. Other patients have had CEL, | ||
| + | precursor-B lymphoblastic leukaemia/ | ||
| + | lymphoma or AML. (.70). | ||
| − | + | 8p11 myeloproliferative syndrome (EMS), also known as 8p11 myeloproliferative neoplasm (8p11 MPN), is a rare disorder molecularly associated with fusion genes between the tyrosine kinase receptor gene FGFR1, located in 8p11, and several partner genes, including ZMYM2 (wang et al). | |
| + | |||
| + | Previous studies have shown that EMS is usually resistant to conventional chemotherapies with a poor median survival rate of less than 12 months.1 Although FGFR1-involved fusion proteins are potential therapeutic targets, no satisfactory results have been achieved using tyrosine kinase inhibitors (TKIs) including imatinib3,4 and dasatinib.5 (wang et al). | ||
| + | |||
| + | In EMS, multiple genes, including ZMYM2, FGFR1OP, BCR, NUP98, FGFR1OP2, TRIM24, MYO18A, CPSF6, LRRFIP1, CNTRL, ERVK-61 and the recently identified SQSTM1,6 were detected as fusion partners with FGFR1 with a breakpoint in the 8p11–12 locus. Among these fusion genes, ZMYM2-FGFR1 is the most common type. The ZMYM2 proline-rich region, which mediates protein oligomerization, and the FGFR1 tyrosine kinase domain are conserved in the fusion protein. The abnormal oligomerization of ZMYM2-FGFR1 leads to constitutive activation of its tyrosine kinase.7 (wang et al). | ||
| + | |||
| + | FGFR1 fusion genes are associated with a disease entity initially referred to as the 8p11 myeloproliferative syndrome or stem cell leukemia/lymphoma.9,53 Fourteen different fusion genes have now been described. The 3 most common reciprocal translocations include t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), resulting in fusions of ZMYM2, CNTRL, and FGFR1OP, respectively, to FGFR1.54⇓-56 The transforming activity of the various FGFR1 fusion proteins has been demonstrated by conversion of the IL-3-dependent Ba/F3 cell line to growth factor independence and induction of a myeloproliferative neoplasm in murine models.57,58 (Reiter and Gotleib) | ||
| + | |||
| + | The clinical/laboratory characteristics typically reflect features of chronic myeloid neoplasms and variable eosinophilia.9 Patients may also present as de novo AML without an antecedent MPN. There is a high incidence of T-lymphoblastic lymphomas, particularly in association with a t(8;13) and a ZMYM2-FGFR1 fusion gene,9,53,54 which may occur at diagnosis or during the course of disease, reflecting a myeloid/lymphoid stem cell origin. The clinical course is aggressive as a result of rapid progression to blast phase/secondary acute leukemia, usually of myeloid phenotype, less commonly B-ALL, within 1 or 2 years of diagnosis. The variability in the clinical presentation may be a result of specific moieties of the partner genes and signaling via different intracellular pathways.59 The t(8;22) is often associated with a clinical and hematologic picture very similar to that seen in BCR-ABL1-positive CML with basophilia,58,60 whereas thrombocytopenia and monocytosis resembling CMML are more frequently present in t(6;8)56 and t(8;9).55,61 The t(6;8) may also present with a PV-like disease,62 and eosinophilia may be absent in t(6;8) and t(8;22).(Reiter and Gotleib) | ||
| − | + | In a recent report (Wehrli et al, 2017) a patient diagnosed with EMS and a CEP110-FGFR1 rearrangement responded to treatment with the tyrosine kinase inhibitor (TKI) dasatinib. | |
==Gene Overview== | ==Gene Overview== | ||
| − | + | FGFR1 is a tyrosine kinase receptor and is a member (1 of 4) of the fibroblast growth factor receptor (FGFR) family. FGFR1 differs from other members in the family in part by affinity to fibroblast growth factors(FGF) of which there are 22 members), having highest affinity for FGF1 (acidic) and FGF2 (basic). Upon binding ligand, the ligand:receptor complex dimerizes and signals activation of downstream pathways, including RAS/RAF/MAPK, PI3K/ATK/mTor, Phospholipase C and Jak/STAT pathways, among others. | |
==Common Alteration Types== | ==Common Alteration Types== | ||
| − | + | A number of genes can serve as partner with FGFR1 and 13 are described in the literature. The translocation wiht ZMYM2 is hte most common (approx 40%) as well as other common partners BCR, CNTRL and FGFR1OP (Wilberger et al. 2018 and references within). | |
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
| Line 38: | Line 59: | ||
|- | |- | ||
| EXAMPLE: X ||EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X | | EXAMPLE: X ||EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X || EXAMPLE: X | ||
| + | |||
|} | |} | ||
| + | From WHO book: | ||
| + | |||
| + | Cytogenetics Molecular genetics N† | ||
| + | t(8;13)(p11;q12) ZNF198-FGFR1 21 | ||
| + | t(8;9)(p11;q33) CEP110-FGFR1 8 | ||
| + | t(6;8)(q27;p11-12) FGFR1OP1-FGFR1 6 | ||
| + | t(8;22)(p11;q11) BCR-FGFR1 5 | ||
| + | t(7;8)(q34;p11) TRIM24-FGFR1 1 | ||
| + | t(8;17)(p11;q23) MYO18A-FGFR1 1 | ||
| + | t(8;19)(p12;q13.3) HERVK-FGFR1 1 | ||
| + | ins(12;8)(p11;p11p22) FGFR1OP2-FGFR1 1 | ||
| + | * In addition, FGFR1 rearrangement has been found in | ||
| + | association with t(8;12)(p11;q15) and t(8;17)(p11;q25) | ||
| + | but the suspected involvement of FGFR1 in t(8;11) | ||
| + | (p11;p15) was not confirmed. | ||
| + | † Numbers updated from MacDonald and Cross {1354}. | ||
==Internal Pages== | ==Internal Pages== | ||
| Line 48: | Line 86: | ||
==External Links== | ==External Links== | ||
| − | + | '''[http://atlasgeneticsoncology.org//Genes/FGFR1ID113.html ''FGFR1'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information | |
| − | + | '''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FGFR1 ''FGFR1'' by COSMIC]''' - sequence information, expression, catalogue of mutations | |
| − | '''[ | + | '''[https://civicdb.org/events/genes/1885/summary/variants/569/summary ''FGFR1'' by CIViC]''' - general knowledge and evidence-based variant specific information |
| − | '''[https:// | + | '''[https://pecan.stjude.cloud/proteinpaint/FGFR1 ''FGFR1'' by St. Jude ProteinPaint]''' mutational landscape and matched expression data. |
| − | '''[https:// | + | '''[https://pmkb.weill.cornell.edu/variants/2442 ''FGFR1'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs |
| − | '''[http:// | + | '''[http://www.cancerindex.org/geneweb/FGFR1.htm ''FGFR1'' by Cancer Index]''' - gene, pathway, publication information matched to cancer type |
| − | '''[ | + | '''[http://oncokb.org/#/gene/FGFR1 ''FGFR1'' by OncoKB]''' - mutational landscape, mutation effect, variant classification |
| − | '''[https:// | + | '''[https://www.ncbi.nlm.nih.gov/gene/2260 ''FGFR1'' by NCBI Gene]''' - brief gene overview |
| − | '''[ | + | '''[https://www.mycancergenome.org/content/gene/FGFR1/ ''FGFR1'' by My Cancer Genome]''' - brief gene overview |
| − | '''[ | + | '''[https://www.uniprot.org/uniprot/P11362 ''FGFR1'' by UniProt]''' - protein and molecular structure and function |
| − | '''[ | + | '''[http://pfam.xfam.org/protein/P11362 ''FGFR1' by Pfam]''' - gene and protein structure and function information |
| − | '''[http://www. | + | '''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=FGFR1 ''FGFR1'' by GeneCards]''' - general gene information and summaries |
| − | '''[ | + | '''[http://www.omim.org/entry/136350 ''FGFR1'' by OMIM]''' - compendium of human genes and genetic phenotypes |
| − | '''[ | + | '''[https://databases.lovd.nl/shared/genes/FGFR1 ''FGFR1' by LOVD(3)]''' - Leiden Open Variation Database |
| − | '''[ | + | '''[http://www.unav.es/genetica/TICdb/results.php?hgnc=FGFR1 ''FGFR1'' by TICdb]''' - database of Translocation breakpoints In Cancer |
==References== | ==References== | ||
| − | + | Swerdlow SH, Campo E, Harris NLJ, et al. Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p71-9. | |
| − | |||
| − | + | Adam C. Wilberger, Brandon McMahon & Mark D. Ewalt (2018) The power of the partner: defying expectations in a case of a myeloproliferative neoplasm with FGFR1 rearrangement, Leukemia & Lymphoma, DOI: 10.1080/10428194.2018.1516038 | |
| − | + | ||
| + | Baer C, Muehlbacher V, Kern W, Haferlach C, Haferlach T. Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2. Haematologica. 2018;103(8):e348-e350. doi:10.3324/haematol.2017.187302. | ||
| + | |||
| + | Wang Y, Wu X, Deng J, et al. Diagnostic application of next-generation sequencing in ZMYM2-FGFR1 8p11 myeloproliferative syndrome: A case report. Cancer Biology & Therapy. 2016;17(8):785-789. doi:10.1080/15384047.2016.1210727. | ||
| + | |||
| + | Reiter, A., & Gotlib, J. (2017). Myeloid neoplasms with eosinophilia. Blood, 129(6), 704-714. Accessed October 10, 2018. https://doi.org/10.1182/blood-2016-10-695973. | ||
| + | |||
| + | Wehrli M, Oppliger Leibundgut E, Gattiker HH, Manz MG, Müller AMS, Goede JS. Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110‐FGFR1 Rearrangement. The Oncologist. 2017;22(4):480-483. doi:10.1634/theoncologist.2016-0354. | ||
== Notes == | == Notes == | ||
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. | <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. | ||
| + | |||
| + | [[Category:Cancer Genes F]] | ||
Latest revision as of 17:05, 11 October 2018
Primary Author(s)*
Brian Davis PhD
Synonyms
"Fibroblast Growth Factor Receptor 1"; "Basic Fibroblast Growth Factor Receptor 1"; BFGFR; "Heparin-Binding Growth Factor Receptor "; HBGFR; "Fms-Related Tyrosine Kinase 2"; "Fms-Like Tyrosine Kinase 2"; FLT2; CEK; FLG; CD331; ECCL; KAL2
Genomic Location
Cytoband: 8p11.23
Genomic Coordinates:
chr8:38,411,138-38,468,834 [hg38]
chr8:38,268,656-38,326,352 [hg19]
Cancer Category/Type
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1
According to "WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues", "...clinical and morphologic presentations associated with FGFR1 rearrangement are variable, and include not only presentation as a myeloproliferative neoplasm with eosinophilia, but also as AML and they may even present as, or evolve to, precursor T or B lymphoblastic leukaemia/lymphoma with prominent eosinphils." (p.28).
FGFR1 rearrangements are used to rule out diagnoses of Chronic Eosinophilic Leukaemia (p.54) and Myeloproliferative neoplasm,unclassifiable (p.66).
In the case of FGFR1-related disease, a lymphomatous presentation is common, particularly T-LBL with accompanying eosinophilia. Other patients have had CEL, precursor-B lymphoblastic leukaemia/ lymphoma or AML. (.70).
8p11 myeloproliferative syndrome (EMS), also known as 8p11 myeloproliferative neoplasm (8p11 MPN), is a rare disorder molecularly associated with fusion genes between the tyrosine kinase receptor gene FGFR1, located in 8p11, and several partner genes, including ZMYM2 (wang et al).
Previous studies have shown that EMS is usually resistant to conventional chemotherapies with a poor median survival rate of less than 12 months.1 Although FGFR1-involved fusion proteins are potential therapeutic targets, no satisfactory results have been achieved using tyrosine kinase inhibitors (TKIs) including imatinib3,4 and dasatinib.5 (wang et al).
In EMS, multiple genes, including ZMYM2, FGFR1OP, BCR, NUP98, FGFR1OP2, TRIM24, MYO18A, CPSF6, LRRFIP1, CNTRL, ERVK-61 and the recently identified SQSTM1,6 were detected as fusion partners with FGFR1 with a breakpoint in the 8p11–12 locus. Among these fusion genes, ZMYM2-FGFR1 is the most common type. The ZMYM2 proline-rich region, which mediates protein oligomerization, and the FGFR1 tyrosine kinase domain are conserved in the fusion protein. The abnormal oligomerization of ZMYM2-FGFR1 leads to constitutive activation of its tyrosine kinase.7 (wang et al).
FGFR1 fusion genes are associated with a disease entity initially referred to as the 8p11 myeloproliferative syndrome or stem cell leukemia/lymphoma.9,53 Fourteen different fusion genes have now been described. The 3 most common reciprocal translocations include t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), resulting in fusions of ZMYM2, CNTRL, and FGFR1OP, respectively, to FGFR1.54⇓-56 The transforming activity of the various FGFR1 fusion proteins has been demonstrated by conversion of the IL-3-dependent Ba/F3 cell line to growth factor independence and induction of a myeloproliferative neoplasm in murine models.57,58 (Reiter and Gotleib)
The clinical/laboratory characteristics typically reflect features of chronic myeloid neoplasms and variable eosinophilia.9 Patients may also present as de novo AML without an antecedent MPN. There is a high incidence of T-lymphoblastic lymphomas, particularly in association with a t(8;13) and a ZMYM2-FGFR1 fusion gene,9,53,54 which may occur at diagnosis or during the course of disease, reflecting a myeloid/lymphoid stem cell origin. The clinical course is aggressive as a result of rapid progression to blast phase/secondary acute leukemia, usually of myeloid phenotype, less commonly B-ALL, within 1 or 2 years of diagnosis. The variability in the clinical presentation may be a result of specific moieties of the partner genes and signaling via different intracellular pathways.59 The t(8;22) is often associated with a clinical and hematologic picture very similar to that seen in BCR-ABL1-positive CML with basophilia,58,60 whereas thrombocytopenia and monocytosis resembling CMML are more frequently present in t(6;8)56 and t(8;9).55,61 The t(6;8) may also present with a PV-like disease,62 and eosinophilia may be absent in t(6;8) and t(8;22).(Reiter and Gotleib)
In a recent report (Wehrli et al, 2017) a patient diagnosed with EMS and a CEP110-FGFR1 rearrangement responded to treatment with the tyrosine kinase inhibitor (TKI) dasatinib.
Gene Overview
FGFR1 is a tyrosine kinase receptor and is a member (1 of 4) of the fibroblast growth factor receptor (FGFR) family. FGFR1 differs from other members in the family in part by affinity to fibroblast growth factors(FGF) of which there are 22 members), having highest affinity for FGF1 (acidic) and FGF2 (basic). Upon binding ligand, the ligand:receptor complex dimerizes and signals activation of downstream pathways, including RAS/RAF/MAPK, PI3K/ATK/mTor, Phospholipase C and Jak/STAT pathways, among others.
Common Alteration Types
A number of genes can serve as partner with FGFR1 and 13 are described in the literature. The translocation wiht ZMYM2 is hte most common (approx 40%) as well as other common partners BCR, CNTRL and FGFR1OP (Wilberger et al. 2018 and references within).
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X |
From WHO book:
Cytogenetics Molecular genetics N† t(8;13)(p11;q12) ZNF198-FGFR1 21 t(8;9)(p11;q33) CEP110-FGFR1 8 t(6;8)(q27;p11-12) FGFR1OP1-FGFR1 6 t(8;22)(p11;q11) BCR-FGFR1 5 t(7;8)(q34;p11) TRIM24-FGFR1 1 t(8;17)(p11;q23) MYO18A-FGFR1 1 t(8;19)(p12;q13.3) HERVK-FGFR1 1 ins(12;8)(p11;p11p22) FGFR1OP2-FGFR1 1
- In addition, FGFR1 rearrangement has been found in
association with t(8;12)(p11;q15) and t(8;17)(p11;q25) but the suspected involvement of FGFR1 in t(8;11) (p11;p15) was not confirmed. † Numbers updated from MacDonald and Cross {1354}.
Internal Pages
Put your text here
EXAMPLE Germline Cancer Predisposition Genes
External Links
FGFR1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
FGFR1 by COSMIC - sequence information, expression, catalogue of mutations
FGFR1 by CIViC - general knowledge and evidence-based variant specific information
FGFR1 by St. Jude ProteinPaint mutational landscape and matched expression data.
FGFR1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
FGFR1 by Cancer Index - gene, pathway, publication information matched to cancer type
FGFR1 by OncoKB - mutational landscape, mutation effect, variant classification
FGFR1 by NCBI Gene - brief gene overview
FGFR1 by My Cancer Genome - brief gene overview
FGFR1 by UniProt - protein and molecular structure and function
FGFR1' by Pfam - gene and protein structure and function information
FGFR1 by GeneCards - general gene information and summaries
FGFR1 by OMIM - compendium of human genes and genetic phenotypes
FGFR1' by LOVD(3) - Leiden Open Variation Database
FGFR1 by TICdb - database of Translocation breakpoints In Cancer
References
Swerdlow SH, Campo E, Harris NLJ, et al. Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p71-9.
Adam C. Wilberger, Brandon McMahon & Mark D. Ewalt (2018) The power of the partner: defying expectations in a case of a myeloproliferative neoplasm with FGFR1 rearrangement, Leukemia & Lymphoma, DOI: 10.1080/10428194.2018.1516038
Baer C, Muehlbacher V, Kern W, Haferlach C, Haferlach T. Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2. Haematologica. 2018;103(8):e348-e350. doi:10.3324/haematol.2017.187302.
Wang Y, Wu X, Deng J, et al. Diagnostic application of next-generation sequencing in ZMYM2-FGFR1 8p11 myeloproliferative syndrome: A case report. Cancer Biology & Therapy. 2016;17(8):785-789. doi:10.1080/15384047.2016.1210727.
Reiter, A., & Gotlib, J. (2017). Myeloid neoplasms with eosinophilia. Blood, 129(6), 704-714. Accessed October 10, 2018. https://doi.org/10.1182/blood-2016-10-695973.
Wehrli M, Oppliger Leibundgut E, Gattiker HH, Manz MG, Müller AMS, Goede JS. Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110‐FGFR1 Rearrangement. The Oncologist. 2017;22(4):480-483. doi:10.1634/theoncologist.2016-0354.
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.