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==Cancer Category/Type==
==Cancer Category/Type==
'''[http://www.ccga.io/index.php/Chronic_Myeloid_Leukemia_(CML)_with_t(9;22)(q34.1;q11.2);_BCR-ABL1 Chronic Myeloid Leukemia]''' (also referred as (Chronic Myelogenous Leukemia)
'''[http://www.ccga.io/index.php/Chronic_Myeloid_Leukemia_(CML)_with_t(9;22)(q34.1;q11.2);_BCR-ABL1 Chronic Myeloid Leukemia with BCR-ABL1]''' (also referred as Chronic Myelogenous Leukemia)
More than 90% of patients diagnosed with Chronic Myeloid Leukemia have a Philadelphia chromosome resulting from t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (''BCR'' locus) and chromosome 9 (''ABL1'' locus) (see '''[http://www.omim.org/entry/613065 OMIM]''') [1]. The Drug Imatinib mesylate, also known as Gleevec, was the one of the first molecularly developed drugs, and has a remarkably high success rate in treatment of patients with Chronic Myeloid Leukemia by targeting the BCR/ABL1 fusion product [5].
'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
Approximately 20% of patients (25 - 30% of adults and 2 - 10% of children) diagnosed with Acute Lymphoblastic Leukemia bear a Philadelphia chromosome resulting from t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (''BCR'' locus) and chromosome 9 (''ABL1'' locus) (see '''[http://www.omim.org/entry/613065 OMIM]''') [1]. Treatment of Acute Lymphoblastic Leukemia patients with Gleevec does not have the same success as in Chronic Myeloid Leukemia patients because the genomic instability of ALL cells contributes to point mutations arising in the BRC-ABL1 kinase domain, leading to Gleevec resistance [4].
Approximately 20% of patients (25 - 30% of adults and 2 - 10% of children) diagnosed with Acute Lymphoblastic Leukemia have a Philadelphia chromosome resulting from t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (''BCR'' locus) and chromosome 9 (''ABL1'' locus) (see '''[http://www.omim.org/entry/613065 OMIM]''') [1]. Treatment of Acute Lymphoblastic Leukemia patients with Gleevec does not have the same success as in Chronic Myeloid Leukemia patients because the genomic instability of ALL cells contributes to point mutations arising in the BRC-ABL1 kinase domain, leading to Gleevec resistance [4].
'''[http://www.ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_BCR::ABL1_fusion Mixed Phenotype Acute Leukemia (MPAL) with BCR-ABL1]'''
BCR-ABL1 translocations (Ph+) are more prevalent in adult vs. pediatric patients diagnosed as Mixed Phenotype Acute Leukemia (MPAL) [16,17]. The BCR-ABL1 translocations are considered to be prognostic of poorer outcomes in the context of patients diagnosed with Mixed Phenotype Acute Leukemia (MPAL) [16]. However, a number of individual studies indicate that Ph+ MPAL patients can be treated successfully with tyrosine kinase inhibitors (TKI) such as Imatinab and second generation TKIs [18,19].
'''[http://www.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion Acute Myeloid Leukemia with BCR-ABL1]'''
This rare entity, accounting for <1% of AML and <1% of BCR-ABL1 positive acute and chronic leukemias, typically occurs in adults. AML with BCR-ABL1 is aggressive with poor response to traditional AML therapy or isolated tyrosine kinase (TK) therapy alone; TK therapy with subsequent allogeneic hematopoietic cell transplantation may improve survival [20].
==Gene Overview==
==Gene Overview==
The head to tail arrangement of the BCR-ABL1 fusion gene results in an activated tyrosine kinase activity [6]. It appears that the N-terminal domain of ''BCR'' can cause oligomerization of the BCR-ABL1 protein product, thus activating the ''ABL1'' tyrosine kinase domain of the fusion protein [6,10,11].
The head to tail arrangement of the BCR-ABL1 fusion gene results in an activated tyrosine kinase activity [6]. It appears that the N-terminal domain of ''BCR'' can cause oligomerization of the BCR-ABL1 protein product, thus activating the ''ABL1'' tyrosine kinase domain of the fusion protein [6,10,11].
See the '''[http://www.ccga.io/index.php/BCR "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
See the '''[http://www.ccga.io/index.php/ABL "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
==Common Alteration Types==
==Common Alteration Types==
By far the most common ''BCR'' alteration associated with cancer is the BCR-ABL1 fusion as described above in CML and ALL.
By far the most common ''BCR'' alteration associated with cancer is the BCR-ABL1 fusion as described above in CML and ALL.
A small number of individual patients have been described with a BCR-JAK2 (Janus Kinase 2) fusion gene leading to CML and other hematological neoplasms, but this fusion gene appears to be rare (see '''[http://atlasgeneticsoncology.org/Anomalies/t0922p24q11ID1331.html] Atlas of Genetics and Cytogenetics in Oncology and Haematology]''') [12,13,14].
A small number of individual patients have been described with a BCR-JAK2 (Janus Kinase 2) fusion gene leading to CML and other hematological neoplasms, but this fusion gene appears to be rare (see '''[http://atlasgeneticsoncology.org/Anomalies/t0922p24q11ID1331.html] Atlas of Genetics and Cytogenetics in Oncology and Haematology]''') [12,13,14].
A small number of chronic myeloproliferative disorders patients have been described with BCR-FGFR1 and BCR-PDGFRA fusion genes [15].
A small number of chronic myeloproliferative disorders patients have been described with BCR-FGFR1 and BCR-PDGFRA fusion genes [15].
Somatic mutations of ''BCR'' have rarely been found spread throughout the gene (see '''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=BCR COSMIC June 2018]''', indicating these are probably mostly carrier mutations. The exception may be the point mutation D1106N in the RhoGAP domain which occurs more frequently and has been associated with Colon Cancer.
Somatic mutations of ''BCR'' have rarely been found spread throughout the gene (see '''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=BCR COSMIC June 2018]'''), indicating these are probably mostly carrier mutations. The exception may be the point mutation D1106N in the RhoGAP domain which occurs more frequently and has been associated with Colon Cancer.
{| class="wikitable sortable"
{| class="wikitable sortable"
'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
See the '''[http://www.ccga.io/index.php/BCR "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
'''[http://www.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion Acute Myeloid Leukemia (AML) with BCR-ABL1]'''
'''[http://www.ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_BCR::ABL1_fusion Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1]'''
See the '''[http://www.ccga.io/index.php/ABL1 "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
==External Links==
==External Links==
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=bcr ''BCR'' by GeneCards]''' - general gene information and summaries
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=bcr ''BCR'' by GeneCards]''' - general gene information and summaries
'''[https://www.ncbi.nlm.nih.gov/gene/613 ''BCR'' by NCBI Gene]''' - general gene information and summaries
'''[http://omim.org/entry/151410 ''BCR'' by OMIM]''' - compendium of human genes and genetic phenotypes
'''[http://omim.org/entry/151410 ''BCR'' by OMIM]''' - compendium of human genes and genetic phenotypes
'''[https://databases.lovd.nl/shared/genes/BCR ''BCR'' by LOVD(3)]''' - Leiden Open Variation Database
'''[http://www.unav.es/genetica/TICdb/results.php?hgnc=BCR ''BCR'' by TICdb]''' - database of Translocation breakpoints In Cancer
==References==
==References==
15. Cross NCP and Reiter A, (2002). Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 16:1207-1212, PMID 12094244. https://doi.org/10.1038/sj.leu.2402556.
15. Cross NCP and Reiter A, (2002). Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 16:1207-1212, PMID 12094244. https://doi.org/10.1038/sj.leu.2402556.
16. Charles NJ and Boyer DF, (2017). Mixed-Phenotype Acute Leukemia: Diagnostic Criteria and Pitfalls. Arch Pathol Lab Med. 141:1462-1468. PMID 29072953. doi: 10.5858/arpa.2017-0218-RA.
17. Manola KN, (2013). Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview. Br J Haematol. 163:24-39. PMID 23888868. doi: 10.1111/bjh.12484.
18. Wolach O and Stone RM, (2014). How I treat mixed-phenotype acute leukemia. Blood 125:2477-2485. PMID 25605373. DOI: 10.1182/blood-2014-10-551465.
19. Kawajiri C, et al., (2014). Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status. Blood 99:513-518. PMID 24532437. DOI: 10.1007/s12185-014-1531-0.
20. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.
== 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 B]]