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==Synonyms==
==Synonyms==
BCR, RhoGEF and GTPase activating protein; Breakpoint Cluster Region; BCR1; ALL; CML; PHL; D22S11; D22S662
BCR, RhoGEF and GTPase activating protein; Breakpoint Cluster Region; BCR1; ALL; CML; PHL; D22S11; D22S662
==Genomic Location==
==Genomic Location==
'''[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]''' (also referred as (Chronic Myelogenous Leukemia)
More than 90% of patients diagnosed with Chronic Myeloid 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]. 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 [5].
More than 90% of patients diagnosed with Chronic Myeloid 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]. 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 treated with Gleevec because the genomic instability of ALL cells contributes to point mutations arising in the BRC-ABL 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 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].
==Gene Overview==
==Gene Overview==
The function of the normal ''BCR'' gene product is as a GTPase-activating protein for RAC1 and CDC42. ''BCR'' promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them. The protein has serine/threonine kinase activity [9].
The function of the normal ''BCR'' gene product is as a GTPase-activating protein for RAC1 and CDC42. ''BCR'' promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them. The protein has serine/threonine kinase activity [9]. By far the most prevalent ''BCR'' alteration associated with cancer are the fusions of the ''ABL1'' gene with a number of partners, but especially with the ''BCR'' gene in CML [1,2] and to a lesser extent in B-ALL and T-ALL.
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 ''ABL1'' and ''ABL2'' genes encode tyrosine kinases which share overlapping physiological roles, and ''ABL2'' somatic or amplification mutations are more common than similar mutations in ''ABL1'' [6].
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/BCR "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
==Common Alteration Types==
==Common Alteration Types==
By far the most common ''ABL1'' alteration associated with cancer is the BCR-ABL1 fusion, a reciprocal translocation between chromosome 22 (BCR locus) and chromosome 9 (ABL1 locus) produces the Philadelphia chromosome t(9;22)(q34.1;q11.2), which is prevalent in Chronic Myeloid Leukemia (1, 2) and to a lesser extent in B-cell Acute Lymphoblastic Leukemia and T-cell Acute Lymphoblastic Leukemia. The head to tail arrangement of the BCR-ABL1 fusion gene results in an activated tyrosine kinase activity.
By far the most common ''ABL1'' alteration associated with cancer is the BCR-ABL1 fusion as described above in CML and ALL.
A number of other gene fusion partners have been identified with ABL1 and linked to other hematological cancers, but at a much smaller prevalence than BCR-ABL1.
A number of other gene fusion partners have been identified with ''ABL1'' and linked to other hematological cancers, but at a much smaller prevalence than BCR-ABL1.
A small number of individual patients have been described with a BCR-JAK2 (Janus Kinase 2) fusion gene leading to Chronic myeloid leukemia (CML) and other hematological neoplasms, but this fusion gene appears to be rare (12, 13, 14, also see '''[http://atlasgeneticsoncology.org/Anomalies/t0922p24q11ID1331.html] Atlas of Genetics and Cytogenetics in Oncology and Haematology]''').
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.
{| class="wikitable sortable"
{| class="wikitable sortable"
! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion
! 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
| || || || || X || X
|}
|}
==External Links==
==External Links==
'''[http://atlasgeneticsoncology.org//Genes/BCRID55.html ''BCR'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
'''[http://atlasgeneticsoncology.org//Genes/BCRID55.html ''BCR'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information