Cancer, blood disorders

Cryoglobulinemia; Xeroderma pigmentosum, group B; Distal 22q11.2 microdeletion syndrome

Cryoglobulinemia is a disease characterized by the presence of cryoglobulins in the blood stream, which become solid at low temperatures leading to the blockage of blood flow through smaller vessels. Symptoms of this disease include difficulty breathing, tiredness, glomerulonephritis, joint and muscle pain, skin ulcers, and skin death. Xeroderma pigmentosum is a skin disease characterized by extreme sensitivity to ultraviolet (UV) light, which may be accompanied by neurological defects. This disease is inherited in an autosomal recessive manner. BCR (breakpoint cluster region) is a protein-serine/threonine kinase which also acts as a GTPase-activating protein for RAC1 and CDC42.
 

Chronic myeloid leukemias (CML); Myeloproliferative disorder; Lymphoblastic leukemias; Precursor T-cell acute lymphoblastic leukemias (ALL); Acute lymphocytic leukemias (ALL); Philadelphia chromosome-negative chronic myeloid leukemias (CML); Pilomyxoid astrocytomas; Gastrointestinal stromal tumours; 8p11 myeloproliferative syndrome; Myeloproliferative disorder with eosinophilias; leukemias, acute lymphoblastic 3; leukemias; Myeloid leukemias

BCR appears to be an oncoprotein (OP). The BCR gene is located on chromosome 22q11. 2, which is the site of a common breakpoint for chromosomal translocations commonly found in specific human cancers. These chromosomal translocations are observed in chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) and produce two alternative forms of the Philadelphia chromosome, in which different sets of exons from the BCR gene are joined to a common group of exons from the ABL1 gene. This creates two chimeric oncogene products referred to as p210(BCR-ABL) and p185(BCR-ABL), which both display oncogenic tyrosine kinase activity. The p210(BCR-ABL) is the more common form and is found in more than 90% of patients with CML and in 25-30% of adult and 2-10% of childhood cases of acute lymphoblastic leukemia. The twon chimeric protein products exhibit a gain-of-function in the ABL tyrosine kinase activity, which is predicted to be involved in the malignant process and development of the cancer. Approximately 10% of patients with ALL have the translocation t(9;22)(q34;q11), which is identical to the translocation observed in CML. The inhibtion of myeloid precursor cell differentiation is a key feature of the cancer progression in patients with CML that express the p210(BCR-ABL) oncoprotein. This differentiation arrest is mediated through the transcriptional suppression of the granulocyte-stimulating factor receptor (CSF3R) gene through phosphorylation by the ABL kinase domain of the fusion protein. In animal studies, transplantation of a retrovirus encoding the p210(BCR-ABL) oncoprotein into irradiated immuno-deficient mice induced hematologic malignancies with similar features as human leukemia, specifically CML.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +47, p<0.002); Colon mucosal cell adenomas (%CFC= +51, p<0.0001); and Pituitary adenomas (aldosterone-secreting) (%CFC= +49, p<0.073). The COSMIC website notes an up-regulated expression score for BCR in diverse human cancers of 423, which is 0.9-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 96 for this protein kinase in human cancers was 1.6-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25580 diverse cancer specimens. This rate is only -22 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.29 % in 805 skin cancers tested; 0.24 % in 1093 large intestine cancers tested; 0.16 % in 589 stomach cancers tested; 0.14 % in 602 endometrium cancers tested; 0.12 % in 864 upper aerodigestive tract cancers tested; 0.06 % in 1753 lung cancers tested; 0.04 % in 2161 haematopoietic and lymphoid cancers tested.

None > 4 in 20,674 cancer specimens

Only 4 deletions, 2 insertions, and no complex mutations are noted on the COSMIC website.