Cancer, neurological, and muscle disorders

Mosaic variegated aneuploidy syndrome 1; Premature chromatid separation trait

In five families with Mosaic variegated aneuploidy syndrome 1 (MVA1), including two with embryonal rhabdomyosarcoma, truncating and missense mutations of BUBR1 have been observed, including an R550Q mutation. MVA1 is a rare, recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaic aneuploides with chromosomal gains and losses. It is lkely that loss of function of BUBR1 contributions to MVA1.
 

Colorectal cancer (CRC); Plexiform neurofibromas (PNF); Colorectal cancer (CRC), somatic

BUBR1 may be a tumour suppressor protein (TSP). An R36Q mutation is linked with premature chromatid separation trait (PCS), which is an autosomal dominant disease. An R550Q mutation is found in Mosaic variegated aneuploidy syndrome 1 (MVA1), which is a severe developmental disease with characterized mosaic aneuploidies. BUBR1 acts as a tumour suppresser, and loss of function mutations are associated with tumour formation.
 

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: Barrett's esophagus epithelial metaplasia (%CFC= +71, p<0.01); Bladder carcinomas (%CFC= +187, p<0.006); Brain glioblastomas (%CFC= +150, p<0.016); Brain oligodendrogliomas (%CFC= +208, p<0.011); Breast epithelial carcinomas (%CFC= +193, p<0.068); Breast non-basal-like cancer (BLC) (%CFC= +80, p<0.0001); Breast sporadic basal-like cancer (BLC) (%CFC= +94, p<0.0001); Cervical cancer (%CFC= -53, p<0.0001); Cervical cancer stage 1B (%CFC= -64, p<0.047); Cervical cancer stage 2A (%CFC= -51, p<0.09); Classical Hodgkin lymphomas (%CFC= +164, p<0.002); Colon mucosal cell adenomas (%CFC= +158, p<0.0001); Head and neck squamous cell carcinomas (HNSCC) (%CFC= +59, p<0.0002); Large B-cell lymphomas (%CFC= +365, p<0.006); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +79, p<0.019); Oral squamous cell carcinomas (OSCC) (%CFC= +102, p<0.032); Ovary adenocarcinomas (%CFC= +747, p<0.0002); Skin squamous cell carcinomas (%CFC= +54, p<0.029); and Vulvar intraepithelial neoplasia (%CFC= +218, p<0.0002). The COSMIC website notes an up-regulated expression score for BUBR1 in diverse human cancers of 472, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 16 for this protein kinase in human cancers was 0.3-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis. A K795R mutation can inhibit the phosphotransferase activity of BUBR1, but does not abolish its ability to inhibit the anaphase promoting complex (APC)/cycolsome.

Percent mutation rates per 100 amino acids length in human cancers: 0.05 % in 25634 diverse cancer specimens. This rate is only -34 % 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: 0.22 % in 805 skin cancers tested; 0.18 % in 589 stomach cancers tested; 0.18 % in 1152 large intestine cancers tested; 0.09 % in 1270 liver cancers tested; 0.08 % in 1942 lung cancers tested.

None > 6 in 20,872 cancer specimens

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