Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk.
The B-MYB proto-oncogene is a transcription factor belonging to the MYB family that is frequently overexpressed or amplified in different types of human malignancies. While it is suspected that B-MYB plays a role in human cancer, there is still no direct evidence of its causative role. Looking for mutations of the B-MYB gene in human cell lines and primary cancer samples, we frequently isolated two nonsynonymous B-MYB polymorphic variants (rs2070235 and rs11556379). Compared to the wild-type protein, the B-MYB isoforms display altered conformation, impaired regulation of target genes and decreased antiapoptotic activity, suggesting that they are hypomorphic variants of the major allele. Importantly, the B-MYB polymorphisms are common; rs2070235 and rs11556379 are found, depending on the ethnic background, in 10-50% of human subjects. We postulated that, if B-MYB activity is important for transformation, the presence of common, hypomorphic variants might modify cancer risk. Indeed, the B-MYB polymorphisms are underrepresented in 419 cancer patients compared to 230 controls (odds ratio 0.53; (95%) confidence interval 0.385-0.755; P=0.001). This data imply that a large fraction of the human population is carrier of B-MYB alleles that might be associated with a reduced risk of developing neoplastic disease.
Schwab
R
R
Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London, UK.
Bussolari
R
R
Corvetta
D
D
Chayka
O
O
Santilli
G
G
Kwok
J M-M
JM
Ferrari-Amorotti
G
G
Amorotti
G F
GF
Tonini
G P
GP
Iacoviello
L
L
Bertorelle
R
R
Menin
C
C
Hubank
M
M
Calabretta
B
B
Sala
A
A
D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D020570:Genes, myb; D014644:Genetic Variation; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000302:isolation & purification*; D012307:Risk Factors; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C064352:MYBL2 protein, human; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators