Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk

Abstract

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 ¼ 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.

Novel Molecular Markers for Breast Cancer

“… 125 Two nonsynonymous B-Myb germline variants (rs2070235 and rs11556379) causing a serine-to-glycine or isoleucine-to-methionine amino acid change (S427G and I624M) were linked to a decrease in overall cancer risk for neuroblastomas, chronic myelogenous leukemia, and colon cancers in a combined data set of cases and controls. 126 Of note, these polymorphisms are commonly found in 10–50% of human beings. 126 Surprisingly, the former polymorphism (S427G) was linked to the increased risk of basal-like BC, 127 although the mechanism remained unknown.…”

“… 126 Of note, these polymorphisms are commonly found in 10–50% of human beings. 126 Surprisingly, the former polymorphism (S427G) was linked to the increased risk of basal-like BC, 127 although the mechanism remained unknown. To study the role of B-Myb in BC, they analyzed the expression of B-Myb in different BC subtypes and found an obvious association between the B-Myb expression and BC subtypes: it was highest in basal-like BC, followed by HER2+/ER− and luminal B, and lowest in normal-like and luminal A, 127 indicating that B-Myb expression was a sign of aggressive BC.…”

In vitro and in vivo analysis of B-Myb in basal-like breast cancer

“…B-Myb is also an important marker of poor outcome in embryonal tumors of the central nervous system (CNS) ( Pomeroy et al ., 2002 ). Recently, a nonsynonymous B-Myb germline variant (rs2070235) causing a serine to glycine amino acid change (S427G) was linked to a decrease in overall cancer risk for neuroblastomas, chronic myelogenous leukemia, and colon cancers in a combined dataset of cases and controls ( Schwab et al ., 2007 ). However, the molecular roles of B-Myb in disease progression, as well as its transcriptional target genes in the mammary gland, are still poorly understood.…”

An exploratory study of host polymorphisms in genes that clinically characterize breast cancer tumors and pretreatment cognitive performance in breast cancer survivors

“…We found significant relationships with two missense polymorphisms in MYBL2 : rs11556379 (Ile624Met, C>G) and rs2070235 (Ser427Gly, A>G). The MAs of these polymorphisms have been reported to alter protein conformation, impair regulation of downstream targets, decrease antiapoptotic activity, and reduce cancer risk 70. Interestingly, for all study participants, rs2070235–AG+GG genotypes contributed positively to attention and negatively to memory-performance scores, while rs11556379–CG+GG genotypes contributed positively to mental flexibility-performance scores.…”