TY - JOUR
T1 - Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk
AU - Liu, G.
AU - Gramling, S.
AU - Munoz, D.
AU - Cheng, D.
AU - Azad, A. K.
AU - Mirshams, M.
AU - Chen, Z.
AU - Xu, W.
AU - Roberts, H.
AU - Shepherd, F. A.
AU - Tsao, M. S.
AU - Reisman, D.
N1 - Funding Information:
GL is funded by the Alan B Brown Chair in Molecular Genomics, CCO Chair in Experimental Therapeutics and Population Studies, and Posluns Family Foundation; FAS holds the Scott Taylor Chair
PY - 2011/7/21
Y1 - 2011/7/21
N2 - SWI/SNF (SWItch/sucrose non-fermentable) complexes are ATP-dependent chromatin remodeling enzymes critically involved in the regulation of multiple functions, including gene expression, differentiation, development, DNA repair, cell adhesion and cell cycle control. BRM, a key SWI/SNF complex subunit, is silenced in 15-20% of many solid tumors. As BRM-deficient mice develop 10-fold more tumors when exposed to carcinogens, BRM is a strong candidate for a cancer susceptibility gene. In this paper, we show that BRM is regulated by transcription, thus demonstrating that the promoter region is important for BRM expression. We sequenced the BRM promoter region, finding two novel promoter indel polymorphisms, BRM 741 and BRM 1321, that are in linkage disequilibrium (D′0.83). The variant insertion alleles of both polymorphisms produce sequence variants that are highly homologous to myocyte enhancer factor-2 (MEF2) transcription factor-binding sites; MEF2 is known to recruit histone deacetylases that silence BRM expression. Each polymorphic BRM insertion variant is found in 20% of Caucasians, and each correlates strongly with the loss of protein expression of BRM, both in cancer cell lines (P0.009) and in primary human lung tumor specimens (P0.015). With such strong functional evidence, we conducted a case-control study of 1199 smokers. We found an increased risk of lung cancer when both BRM homozygous promoter insertion variants were present: adjusted odds ratio of 2.19 (95% confidence interval, 1.40-3.43). Thus, we here demonstrate a strong functional association between these polymorphisms and loss of BRM expression. These polymorphisms thus have the potential to identify a sub-population of smokers at greater lung cancer risk, wherein this risk could be driven by an aberrant SWI/SNF chromatin-remodeling pathway.
AB - SWI/SNF (SWItch/sucrose non-fermentable) complexes are ATP-dependent chromatin remodeling enzymes critically involved in the regulation of multiple functions, including gene expression, differentiation, development, DNA repair, cell adhesion and cell cycle control. BRM, a key SWI/SNF complex subunit, is silenced in 15-20% of many solid tumors. As BRM-deficient mice develop 10-fold more tumors when exposed to carcinogens, BRM is a strong candidate for a cancer susceptibility gene. In this paper, we show that BRM is regulated by transcription, thus demonstrating that the promoter region is important for BRM expression. We sequenced the BRM promoter region, finding two novel promoter indel polymorphisms, BRM 741 and BRM 1321, that are in linkage disequilibrium (D′0.83). The variant insertion alleles of both polymorphisms produce sequence variants that are highly homologous to myocyte enhancer factor-2 (MEF2) transcription factor-binding sites; MEF2 is known to recruit histone deacetylases that silence BRM expression. Each polymorphic BRM insertion variant is found in 20% of Caucasians, and each correlates strongly with the loss of protein expression of BRM, both in cancer cell lines (P0.009) and in primary human lung tumor specimens (P0.015). With such strong functional evidence, we conducted a case-control study of 1199 smokers. We found an increased risk of lung cancer when both BRM homozygous promoter insertion variants were present: adjusted odds ratio of 2.19 (95% confidence interval, 1.40-3.43). Thus, we here demonstrate a strong functional association between these polymorphisms and loss of BRM expression. These polymorphisms thus have the potential to identify a sub-population of smokers at greater lung cancer risk, wherein this risk could be driven by an aberrant SWI/SNF chromatin-remodeling pathway.
KW - BRG1
KW - SWI/SNF
KW - chromatin remodeling
KW - genetic polymorphism
KW - lung cancer
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U2 - 10.1038/onc.2011.81
DO - 10.1038/onc.2011.81
M3 - Article
C2 - 21478907
AN - SCOPUS:79960717223
SN - 0950-9232
VL - 30
SP - 3295
EP - 3304
JO - Oncogene
JF - Oncogene
IS - 29
ER -