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Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk.

ABSTRACT: 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 (P=0.009) and in primary human lung tumor specimens (P=0.015). 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.

SUBMITTER: Liu G

PROVIDER: S-EPMC3400140 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk.

Liu G G Gramling S S Munoz D D Cheng D D Azad A K AK Mirshams M M Chen Z Z Xu W W Roberts H H Shepherd F A FA Tsao M S MS Reisman D D

Oncogene 20110411 29

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, ...[more]

PMID: 21478907

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Project description:BackgroundBRM (Brahma homologue) is well known for its critical role in tumor suppression and cancer development. Genetic variations in the promoter region of BRM have been suggested to be associated with loss of BRM expression and lung cancer risk. To the authors' knowledge, no study on the role of BRM genetic polymorphisms in hepatocellular carcinoma (HCC) risk has been performed.Methodology/principal findingsIn two independent case-control studies containing 796 HCC cases and 806 cancer-free individuals, we genotyped two putative functional insertion/deletion (indel) polymorphisms [BRM-1321 (rs3832613) and BRM-741 (rs34480940)] within promoter region of BRM in Chinese populations using a PCR-based method. Real-time RT-PCR analysis was used to explore the genotype-phenotype correlation between these polymorphisms and BRM expression in both tissue samples and HCC cell lines. Logistic regression analysis showed that compared to BRM-1321del/del genotype, the ins/del and ins/ins variant genotypes had an increased HCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.19-1.82; adjusted OR = 2.55, 95% CI = 1.75-3.72, respectively]. No significant association between BRM-741 and HCC incidence was observed. However, stratification analysis revealed a significant association between ins/ins genotype of BRM-741 and increased HCC susceptibility in smokers (adjusted OR = 2.07, 95% CI = 1.33-3.22). Quantitative PCR analyses demonstrated that the genotypes of BRM-1321 and the corresponding haplotypes were significantly correlated with BRM expression in vivo. Compared with ins/ins genotype, subjects carrying ins/del and del/del genotype had 2.30 and 4.99 fold higher BRM expression in HCC tissue samples, respectively. Similar trends were observed in western blot analysis at protein level.Conclusions/significanceOur findings suggest that BRM promoter polymorphism (BRM-1321) could regulate BRM expression and may serve as a potential marker for genetic susceptibility to HCC.

Project description:BACKGROUND AND OBJECTIVE:The Brahma gene (BRM) encodes a catalytic ATPase subunit of the Switch/Sucrose non-fermentable (SWI/SNF) complex, which modulates gene expression and many important cellular processes. Two indel polymorphisms in the promoter region of BRM (BRM-741 and BRM-1321) are associated with its reduced expression and the risk of susceptibility or survival outcomes in multiple solid cancers. In this study, we have examined these variants in relation to susceptibility and survival outcomes in colorectal cancer. METHODS:Genotypes were obtained using TaqMan assays in 427 cases and 408 controls. Multivariate logistic and Cox regression models were fitted to examine the associations of the BRM-741 and BRM-1321 genotypes adjusting for relevant covariates. Sub-group analyses based on tumor location and patient sex were also performed. In all analyses, indels were examined individually as well as in combination. RESULTS:Our results showed that there was no association between the BRM polymorphisms and the risk of colorectal cancer. However, genotype combinations of the BRM-741 and BRM-1321 variants were associated with the risk of colon cancer. Particularly, patients having at least one variant allele had increased risk of colon cancer when compared to patients with the double wild-type genotype. In the survival analyses, BRM-741 heterozygosity was associated with longer progression-free survival time in the colorectal cancer patients. A stronger association was detected in the male patients under the recessive genetic model where the homozygosity for the variant allele of BRM-741 was associated with shorter progression-free survival time. CONCLUSIONS:Our analyses suggest that BRM-741 and BRM-1321 indels are associated with the risk of developing colon cancer and the BRM-741 indel is associated with the disease progression in colorectal cancer patients, especially in the male patients. Although our results show a different relationship between these indels and colorectal cancer compared to other cancer sites, they also suggest that BRM and its promoter variants may have biological roles in susceptibility and survival outcomes in colorectal cancers. Performing further analyses in additional and larger cohorts are needed to confirm our conclusions.

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Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk.

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Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk.

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