Association of two BRM promoter polymorphisms with head and neck squamous cell carcinoma risk

Wang, Jennifer Rui; Gramling, Sarah; Goldstein, David P.; Cheng, Dangxiao; Chen, Duoduo; Azad, Abul Kalam; Tse, Alvina; Hon, Henrique; Chen, Zhuo; Mirshams, Maryam; Simpson, Craig D.; Huang, Shao Hui; Marquez, Stephanie; O’Sullivan, Brian; Liu, Fei‐Fei; Roberts, Heidi C.; Xu, Wei; Brown, Dale; Gilbert, Ralph W.; Gullane, Patrick; Irish, Jonathan C.; Reisman, David; Liu, Geoffrey

doi:10.1093/carcin/bgt008

Cited by 28 publications

(35 citation statements)

References 26 publications

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“…As these BRM polymorphisms are germline, the development of Rhabdoid tumors may be genetically linked, and the occurrence of Rhabdoid tumors may be partially predicted by the presence of these polymorphisms. This idea is supported by the fact that these BRM polymorphisms are known to be predictive of the development of lung, head/neck, and hepatocellular cancers thus far [21, 22, 47]. Future case control studies may reveal the relationships of these polymorphisms with cancer risk in other tumor types.…”

Section: Discussionmentioning

confidence: 89%

“…In turn, these polymorphisms are statistically correlated with cancer risk and a worse clinical outcome in a number of adult cancer types [21, 22, 43, 44]. Moreover, we have previously determined that HDAC9 and MEF2D underlie the silencing of BRM, as the shRNA knockdown of either gene results in the induction of BRM [25].…”

Section: Resultsmentioning

confidence: 99%

“…Since these BRM polymorphisms correlate with BRM loss [21], and BRM loss potentiates cancer development [17], we surmised that these BRM polymorphisms might be predictive of cancer development. To this end, we have shown that these BRM polymorphisms, and indirectly BRM loss, are statistically correlated with cancer risk with an odds ratio of 2.4-3.0 [21, 22]. In addition, these polymorphisms and BRM loss are known to predict poor clinical outcomes in lung cancer [23, 24].…”

Section: Introductionmentioning

confidence: 99%

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The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors

Kahali

Marquez

et al. 2014

Oncotarget

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Rhabdoid sarcomas are highly malignant tumors that usually occur in young children. A key to the genesis of this tumor is the mutational loss of the BAF47 gene as well as the widespread epigenetic suppression of other key anticancer genes. The BRM gene is one such epigenetically silenced gene in Rhabdoid tumors. This gene codes for an ATPase catalytic subunit that shifts histones and opens the chromatin. We show that BRM is an epigenetically silenced gene in 10/11 Rhabdoid cell lines and in 70% of Rhabdoid tumors. Moreover, BRM can be induced by BAF47 re-expression and by Flavopiridol. By selective shRNAi knockdown of BRM, we show that BRM re-expression is necessary for growth inhibition by BAF47 re-expression or Flavopiridol application. Similar to lung cancer cell lines, we found that HDAC3, HDAC9, MEF2D and GATA3 controlled BRM silencing and that HDAC9 was overexpressed in Rhabdoid cancer cell lines. In primary BRM-deficient Rhabdoid tumors, HDAC9 was also found to be highly overexpressed. Two insertional BRM promoter polymorphisms contribute to BRM silencing, but only the -1321 polymorphism correlated with BRM silencing in Rhabdoid cell lines. To determine how these polymorphisms were tied to BRM silencing, we conducted ChIP assays and found that both HDAC9 and MEF2D bound to the BRM promoter at or near these polymorphic sites. Using BRM promoter swap experiments, we indirectly showed that both HDAC9 and MEF2D bound to these polymorphic sites. Together, these data show that the mechanism of BRM silencing contributes to the pathogenesis of Rhabdoid tumors and appears to be conserved among tumor types.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors

Kahali

Marquez

et al. 2014

Oncotarget

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“…BRM demonstrates attributes of a tumor susceptibility gene, as the BRM-null mouse does not develop spontaneous tumors, but shows distinct abnormalities in cell cycle control; when combined with a carcinogen, tumor development is potentiated 18 . We reasoned, therefore, that the promoter insertion variants may be associated with cancer risk, and have confirmed that individuals carrying both BRM homozygous promoter insertion variants have a two-fold increase in the risk of lung cancer 24 , particularly early stage lung cancer 25 , and in other cancers 26–28 .…”

Section: Introductionmentioning

confidence: 84%

BRM Promoter Polymorphisms and Survival of Advanced Non–Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial

Liu

Cuffe

Liang

et al. 2017

Clinical Cancer Research

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Introduction BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741, BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression. Methods Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed. Results Carrying the homozygous variants of both polymorphisms (“double homozygotes”, DH) when compared with those carrying the double wild-type, was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95%CI: 1.9–4.0). This was confirmed in the BR.24 trial (aHR 8.97, 95%CI: 3.3–18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (p<0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH. Conclusion Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival.

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“…However, studies in cancer patients have shown that BRM loss appears to affect cancer development [15, 76-78]. Based on data derived from case-controlled studies on the presence of the BRM promoter polymorphisms, BRM loss can be indirectly linked to cancer development as well as inferior clinical outcomes [79-83]. Moreover, the fact that BRM expression can be induced or activated by deacetylation by the vast majority of, if not all, Flavonoids attests to the importance of BRM in cancer development [84].…”

Section: Discussionmentioning

confidence: 99%

Induction of functional Brm protein from Brm knockout mice

et al. 2015

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Once the knockout of the Brm gene was found to be nontumorigenic in mice, the study of BRM's involvement in cancer seemed less important compared with that of its homolog, Brg1. This has likely contributed to the disparity that has been observed in the publication ratio between BRG1 and BRM. We show that a previously published Brm knockout mouse is an incomplete knockout whereby a truncated isoform of Brm is detected in normal tissue and in tumors. We show that this truncated Brm isoform has functionality comparable to wild type Brm. By immunohistochemistry (IHC), this truncated Brm is undetectable in normal lung tissue and is minimal to very low in Brmnull tumors. However, it is significant in a subset (~40%) of Brg1/Brm double knockout (DKO) tumors that robustly express this truncated BRM, which in part stems from an increase in Brm mRNA levels. Thus, it is likely that this mutant mouse model does not accurately reflect the role that Brm plays in cancer development. We suggest that the construction of a completely new mouse Brm knockout, where Brm is functionally absent, is needed to determine whether or not Brm is actually tumorigenic and if Brm might be a tumor suppressor.

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Association of two BRM promoter polymorphisms with head and neck squamous cell carcinoma risk

Cited by 28 publications

References 26 publications

The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors

The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors

BRM Promoter Polymorphisms and Survival of Advanced Non–Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial

Induction of functional Brm protein from Brm knockout mice

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