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Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.
Lee, Min Joon; Kuehne, Nathan; Hueniken, Katrina; Liang, Shermi; Rai, Sudhir; Sorotsky, Hadas; Herman, Michael; Shepshelovich, Daniel; Bruce, Jeffrey; Liang, Mindy; Patel, Devalben; Cheng, Dangxiao; Chen, Zhuo; Eng, Lawson; Brown, M Catherine; Cho, John; Leighl, Natasha B; de Perrot, Marc; Reisman, David; Xu, Wei; Bradbury, Penelope A; Liu, Geoffrey.
Afiliación
  • Lee MJ; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Kuehne N; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • Hueniken K; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Liang S; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Rai S; Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida.
  • Sorotsky H; Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida.
  • Herman M; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Shepshelovich D; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Bruce J; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Liang M; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Patel D; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Cheng D; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Chen Z; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Eng L; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Brown MC; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Cho J; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Leighl NB; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • de Perrot M; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Reisman D; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Xu W; Division of Thoracic Surgery, Department of Surgery, University Health Network, Toronto, ON, Canada.
  • Bradbury PA; Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida.
  • Liu G; Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Mol Carcinog ; 58(11): 1960-1973, 2019 11.
Article en En | MEDLINE | ID: mdl-31355511
ABSTRACT
Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pleurales / Factores de Transcripción / Fumar / Neoplasias Pulmonares / Mesotelioma Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Año: 2019 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Pleurales / Factores de Transcripción / Fumar / Neoplasias Pulmonares / Mesotelioma Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Año: 2019 Tipo del documento: Article