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John Cho

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-23 - Association of Two BRM Promoter Polymorphisms and Tobacco Exposure with Malignant Pleural Mesothelioma (MPM) Risk and Survival (ID 12738)

      16:45 - 18:00  |  Author(s): John Cho

      • Abstract


      Brahma (BRM) is a critical ATPase subunit of the SWI/SNF chromatin remodeling complex. Homozygous 6-7bp insertion variants at two polymorphic promotor sites (BRM-741/BRM-1321) cause epigenetic suppression of BRM expression and they have been reported as susceptibility and/or prognostic markers in many malignancies, including non-small cell lung cancer. As epigenetic silencing of BRM can be reversed pharmacologically, targeting BRM polymorphisms has significant therapeutic potential. We evaluated BRM-741/BRM-1321 polymorphisms’ association with risk and prognosis of malignant pleural mesothelioma (MPM). While the effect of tobacco in MPM remains controversial, its interaction with genetic polymorphisms in MPM is largely unknown. We evaluated associations between BRM polymorphisms-tobacco exposure and MPM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      MPM and age-distribution matched asbestos-exposed controls were recruited as part of an asbestos-exposure surveillance program. Participants were genotyped for BRM polymorphisms. Multivariable logistic regression assessed risk of MPM in case-control analyses. Association of BRM variants with overall survival (OS) was assessed by multivariable Cox regression. Secondary subset analyses were performed, stratified by smoking status.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 265 MPM cases, 146 (55%) were ever-smokers; 51 (19%) were female; median age was 66 (range:21-84) years. Median OS was 18 months; median follow-up time was 15 months. Compared to 795 controls, there were no significant associations of BRM with risk (P>0.10, all comparisons). In contrast, compared to the wild-type genotype, the homozygous variant of BRM-741 and BRM-1321 were associated with lower OS, with adjusted hazard ratio (aHR)=2.56 [95%CI:1.7-3.8] and 2.07 [95%CI:1.4-3.1], respectively. Compared to patients carrying the double wild-type, patients homozygous at both loci had lower OS (aHR=2.70 [95%CI:1.7-4.4]).

      There was a significant differential effect of BRM polymorphisms on risk of MPM, by smoking status (interaction P<0.001): among ever-smokers, BRM homozygous variants in BRM-741, BRM-1321, or both conferred lower risks (adjusted odds ratios, aORs were between 0.18-0.28; each P<0.001), while for never-smokers, there was significantly greater risk conferred by carrying the homozygous variants (aORs between 2.7-4.4). Likewise, a similar differential effect by smoking status was seen in prognosis (interaction P<0.001): there was no association between BRM polymorphisms and OS in ever smokers (P>0.1, all comparisons), but in never-smokers, the aHR of carrying homozygous variants of BRM-741, BRM-1321 or both were 7.7 [95%CI:3.8-16], 4.0 [95%CI:2.1-7.7], and 8.6 [95%CI:3.7-20], respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Never-smokers who develop malignant pleural mesothelioma have an increased chance of carrying BRM homozygous variants in their germline DNA, which results in substantially worse prognosis. In contrast, in smokers, there may be a protective effect, with no difference in overall survival.


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    PC01 - Controversies in Mesothelioma (ID 840)

    • Event: WCLC 2018
    • Type: Pro-Con Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 AC
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      PC01.05 - PRO Radiation Options: Are We SMART Enough? (ID 11602)

      11:30 - 11:45  |  Presenting Author(s): John Cho

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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