Abstract 4840: SNP rs1052566 (Ala273Val) in BRMS1 variant2 promotes metastasis in lung adenocarcinoma
Authors: Neel P. Chudgar, Yuan Liu, Joseph Montecalvo, Marty W. Mayo, Prasad S. Adusumilli, David R. Jones
Journal: Cancer Research (2017)

Abstract Background: Metastatic lung cancer kills over 180,000 people in the United States annually. Family history is one risk factor for lung adenocarcinoma (LUAD), suggesting a putative genetic predisposition to the development of LUAD. Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome and major determinants of variations in disease susceptibility, prognosis, response to medication, and toxicity. Recent studies indicate that SNPs play important roles in the progression of LUAD. We have previously shown that breast cancer metastasis suppressor-1 (BRMS1) plays a critical role in inhibiting the progression of lung cancer. We observed that SNP rs1052566 homo-variant in breast cancer metastasis suppressor-1 (BRMS1) variant 2 (v2) causes an A273V mutation. However, the role of this SNP in the progression of lung cancer remains to be determined. Methods: We utilized next-generation DNA sequencing and Taqman SNP assays to detect the prevalence of rs1052566 in 40 surgically resected LUAD specimens. Next, we generated a retroviral expressional system (pBabe puro) encoding V5-tagged BRMS1v2 wild-type (WT) and A273V mutant and created NSCLC H1299 and A549 cell lines that stably express V5-tagged BRMS1v2 WT, A273V, or vector control. The metastatic capabilities of these stable cells were evaluated by invasion chamber assays in vitro and a tail-vein injection metastasis model in vivo. To explore the mechanism(s) through which BRMS1v2 A273V promotes metastasis, we performed RT profiler PCR assay. Results: We determined that SNP rs1052566 is present in 45% of LUAD patients. Of these, the homo-variant occurs in 7.5% of patients (3 of 40). Importantly, BRMS1v2 A273V significantly promotes metastasis of NSCLC cells in vitro and in vivo. Additionally, in our mouse model, A273V was associated with decreased survival, compared with BRMS1v2 WT or control. On RT profiler PCR array, 7 genes, including L1CAM, were found to be significantly differentially regulated by BRMS1v2 WT and A273V. Confirmatory RT-PCR and immunoblots proved that BRMS1v2 A273V increases both the transcript and protein levels of L1CAM. Furthermore, we found that either c-Jun or c-Fos promotes the transcription of L1CAM. However, BRMS1v2 A273V specifically enhances c-Fos-, but not c-Jun-, induced L1CAM transcription. Conclusion: We observed that BRMS1v2 A273V abolishes the metastasis suppressor function of BRMS1 and promotes metastasis. Up-regulation of c-Fos-induced L1CAM transcription is a putative mechanism of BRMS1v2 A273V-induced metastasis. Our data suggest that SNP rs1052566, especially its homo-variant, is associated with an increased risk of metastasis in LUAD. Note: This abstract was not presented at the meeting. Citation Format: Neel P. Chudgar, Yuan Liu, Joseph Montecalvo, Marty W. Mayo, Prasad S. Adusumilli, David R. Jones. SNP rs1052566 (Ala273Val) in BRMS1 variant2 promotes metastasis in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4840. doi:10.1158/1538-7445.AM2017-4840