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E. Wieben



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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.03 - Oncogene Mutations and Novel Transcript Fusions in Lung Adenocarcinoma from Never Smokers (ID 2939)

      10:50 - 11:00  |  Author(s): E. Wieben

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma from never smoker represents a unique disease entity in that they often involve females of younger age and have a distinct mutation spectrum compared to those of smoker population. Mutations from the tumors of these patients often involve oncogenes that can be targeted for therapy by small molecule kinase inhibitors. We surveyed for tumor specific genetic changes in lung adenocarcinomas from never smokers for common oncogene mutations and transcript fusions.

      Methods
      We first developed a multiplex assay detecting187 mutations in 10 actionable oncogenes frequently affected in lung cancer. We used this assay to examine 89 lung adenocarcinomas from never smokers identified through the Mayo Clinic Epidemiology and Genetics of Lung Cancer Program. NextGen sequencing (RNASeq) was used to identify transcript fusions affecting either a known kinase or an oncogene in 20 of 89 tumors. RT-PCR, FISH and IHC were used to verify the novel fusion identified in this study.

      Results
      Sixty-four tumors had mutation in at least one of the tested oncogenes involving EGFR (49 cases, 55%), k-RAS (5 cases, 6%), MET (9 cases, 10%), BRAF (4 cases, 5%), PIK3CA (2 cases, 2%), and ERBB2 (4 cases, 5%). RNAseq identified five transcript fusions among the 20 tested tumors, involving known fusions of EZR- ROS1 or KIF5B-RET and three novel fusions involving SND1-BRAF, EML4-BIRC6, and GMEB2-TERT genes. We used RT-PCR to confirm the presence of the SND1-BRAF fusion transcript that involved exons 1-9 of SND1 with exon 2 to 3’ end of the BRAF on chromosome 7. Screening all 89 tumors by RT-PCR identified a total of three tumors with the identical fusion. Interestingly, two of these three tumors with a BRAF fusion also had a concurrent mutation in EGFR gene (S768I) and a third tumor had an additional mutation in the ERBB2 gene (M774_A775ins). Four additional samples were positive for EML4-ALK fusion by IHC and FISH.

      Conclusion
      In our study of a primarily Caucasian population, a majority of lung adenocarcinomas from never smokers (70/89, or 78.6%) carry at least one genetic mutation in a targetable gene. For the first time, we report the presence of a transcript fusion involving SND1-BRAF in lung adenocarcinoma and that these fusions are present in tumors also having EGFR or ERBB2 mutations. Combined together, activation of BRAF by either point mutation or transcript fusion is one of the most frequent events in our study accounting for 7/89 (8%) cases. These findings support a rapid and targeted gene mutation testing strategy for lung adenocarcinoma from never smokers, as the knowledge of these mutations can be readily used to augment therapeutic management.

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