Author of

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  MO10 - Molecular Pathology II (ID 127)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Pathology
  • Presentations: 1
  • Moderators:W.A. Franklin, A. Mahar
  • Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 104, Level 1

  • 11352

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    MO10.08 - Genomic alterations in pulmonary carcinoid tumors (ID 3162)

    16:55 - 17:00  |  Author(s): C. Thomas
    • Abstract
    • Presentation
    • Slides

    Background
    Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Relatively little is known about bronchopulmonary carcinoid tumorigenesis, and understanding of these tumors has yet to benefit from the insight of genomic studies. This unfortunately has translated into relatively limited treatment options for these patients and no recent advances in therapy. We aimed to characterize genomic alterations in pulmonary carcinoid tumors under the hypothesis that a better molecular understanding may lead to improved therapeutic approaches and patient outcomes.

    Methods
    We characterized genomic alterations in pulmonary carcinoid tumors using whole genome, exome, and RNA sequencing, in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Fresh-frozen specimens from 54 patients with primary lung neuroendocrine tumors were obtained from our lung specimen registry and clinical data collected. This included a total of 31 typical and 11 atypical carcinoid tumors with associated normal tissue, and 12 SCLC. Whole transcriptome mRNA expression profiling and SNP genotyping for evaluating copy number variation was performed using Illumina array platforms. For a subset of tumors, whole genome sequencing was performed through Complete Genomics, and exome and RNA sequencing performed through BGI and the Mayo Clinic Genomics Facility. These data were correlated with the histologic subtype, stage and survival data available from this cohort of patients.

    Results
    Gene expression clearly identified distinct profiles differentiating carcinoid tumors from SCLC, though not between typical and atypical carcinoids. Copy number variations (CNV) were widely prevalent in SCLC, less frequent in AC, while TC had the lowest frequency of CNV. Validated sequencing data from exome and WGS platforms revealed a number of novel mutations for pulmonary carcinoid tumors, including ADNP, BRIP1, cyclin B3, CREBL2, GLI3, HERC1, IRAK3, NEDD4L, PRRX2, and ZDBF2, among others. RNA sequencing data did not reveal any novel fusions from analysis to date. Despite a low overall mutation frequency versus other forms of lung cancer, each carcinoid tumor had at least one potential driver mutation, suggesting possible targeted therapy opportunities for a disease where currently none exist.

    Conclusion
    Despite a low overall mutation frequency and an absence of frequently recurring mutations from the tumors sequenced to date, targeted therapy opportunities may exist through mutation profiling in broncopulmonary carcinoid tumors.

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