Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes

  1. G. TONON§,
  2. C. BRENNAN*,,
  3. A. PROTOPOPOV§,
  4. G. MAULIK*,
  5. B. FENG§,
  6. Y. ZHANG§,
  7. D.B. KHATRY§,
  8. M.J. YOU,
  9. A.J. AGUIRRE*,
  10. E.S. MARTIN*,
  11. Z. YANG*,
  12. H. JI*,
  13. L. CHIN§,,
  14. K.-K. WONG*, and
  15. R.A. DEPINHO,§
  1. *Departments of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115
  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
  3. Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02115
  4. Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115
  5. §Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

Abstract

Lung cancer is the leading cause of cancer mortality worldwide. With the recent success of molecularly targeted therapies inthis disease, a detailed knowledge of the spectrum of genetic lesions in lung cancer represents a critical step in the developmentof additional effective agents. An integrated high-resolution survey of regional amplifications and deletions and geneexpression profiling of non-small-cell lung cancers (NSCLC) identified 93 focal high-confidence copy number alterations(CNAs), with 21 spanning less than 0.5 Mb with a median of five genes. Most CNAs were novel and included high-amplitudeamplification and homozygous deletion events. Pathogenic relevance of these genomic alterations was further reinforcedby their recurrence and overlap with focal alterations of other tumor types. Additionally, the comparison of the genomic profilesof the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC), showed an almostcomplete overlap with the exception of one amplified region on chromosome 3, specific for SCC. Among the few genes overexpressedwithin this amplicon was p63, a known regulator of squamous cell differentiation. These findings suggest that theAC and SCC subtypes may arise from a common cell of origin and they are driven to their distinct phenotypic end points byaltered expression of a limited number of key genes such as p63.

Footnotes

| Table of Contents