Integrative analysis of the melanoma transcriptome (original) (raw)

  1. Joshua Z. Levin1,
  2. Krishna Vijayendran1,2,
  3. Andrey Sivachenko1,
  4. Xian Adiconis1,
  5. Jared Maguire1,
  6. Laura A. Johnson1,2,
  7. James Robinson1,
  8. Roel G. Verhaak1,2,
  9. Carrie Sougnez1,
  10. Robert C. Onofrio1,
  11. Liuda Ziaugra1,
  12. Kristian Cibulskis1,
  13. Elisabeth Laine3,
  14. Jordi Barretina1,
  15. Wendy Winckler1,
  16. David E. Fisher4,5,
  17. Gad Getz1,
  18. Matthew Meyerson1,2,6,
  19. David B. Jaffe1,
  20. Stacey B. Gabriel1,
  21. Eric S. Lander1,7,8,
  22. Reinhard Dummer3,
  23. Andreas Gnirke1,
  24. Chad Nusbaum1 and
  25. Levi A. Garraway1,2,6,9
  26. 1 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
  27. 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
  28. 3 Department of Dermatology, University of Zurich Hospital, Zurich 8091, Switzerland;
  29. 4 Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
  30. 5 Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital of Boston, Boston, Massachusetts 02199, USA;
  31. 6 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
  32. 7 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;
  33. 8 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

Abstract

Global studies of transcript structure and abundance in cancer cells enable the systematic discovery of aberrations that contribute to carcinogenesis, including gene fusions, alternative splice isoforms, and somatic mutations. We developed a systematic approach to characterize the spectrum of cancer-associated mRNA alterations through integration of transcriptomic and structural genomic data, and we applied this approach to generate new insights into melanoma biology. Using paired-end massively parallel sequencing of cDNA (RNA-seq) together with analyses of high-resolution chromosomal copy number data, we identified 11 novel melanoma gene fusions produced by underlying genomic rearrangements, as well as 12 novel readthrough transcripts. We mapped these chimeric transcripts to base-pair resolution and traced them to their genomic origins using matched chromosomal copy number information. We also used these data to discover and validate base-pair mutations that accumulated in these melanomas, revealing a surprisingly high rate of somatic mutation and lending support to the notion that point mutations constitute the major driver of melanoma progression. Taken together, these results may indicate new avenues for target discovery in melanoma, while also providing a template for large-scale transcriptome studies across many tumor types.

Footnotes

Freely available online through the Genome Research Open Access option.