Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line

  1. Michael C. Schatz1,4
  1. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
  2. 2Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada;
  3. 3Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
  4. 4Johns Hopkins University, Baltimore, Maryland 21211, USA;
  5. 5Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
  6. 6Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, A-1030 Wien, Austria;
  7. 7Pacific Biosciences, Menlo Park, California 94025, USA;
  8. 8UC Davis Comprehensive Cancer Center, Sacramento, California 95817, USA
  • Corresponding author: mschatz{at}cs.jhu.edu
  • Abstract

    The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged, although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available, with nearly 20,000 variants present, most of which were missed by short-read sequencing. Surrounding the important ERBB2 oncogene (also known as HER2), we discover a complex sequence of nested duplications and translocations, suggesting a punctuated progression. Full-length transcriptome sequencing further revealed several novel gene fusions within the nested genomic variants. Combining long-read genome and transcriptome sequencing enables an in-depth analysis of how SVs disrupt the genome and sheds new light on the complex mechanisms involved in cancer genome evolution.

    Footnotes

    • Received October 9, 2017.
    • Accepted June 27, 2018.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

    | Table of Contents

    Preprint Server