Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line
- Maria Nattestad1,
- Sara Goodwin1,
- Karen Ng2,
- Timour Baslan1,
- Fritz Sedlazeck3,
- Philipp Rescheneder4,
- Tyler Garvin1,
- Han Fang1,
- James Gurtowski1,
- Elizabeth Hutton1,
- Elizabeth Tseng5,
- Jason Chin5,
- Timothy Beck2,
- Yogi Sundaravadanam2,
- Melissa Kramer1,
- Eric Antoniou1,
- John McPherson2,
- James Hicks1,
- W. Richard McCombie1 and
- Michael C Schatz6,7
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.
- Received October 9, 2017.
- Accepted June 27, 2018.
- Published by Cold Spring Harbor Laboratory Press
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