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Genome Res. 2018 Aug;28(8):1126-1135. doi: 10.1101/gr.231100.117. Epub 2018 Jun 28.

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

Author information

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

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.

PMID:
29954844
PMCID:
PMC6071638
DOI:
10.1101/gr.231100.117
[Indexed for MEDLINE]
Free PMC Article

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