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

Nattestad, M.; Goodwin, S.; Ng, K.; Baslan, T.; Sedlazeck, F. J.; Rescheneder, P.; Garvin, T.; Fang, H.; Gurtowski, J.; Hutton, E.; Tseng, E.; Chin, C.-S.; Beck, T.; Sundaravadanam, Y.; Kramer, M.; Antoniou, E.; McPherson, J. D.; Hicks, J.; McCombie, W. R.; Schatz, M. C.

doi:10.1101/174938

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bioRxiv · 10.1101/174938

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

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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 prior efforts. Surrounding the important HER2 locus, 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 transcriptome and sheds new light on the complexity of cancer progression.

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Nattestad, M., Goodwin, S., Ng, K., Baslan, T., Sedlazeck, F. J., Rescheneder, P., Garvin, T., Fang, H., Gurtowski, J., Hutton, E., Tseng, E., Chin, C.-S., Beck, T., Sundaravadanam, Y., Kramer, M., Antoniou, E., McPherson, J. D., Hicks, J., McCombie, W. R., Schatz, M. C.. 2017-08-10. Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line. https://doi.org/10.1101/174938

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