Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Genome Res. 2018 Aug;28(8):1126-1135. doi: 10.1101/gr.231100.117. Epub 2018 Jun 28.
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 oncogene (also known as ), 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.
SK-BR-3 细胞系是 HER2+乳腺癌最重要的模型之一，约五分之一的乳腺癌患者受到此类癌症影响。已知 SK-BR-3 高度重排，尽管大部分变异发生在复杂且重复的区域，这些区域可能报告不足。为了解决这个问题，我们使用 Pacific Biosciences 的长读长单分子测序对 SK-BR-3 进行了测序，并开发了一种在癌症基因组中可用的最详细的结构变异 (SV) 图谱，其中存在近 20,000 个变体，其中大多数被短读长测序遗漏。在重要的 癌基因（也称为 ）周围，我们发现了嵌套重复和易位的复杂序列，表明存在间断性进展。全长转录组测序进一步揭示了嵌套基因组变异内的几个新的基因融合。长读长基因组和转录组测序的结合能够深入分析 SV 如何破坏基因组，并为癌症基因组进化中涉及的复杂机制提供新的认识。
