Integrative analysis of the melanoma transcriptome
Integrative analysis of the melanoma transcriptome
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DOI：
10.1101/gr.103697.109
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发表时间：
2010-04-01
期刊：
影响因子：
7
通讯作者：
Garraway, Levi A.
中科院分区：
文献类型：
--
作者：
Berger, Michael F.;Levin, Joshua Z.;Garraway, Levi A.
对癌细胞中转录本结构和丰度的全球研究使得能够系统地发现导致致癌的异常，包括基因融合、选择性剪接亚型和体细胞突变。我们开发了一种系统的方法，通过整合转录组和结构基因组数据来表征癌症相关mRNA改变的谱，并应用这种方法对黑色素瘤生物学产生新的见解。使用配对末端大规模并行cDNA测序（RNA-seq），结合高分辨率染色体拷贝数数据分析，我们确定了11种由潜在基因组重排产生的新型黑色素瘤基因融合，以及12种新型通读转录本。我们将这些嵌合体转录物映射到碱基对分辨率，并使用匹配的染色体拷贝数信息追踪它们的基因组起源。我们还使用这些数据来发现和验证在这些黑色素瘤中积累的碱基对突变，揭示了令人惊讶的高体细胞突变率，并支持点突变构成黑色素瘤进展的主要驱动力的观点。总之，这些结果可能表明黑色素瘤靶点发现的新途径，同时也为许多肿瘤类型的大规模转录组研究提供了模板。
Global studies of transcript structure and abundance in cancer cells enable the systematic discovery of aberrations that contribute to carcinogenesis, including gene fusions, alternative splice isoforms, and somatic mutations. We developed a systematic approach to characterize the spectrum of cancer-associated mRNA alterations through integration of transcriptomic and structural genomic data, and we applied this approach to generate new insights into melanoma biology. Using paired-end massively parallel sequencing of cDNA (RNA-seq) together with analyses of high-resolution chromosomal copy number data, we identified 11 novel melanoma gene fusions produced by underlying genomic rearrangements, as well as 12 novel readthrough transcripts. We mapped these chimeric transcripts to base-pair resolution and traced them to their genomic origins using matched chromosomal copy number information. We also used these data to discover and validate base-pair mutations that accumulated in these melanomas, revealing a surprisingly high rate of somatic mutation and lending support to the notion that point mutations constitute the major driver of melanoma progression. Taken together, these results may indicate new avenues for target discovery in melanoma, while also providing a template for large-scale transcriptome studies across many tumor types.