《Nature》封面 癌基因组转录组变化启示录

　　

生物通报道，加拿大英属哥伦比亚大学，加拿大Michael Smith基因组科学研究中心等处的科学家在癌症基因组和转录组的研究方面取得新的进展，相关文章Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution发表在Nature杂志上，并被列为本期的封面文章。

 

随着测序技术的进步，科学家们对癌症基因组以及转录组的研究变得越来越简单快捷，人类离解开癌症奥秘的一天也越来越近。

 

加拿大的科学家们用下一代测序方法研究来自一个雌激素-受体-阿尔法-阳性的转移性小叶乳腺癌患者的基因组和转录组。

 

从原发肿瘤被诊断出到出现转移之间的9年时间内，科学家们对患者的基因组和转录组的变化进行详细的跟踪研究。对同一患者转移肿瘤和原发肿瘤中的体细胞非同义编码突变所做比较，以及对基因组和转录组数据的组合分析。

 

研究结果表明，转移灶的体细胞中发现有32个非同义编码突变，并且对这些突变位点进行了突变频率的测试。在原肿瘤组织中以上32个突变点有5个同样发生高频率突变(in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2)，有6个突变点频率低（in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A)，有19个没在原发肿瘤组织中发现。

 

这些数据表明，在癌症患者体内有一种新的RNA编辑模式，重新编码SRP9和COG3的氨基酸序列。研究者得出结论，不均匀性的单个核苷酸突变可导致乳腺癌低水平的扩散加剧疾病的发展进程。

 

封面背景图片所示为来自这项研究中所用原发小叶肿瘤的组织。

（生物通 小茜）

Nature 461, 809-813 (8 October 2009) | doi:10.1038/nature08489; Received 4 September 2009; Accepted 10 September 2009

 

Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution

 

Sohrab P. Shah1,2,8, Ryan D. Morin3,8, Jaswinder Khattra1, Leah Prentice1, Trevor Pugh3, Angela Burleigh1, Allen Delaney3, Karen Gelmon4, Ryan Guliany1, Janine Senz2, Christian Steidl2,5, Robert A. Holt3, Steven Jones3, Mark Sun1, Gillian Leung1, Richard Moore3, Tesa Severson3, Greg A. Taylor3, Andrew E. Teschendorff6, Kane Tse1, Gulisa Turashvili1, Richard Varhol3, René L. Warren3, Peter Watson7, Yongjun Zhao3, Carlos Caldas6, David Huntsman2,5, Martin Hirst3, Marco A. Marra3 & Samuel Aparicio1,2,5

 

Molecular Oncology,Centre for Translational and Applied Genomics,

Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada

Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver V5Z 1L3, Canada

Department of Pathology, University of British Columbia, G227-2211 Wesbrook Mall, British Columbia, Vancouver V6T 2B5, Canada

Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

Deeley Research Centre, BC Cancer Agency, Victoria V8R 6V5, Canada

【Abstract】

Recent advances in next generation sequencing1, 2, 3, 4 have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (>43-fold coverage) and transcriptomes of an oestrogen-receptor--positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1–13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneit