Nature：大规模绘制乳腺癌基因组

近日，国际著名杂志Nature在线刊登了来自加拿大英属哥伦比亚国际大学、西蒙菲莎大学和南加州大学等研究机构研究人员的最新研究成果“The clonal and mutational evolution spectrum of primary triple-negative breast cancers，”，文章中，科学家们开展了史上最大规模的三阴性乳腺癌(triple negative breast cancer，TNBC)遗传分析研究，他们通过对超过100种三阴性乳腺癌的肿瘤样品绘制基因组，解开了这种最致命的乳腺癌的遗传密码，揭示了该疾病难于治疗的根源。

三阴性乳腺癌是指雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)均为阴性的乳腺癌。主要好发于40以下的妇女，约占乳腺癌患者总数的16%，乳腺癌死亡总数的25%。由于采用现代药物治疗效果不佳，科学家们将其视为最具致命性的乳腺癌形式。

该研究的领导者Sam Aparicio表示新研究表明三阴性乳腺癌并非仅是一种乳腺癌亚型，实际上它非常的复杂。

起初，59位科学家希望通过绘制104种肿瘤基因组找到它们之间的相似基因谱（gene profiles）。然而令他们感到惊讶的是，他们发现没有任何两个基因组是相似的，更不用说相同。

在这篇文章中，研究人员发现这104种TNBC显示了广泛和连续的基因组进化谱。一些仅包含少数的编码体细胞畸变，而另一些则包含了数百个的编码体细胞突变。高通量RNA测序(RNA-seq)揭示大约只有36%的突变得到表达。利用深度再测序（deep re-sequencing）测量2，414个体细胞突变的等位基因丰度，研究人员第一次确定了肿瘤样品间克隆频率的相对丰度，分析结果表明TNBCs克隆频率差异颇大。

“在分子水平上检测这些肿瘤让我们知道所处理的并非是一种乳腺癌亚型，而是一系列不同的乳腺癌类型，”文章的共同作者、西蒙菲莎大学分子生物学和生物化学教授Steven Jones说。

Steven Jones补充说：“尽管它们在临床上相似，然而却显示出遗传多样性，这或可解释为什么这类疾病难于治疗。这些研究发现证实了个体化癌症药物治疗的重要性，靶向特定肿瘤的基因结构而非单一治疗更适合于治疗多种看起来相似的肿瘤。”

卑诗癌症机构(BC Cancer Agency) Samuel Abraham博士说该研究强调了个体化癌症药物治疗的重要性。“通过准确区分不同类型三阴性乳腺癌，可能使我们具备解析复杂性的能力。从而为我们提供了一个潜在治疗这一疾病的把手，”Abraham说。（生物谷Bioon.com）

doi:10.1038/nature10933
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The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Sohrab P. Shah, Andrew Roth, Rodrigo Goya, Arusha Oloumi, Gavin Ha, Yongjun Zhao, Gulisa Turashvili, Jiarui Ding, Kane Tse, Gholamreza Haffari, Ali Bashashati, Leah M. Prentice, Jaswinder Khattra, Angela Burleigh, Damian Yap, Virginie Bernard, Andrew McPherson, Karey Shumansky, Anamaria Crisan, Ryan Giuliany, Alireza Heravi-Moussavi, Jamie Rosner, Daniel Lai, Inanc Birol, Richard Varhol et al.

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers1. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time—to our knowledge—in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC2, 3 showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.