Nature：研究揭示三阴乳腺癌难治的根源

一个由加拿大、英国、美国的59名研究人员组成的国际研究小组最新发表的研究报告显示，他们从分子层面的研究发现，不同三阴乳腺癌肿瘤的基因组其实存在很大差异，这也是常用药物对这类癌症疗效不大的重要因素，未来可能需要调整相关的治疗手法。相关论文4月4日在线发表于《Nature》.

研究人员利用电脑技术分析了100个三阴乳腺癌肿瘤的基因组，结果发现它们中没有任何两个相似，更不用说完全一样。研究人员说，鉴于它们是临床上同一类型的肿瘤，这一结果出乎意料。

报告的作者之一、加拿大西门菲沙大学教授史蒂文·琼斯解释说，通过在分子层面观察，发现上述肿瘤其实是一系列不同类型的乳腺癌肿瘤，而并非原来认为的完全一样，新发现有助解释三阴乳腺癌为何如此难治。

三阴乳腺癌约占所有乳腺癌病例中的16%，特征是雌激素受体、孕激素受体以及人表皮生长因子受体呈阴性。医学界一直认为它是乳腺癌中最致命的类型。

琼斯说，新研究发现证明有针对性的癌症药物治疗非常重要，也就是说需要根据某一类型肿瘤的基因组成选用不同药物进行治疗，而不是像以往那样，仅用一种治疗手法应对所有类型的三阴乳腺癌肿瘤。

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,Angela Tam,Noreen Dhalla,Thomas Zeng,Kevin Ma,Simon K. Chan,Malachi Griffith,Annie Moradian,S.-W. Grace Cheng,Gregg B. Morin,Peter Watson,Karen Gelmon,Stephen Chia,Suet-Feung Chin,Christina Curtis,Oscar M. Rueda,Paul D. Pharoah,Sambasivarao Damaraju,John Mackey,Kelly Hoon,Timothy Harkins,Vasisht Tadigotla,Mahvash Sigaroudinia,Philippe Gascard,Thea Tlsty,Joseph F. Costello,Irmtraud M. Meyer,Connie J. Eaves,Wyeth W. Wasserman,Steven Jones,David Huntsman,Martin Hirst,Carlos Caldas,Marco A. Marra& Samuel Aparicio

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.