《自然》发布迄今为止最大规模乳腺癌全基因组测序研究

　　2016年5月2日，《自然》（Nature）与《自然·通讯》（Nature Communications）在线发表了迄今为止最大规模的乳腺癌全基因组测序研究，揭示出了与这一疾病相关的5个新基因，以及影响肿瘤生长的13个新突变标记，还揭示出了存在于乳腺癌中的一些遗传变异及其出现在基因组中的位置。

　　该研究分析了560个乳腺癌基因组；其中556个基因组来自于女性，另外4个来自于男性。这一国际合作涉及来自世界各地，包括美国、欧洲和亚洲的一些乳腺癌患者。研究结果揭示出了更多关于乳腺癌的原因，并提供了证据证实乳腺癌基因组高度个体化。

　　每个人的癌症基因组是他们一生中获得的遗传改变的完整历史记述。随着个体从受精卵发育为成人，他们细胞中的DNA会一路收集遗传改变。这些因为人类的DNA在不断地遭受环境中一些事物的损害或是在细胞中受到磨损。这些突变会形成一些人们可以检测到的模式或突变标记，它们可提示人们一些有关癌症原因的线索。

　　该研究在每位患者的肿瘤中搜寻了促进癌症生长的突变，并寻找了突变标记。他们发现携带BRCA1或BRCA2基因，因此罹患乳腺癌和卵巢癌风险增高的妇女，彼此之间整体癌症基因组图谱高度差异，且与其他的乳腺癌也非常的不同。这一研究发现可利用来更准确地对治疗患者进行分类。在未来，人们希望可以分析个体的癌症基因组，让人们能够鉴别出针对确诊乳腺癌的女性或男性最有可能取得成功的治疗。这朝着个体化的癌症医疗又近了一步。

　　突变在乳腺癌基因组中的确切位置也很重要。该研究利用一些计算技术，分析了每个样品基因组中的遗传信息序列。遗传改变及其在癌症基因组中的位置可影响个体对癌症治疗的反应。多年来人们一直在试图弄清楚，不编码任何特定事物的一些DNA区域是否驱动了癌症发展。这项研究让人们第一次大规模地查看了基因组其余的区域，揭示出了一些乳腺癌产生的新原因，并为人们提供了一种意想不到的方式来确定发生于某些乳腺癌中的突变类型的特征。

　　所有的癌症都是在人们的一生中出现于细胞DNA中的突变所导致。寻找这些突变对于了解癌症的原因及开发改良疗法至关重要。这项庞大的研究极详细地检测了560个基因组中每一个的数千种突变，让人们朝着完整地描述乳腺癌中的DNA改变，由此全面地了解这一疾病的原因，及获得开发新疗法的机会更近了一步。

Nature. 2016 May 2. [Epub ahead of print]

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

PMID: 27135926

DOI: 10.1038/nature17676

Nat Commun. 2016 May 2;7:11383.

The topography of mutational processes in breast cancer genomes.

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

PMID: 27136393

DOI: 10.1038/ncomms11383