基因君官网
图片来源：medicalxpress.com
2016年5月4日 讯 /生物谷BIOON/ –近日，刊登在国际杂志Nature和Nature Communications上的两项研究报告中，来自桑格学院研究所等机构（Wellcome Trust Sanger Institute）科学家们进行了一项有史以来最大的乳腺癌全基因组序列研究，研究者揭示了5个疾病发生的新型基因以及13个影响肿瘤发展的新型突变标记。
研究者Serena Nik-Zainal表示，我们对560个乳腺癌基因组进行了分析，其中包括556份女性样本和4名男性样本，所有乳腺癌患者来自欧洲、美国以及亚洲等地区。每位患者的癌症基因组都是机体后天获得遗传改变的一个完整历史模板，随着个体从受精卵发育到成年期，细胞中的DNA会积累多个遗传改变。
文章中研究人员就开始寻找这些突变，而这些突变可以促进癌症发展，同时研究者还在寻找每位患者机体肿瘤的突变特性；结果发现，携带BRAC1和BRAC2基因的女性（往往患乳腺癌和卵巢癌的风险较高），不同个体之间的癌症基因组的情况并不相同，而且这些患者同其它乳腺癌患者的表现也并不相同，这或许就可以帮助研究者精确有效地区分不同类型的癌症患者。
未来研究者希望对每个个体的癌症基因组进行描述，以便他们可以开发出针对不同患者的新型个体化癌症疗法。研究者Ewan Birney说道，我们知道癌症基因组的位置和遗传改变会影响个体对癌症疗法的反应情况，而且很多年来我们一直在尽力去研究是否不从事编码工作的DNA在驱动癌症发生上扮演着重要作用，本文研究或可帮助我们理解为何乳腺癌患者的发病数量不断上升。
最后研究者Sir Mike Stratton说道，所有癌症都是由细胞中DNA的突变引发，阐明这些突变发生的机制对于理解癌症发生及开发相关疗法非常关键，本文研究的开展对于后期研究者们更加深入阐明乳腺癌发生的机制，以及开发新型个体化癌症疗法提供了新的思路和希望。（基因宝jiyinbao.com）
本文系生物谷原创编译整理，欢迎转载！点击 获取授权 。更多资讯请下载生物谷APP.
Landscape of somatic mutations in 560 breast cancer whole-genome sequences
Serena Nik-Zainal, Helen Davies, Johan Staaf, Manasa Ramakrishna, Dominik Glodzik, Xueqing Zou, Inigo Martincorena, Ludmil B. Alexandrov, Sancha Martin, David C. Wedge, Peter Van Loo, Young Seok Ju, Marcel Smid, Arie B. Brinkman, Sandro Morganella, Miriam R. Aure, Ole Christian Lingjærde, Anita Langerød, Markus Ringnér, Sung-Min Ahn, Sandrine Boyault, Jane E. Brock, Annegien Broeks, Adam Butler, Christine Desmedt et al.
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.
The topography of mutational processes in breast cancer genomes
Sandro Morganella, Ludmil B. Alexandrov, Dominik Glodzik, Xueqing Zou, Helen Davies, Johan Staaf, Anieta M. Sieuwerts, Arie B. Brinkman, Sancha Martin, Manasa Ramakrishna, Adam Butler, Hyung-Yong Kim, Åke Borg, Christos Sotiriou, P. Andrew Futreal, Peter J. Campbell, Paul N. Span, Steven Van Laere, Sunil R. Lakhani, Jorunn E. Eyfjord et al.
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.