National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Pathol. 2010 Jan;220(2):231-43. doi: 10.1002/path.2645.
Sporadic tumours, which account for the majority of all human cancers, arise from the acquisition of somatic, genetic and epigenetic alterations leading to changes in gene sequence, structure, copy number and expression. Within the last decade, the availability of a complete sequence-based map of the human genome, coupled with significant technological advances, has revolutionized the search for somatic alterations in tumour genomes. Recent landmark studies, which resequenced all coding exons within breast, colorectal, brain and pancreatic cancers, have shed new light on the genomic landscape of cancer. Within a given tumour type there are many infrequently mutated genes and a few frequently mutated genes, resulting in incredible genetic heterogeneity. However, when the altered genes are placed into biological processes and biochemical pathways, this complexity is significantly reduced and shared pathways that are affected in significant numbers of tumours can be discerned. The advent of next-generation sequencing technologies has opened up the potential to resequence entire tumour genomes to interrogate protein-encoding genes, non-coding RNA genes, non-genic regions and the mitochondrial genome. During the next decade it is anticipated that the most common forms of human cancer will be systematically surveyed to identify the underlying somatic changes in gene copy number, sequence and expression. The resulting catalogues of somatic alterations will point to candidate cancer genes requiring further validation to determine whether they have a causal role in tumourigenesis. The hope is that this knowledge will fuel improvements in cancer diagnosis, prognosis and therapy, based on the specific molecular alterations that drive individual tumours. In this review, I will provide a historical perspective on the identification of somatic alterations in the pre- and post-genomic eras, with a particular emphasis on recent pioneering studies that have provided unprecedented insights into the genomic landscape of human cancer.
散发性肿瘤占所有人类癌症的大多数，它们是由获得体细胞遗传和表观遗传改变引起的，这些改变导致基因序列、结构、拷贝数和表达的变化。在过去的十年中，人类基因组完整序列图谱的可用性，加上重大技术进步，彻底改变了肿瘤基因组中体细胞改变的寻找。最近的一些具有里程碑意义的研究对乳腺癌、结直肠癌、脑癌和胰腺癌的所有编码外显子进行了重测序，为癌症的基因组景观提供了新的认识。在给定的肿瘤类型中，有许多罕见突变的基因和少数频繁突变的基因，导致了令人难以置信的遗传异质性。然而，当改变的基因被放置到生物过程和生化途径中时，这种复杂性显著降低，可以识别出在大量肿瘤中受到影响的共享途径。下一代测序技术的出现为重新测序整个肿瘤基因组以检测蛋白质编码基因、非编码 RNA 基因、非基因区域和线粒体基因组提供了潜力。在未来十年，预计将对最常见的人类癌症进行系统调查，以确定基因拷贝数、序列和表达的潜在体细胞变化。由此产生的体细胞改变目录将指向候选癌症基因，需要进一步验证以确定它们是否在肿瘤发生中具有因果作用。希望这些知识将基于驱动个体肿瘤的特定分子改变，为癌症诊断、预后和治疗的改进提供动力。在这篇综述中，我将提供一个历史视角，介绍在基因组前和基因组时代鉴定体细胞改变的情况，特别强调最近的开创性研究，这些研究为人类癌症的基因组景观提供了前所未有的见解。
