Our changing view of the genomic landscape of cancer.

Abstract

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.