The Genomic Landscapes of Human Breast and Colorectal Cancers

Abstract

Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…45 After the completion of the Human Genome Project, 1 cancer cells have been investigated by hybridizationbased technologies, at both the genomic and the transcriptomic level. Array comparative genome hybridization -combining the genomewide coverage of chromosome banding and the high resolution of fluorescent in situ hybridization (FISH) -has allowed to detect a large number of microscopic and submicroscopic chromosomal abnormalities with clear advantages over conventional analyses.…”

Towards novel paradigms for cancer therapy

“…In contrast, a vast majority of solid cancers display multiple (epi)genetic alterations and somatic mutations that increase during progression (Shah et al, 2009), involving not only coding sequences but also non-coding RNAs. Furthermore, o10% of (epi)mutations found in tumors are indeed 'driver' mutations causally involved in tumorigenesis, whereas the rest are 'passenger' mutations that neither contribute to the onset nor to the development of the disease (Greenman et al, 2007;Wood et al, 2007). It is conceivable that tumor cells become independent of the initial (epi)mutation(s) as a result of the inherent genetic instability.…”

“…This process shapes each tumor in such a dynamic and unique way that it is extremely difficult to determine the alterations that cause, maintain and spread the disease (Greenman et al, 2007;Wood et al, 2007).…”

Grand Challenges in Computational Physiology and Medicine

“…This transformation has been driven in part by development of new technologies for high-throughput data acquisition that now make it possible to sequence genomes (Metzker, 2009), and to measure RNA (Wang et al, 2009) and protein (Maerkl, 2011) expression levels with ever increasing accuracy and lower cost. These extraordinary achievements have contributed to advances in genetic medicine (Amberger et al, 2009) and the discovery of gene and protein signatures of disease (Wood et al, 2007; Hanash and Taguchi, 2010; Addona et al, 2011; Cancer Genome Atlas Research Network, 2011; Heidecker et al, 2011; Majewski and Bernards, 2011). There is, however, growing recognition that the tabulation of molecular building blocks from which biological systems are composed is not sufficient for understanding the functional properties of these systems.…”