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Experts Review Cancer Genomics Progress

NEW YORK (GenomeWeb News) – Researchers' current understanding of the cancer genome — and future cancer genomics goals — were the focus of a review article appearing online today in Nature.

Wellcome Trust Sanger Institute Cancer Genome Project members Michael Stratton, Peter Campbell, and Andrew Futreal penned the review, which discuss everything from the general role of somatic mutations in cancer to cancer genome sequencing. The trio also addressed the role of international projects in these sequencing efforts.

In general, cancers appear to evolve from individual cells to tumors through a process involving randomly-acquired mutations selected by natural selection within a cell population and microenvironment, the authors explained.

Cancer cells may harbor a range of somatic mutations such as insertions, deletions, substitutions, rearrangements, and copy number changes that accumulate over time due to environmental exposure to mutagens, replication errors, or inherited diseases, the authors noted. Epigenetic changes and virally-induced mutations may also contribute to cancer development.

Researchers discovered the first "cancer gene" — HRAS — in the early 1980s. Over the past few decades, tens of thousands more cancer-related mutations have been identified.

"Although complex and potentially cryptic to decipher, the catalogue of somatic mutations present in a cancer cell ... represents a cumulative archeological record of all the mutational processes the cancer cell has experienced throughout the lifetime of the patient," the authors wrote. "It provides a rich, and predominantly unmined, source of information for cancer epidemiologists and biologists with which to interrogate the development of individual tumors."

Along with identifying such mutations in general, the authors noted, studying cancer genomes helps to distinguish between driver mutations that offer a growth advantage for cancer cells and passenger mutations that don't, Stratton and co-authors explained. By finding genes that tend to acquire causal mutations, they added, it may be possible to get at some of the biology underlying oncogenesis.

So far, researchers have identified recurrent mutations in at least 350 protein-coding genes that contribute to cancer development. About ten percent of the mutations discovered so far are inherited.

Although the nature and rate of mutation vary by tissue and cancer type, researchers have been able to pick out some mutation patterns. For instance, the authors explained, about 90 percent of mutations are dominant, promoting cancer when they're found on just one allele, while others are recessive, causing cancer when both alleles are affected.

More specifically, identifying mutations in specific genes can provide clues about the biological pathways involved in cancer development. That, in turn, can inform cancer treatment. Studying cancer genomes may also uncover mutations influencing cancer therapy response and treatment outcomes.

The human reference genome sequence has enabled more detailed cancer genetic studies, the authors explained, including sequencing, copy number and other studies. As whole genome sequencing becomes more widespread, researchers are "moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes."

The authors cautioned that cataloguing all somatic mutations in cancer genomes will likely require deep sequencing of both cancer and normal genomes — an effort that could involve sequencing roughly 100 billion bases of DNA sequence for each cancer genome.

Even so, they wrote, there are already efforts being made on this front, including collaborative projects, such as the International Cancer Genome Consortium, which is attempting to sequence 50 cancer types under a set of standard guidelines. And as costs decrease and sequencing becomes more routine, Stratton and his co-authors added, the insights gained from large-scale sequencing efforts could help inform cancer diagnosis, prognosis, and treatment options.

"Approximately 100,000 somatic mutations from cancer genomes have been reported in the quarter of a century since the first somatic mutation was found in HRAS. Over the next few years several hundred million more will be revealed by large-scale, complete sequencing of cancer genomes," the trio wrote. "These data will provide us with a fine-grained picture of the evolutionary processes that underlie our commonest genetic disease, providing new insights into the origins and new directions for the treatment of cancer."

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