Thursday :: Dec 17, 2009

Huge Medical Breakthrough: Cancer Genome Sequenced

by Turkana

In health care news, researchers have mapped the genetic history of two of the most common types of cancer. As reported by The Guardian:

Scientists have reconstructed the biological history of two types of cancer in a genetic tour de force that promises to transform medical treatment of the disease.

The feat, a world first, lays bare every genetic mutation the patients have acquired over their lifetimes that eventually caused healthy cells in their bodies to turn into tumours.

The procedure gives doctors a profound insight into the biological causes of a patient's cancer and marks a major milestone in progress towards personalised anticancer therapies and strategies to prevent the disease.

By mapping both healthy and cancerous cells from the same patients, the researchers were able to isolate the mutations that took place only in the cancerous cells. Skin and lung cancer were studied, because their environmental causes are well-established.

As explained by Erin D. Pleasance, of the Sanger Institute, and her colleagues on the (firewalled) skin cancer study:

The genomes of all cancer cells carry somatic mutations1. These may include base substitutions, small insertions and deletions (indels), rearrangements and copy number alterations together with epigenetic changes. Some of these somatic alterations, known as driver mutations, confer selective clonal growth advantage and are causally implicated in oncogenesis. By definition, these are found in cancer genes. The remainder are passengers which do not contribute to cancer development. However, passenger mutations bear the imprints of the mutational mechanisms that have generated them, unsullied by processes of selection, and thus provide insights into the aetiology and pathogenesis of cancer.

Over the last quarter of a century several strategies have been used to detect the various classes of somatic mutation in cancer genomes1. As a result, approximately 400 cancer genes have been identified1, 2 ( and somatic mutations from thousands of tumours have provided insights into the mutational processes operative in human cancer1, 3.

With the advent of the human genome sequence a new strategy was proposed1, 4. Systematic sequencing would identify all somatic mutations of all classes in individual cancer genomes, yielding complete catalogues of somatic mutation. Technological limitations initially constrained this to polymerase chain reaction (PCR)-based re-sequencing of the coding exons of protein-coding genes in order to find base substitutions and small indels5, 6, 7, 8, 9, 10. Recently, however, several novel technologies have been developed11, 12. These allow sequencing of randomly generated DNA fragments from cancer genomes and thus detect rearrangements and copy number changes as well as base substitutions and small indels, providing sufficient coverage to identify most somatic mutations in an individual cancer genome. These technologies have previously been used to reveal missense mutations in the coding sequences of two acute myeloid leukaemia genomes13, 14. Here, we report the first comprehensive catalogue of somatic mutations from a cancer genome.

And more specifically, Pleasance and her colleagues on the lung cancer study (also firewalled):

Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3–8 of CHD7 in frame, and another two lines carrying PVT1–CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

More than 1 billion people worldwide smoke tobacco1. With 20× greater risk of developing lung cancer than non-smokers and increased risk of many other tumour types, a smoker’s lifestyle choice represents the most significant carcinogenic exposure confronting health services today. Tobacco smoke contains more than 60 mutagens that bind and chemically modify DNA2, 3, and these brand the lung cancer genome with characteristic mutational patterns. Point mutations in, for example, TP53 and KRAS show different signatures between smokers and non-smokers with lung cancer2, 3, 4. However, such studies have been limited to a few genes, and it is unclear how representative these findings are of mutational processes across the whole genome5. In vitro assays and mouse models have been important tools for testing the mutagenicity of individual chemical constituents of tobacco smoke, but are of limited value for generalizing to the complexity of smoking behaviours, systemic metabolism and cancer development in humans. Massively parallel sequencing technologies promise the capacity to paint a genome-wide portrait of mutation in human cancer. Such data will provide unprecedented insights into the relative contributions of different tobacco carcinogens to mutation in vivo, the effects of local DNA structure on mutability and the cellular defence mechanisms against exogenous mutagens.

Lung cancer is the leading cause of cancer-related deaths worldwide, developing in more than a million new patients annually6...

Here, we report the first detailed analysis of a human cancer classically associated with tobacco smoking, giving unprecedented insights into the mutational burden associated with this lifestyle choice. Such analyses highlight the advances that will be made in our understanding of the pathogenesis of cancer as we sequence hundreds to thousands of human tumours15.

As explained in Nature:

Peter Campbell, a haemotologist and cancer-genomics expert at the Sanger Institute who worked on the latest studies, says that the number of genetic mutations they identified — 33,345 for melanoma and 22,910 for lung cancer — was remarkable. The mutations were not distributed evenly throughout the genome — many were present outside of gene-coding regions, suggesting that cells had repaired damaged DNA in those key regions.

Campbell says that the findings help to answer lingering questions about whether carcinogens cause most mutations directly, or if cancer itself contributes to the mutations by disrupting the function of DNA-repair mechanisms. The team found that most mutations were single-base DNA substitutions that could be traced to the carcinogenic effects of chemicals in tobacco smoke (in the case of the small-cell lung cancer genome) or ultraviolet light (in the melanoma genome), supporting the idea that these two cancers are largely preventable. The team estimates that every 15 cigarettes smoked results in a DNA mutation. "Every pack of cigarettes is like a game of Russian roulette," Campbell says. "Most of those mutations will land where nothing happens in the genome and won't do major damage, but every once in a while they'll hit a cancer gene."

Beyond once again being a clear reminder of the dangers of tobacco- more than one mutation for every pack of cigarettes smoked!- this should open the door to entirely new forms of treatment. CNN:

Researchers predict these maps will offer patients a personalized treatment option that ranges from earlier detection to the types of medication used to treat cancer.

The genetic maps will also allow cancer researchers to study cells with defective DNA and produce more powerful drugs to fight the errors, according to the the study's scientists.

"The knowledge we extract over the next few years will have major implications for treatment," Peter Campbell from the Wellcome Trust Sanger Institute said.

Skin cancer and lung cancer are largely preventable. We all know that, and hopefully this will serve as a reminder to those who have yet to consider modifying their lifestyles better to avoid contracting these cancers. But more importantly, it's also a breakthrough towards the day when cancer, itself, will be more completely managed and treated and cured.

Turkana :: 1:14 PM :: Comments (10) :: Spotlight :: Digg It!