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Cancer-Scientists Map Cancer Patients Complete Genome

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Article-Scientists Map Cancer Patients Complete Genome

US scientists have mapped the complete genome of a middle-aged female cancer patient who died of acute myelogenous leukemia; they decoded 3 billion bits of her DNA and identified the genes involved in her disease, including 8 new ones.
The study was the work of a large team of scientists from the Washington University School of Medicine, St Louis, Missouri and the University of Washington, Seattle, Washington and is published in the 6th November issue of the journal Nature.
Acute myelogenous leukemia (AML) is a cancer of the bone marrow that makes new blood cells and it develops as a result of DNA mutations that accumulate as a person grows older.
AML is the most common type of leukemia and occurs mostly in adults over 60 years of age. About 13,000 new cases of AML will be diagnosed in the US this year and 8,800 people will die of it. The five year survival rate is 21 per cent, according to the American Cancer Society.
However, how and why the genes mutate in AML and how the altered DNA disrupts the biological pathways that lead to uncontrolled cell growth that eventually becomes a cancer tumor is still somewhat of a mystery to science.
Senior author of the study Dr Richard K. Wilson, who is director of Washington Universitys Genome Sequencing Center in St Louis, said:
Our work demonstrates the power of sequencing entire genomes to discover novel cancer-related mutations.
A genome-wide understanding of cancer, which is now possible with faster, less expensive DNA sequencing technology, is the foundation for developing more effective ways to diagnose and treat cancer, he added.
The investigators found 10 mutated sequences in the DNA of the patients tumor that appeared to be linked to AML. Eight of them were rare and found in genes that had not been linked with the disease before.
They also found that 9 of the mutations were in every cell of the tumor while the 10th, a mutation in the FLT3 gene, was only in some of them, suggesting this was the last mutation to develop.
Previous studies have discovered some common DNA variations that could be relevant to AML risk, but the enormous contribution of this study is that the investigators sifted throught 3 billion base pairs, the individual bits of code that constitute the fundamental building blocks of a persons genome, to find the individual mutations that contributed to the patients AML.
Basically what the investigators did was a full side by side genomic comparison of the of the patients normal cells DNA (taken from a skin sample) and her cancer cells DNA. This was done before the patient underwent cancer treatment which is known to alter DNA.
This type of detailed genomic comparison has never been done before; previous studies have just looked at cancer cells and sequenced genes known or suspected to be linked to cancer, which means key mutations, especially new ones, could be overlooked.
As lead author Dr Timothy Ley, who is a hematologist and the Alan A and Edith L Wolff Professor of Medicine at the Washington University School of Medicine, explained:
Until now, no one has sequenced a patients genome to find all the mutations that are unique to that persons disease.
We didnt know what we would find, but we felt that the answers to why this patient had AML had to be embedded in her DNA, said Ley.
Geneticist and former director of the National Human Genome Research Institute, Dr Francis Collins said that unlike previous studies that had been looking under the lamppost, the investigators on this landmark study lit up the whole street.
This achievement ushers in a new era of comprehensive understanding of the fundamental nature of cancer, and offers great promise for the development of powerful new approaches to diagnosis, prevention and treatment, said Collins.
Genetic tests carried out before this study had already established that the patient had two mutations known to be common in AML. This was one of the reasons the investigators chose to sequence her genome.
Of the 2.7 million single nucleotide variants in DNA of both normal and tumor cells, they found 98 per cent of them were the same, leaving some 60,000 to look at in more detail.
Using a mix of sophisticated software and analytical tools, some developed just for this study, the investigators then looked at the parts of the DNA that issue instructions for making proteins and found which ones in the tumor sample differed from the normal sample and discovered 10 mutations (including two already known to be involved in AML).
The 8 new mutations included three in genes that normally suppress the growth of tumor cells, one being the PTPRT tyrosine phosphatase gene, which is sometimes found mutated in colon cancer.
Another four of the 8 new genes appear to be ones that promote cancer growth, including one belonging to a family of genes that are switched on in embryonic stem cells and could be playing a role in self-renewal of cells, which is thought be an important characteristic of leukemia cells, said the researchers.
And the remaining gene from the 8 new ones may have contributed to the patients resistance to chemo because it appears to interfere with delivery of drugs into cells.
The investigators are still analyzing parts of the patients DNA that is non-coded, and may still find other mutations, said Dr Elaine Mardis, co-director of the Genome Sequencing Center at Washington University, and co-lead author of the study. But as she explained:
The role of these non-coding mutations will be more of a challenge to elucidate because we do not yet fully understand the function of this part of the genome.
Another interesting discovery in this study was that when they compared the 8 new mutations from this patient with the DNA of tumor samples from 187 other AML patients there were no matches: in other words the 8 mutations appeared to be unique to this patient. Wilson said this suggested:
There is a tremendous amount of genetic diversity in cancer, even in this one disease.
There are probably many, many ways to mutate a small number of genes to get the same result, and were only looking at the tip of the iceberg in terms of identifying the combinations of genetic mutations that can lead to AML, added Wilson.
One theory that Wilson and colleagues are working on is that the mutations happen in sequence, first one mutation occurs, this has a slight tendency toward cancer, then another one and so on, gradually accumulating lots of little tendencies toward cancer, until a final tipping point that causes the cancer cells to become more dangerous is reached, explained Ley.
Wilson, Ley and colleagues are now sequencing the genome of other AML patients and they also hope to extend their whole-genome method to investigate breast and lung cancers.

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