December 23, 2009 — The first comprehensive analyses of cancer genomes have been completed, according to new research published in the December 16 online issue of Nature. Led by researchers from the Wellcome Trust Sanger Institute in Cambridge, the United Kingdom, the entire genome of malignant melanoma and lung cancer has been sequenced.
Cancer is driven by mutation, the study authors note, and all cancer cells carry genetic mutations that are not inherited but have accumulated as the cell progresses to disease. There are more than 100 different types of cancer, but all have one thing in common: they all develop as a result of the acquisition of somatic mutations throughout the lifetime of an individual.
For both types of cancer, the researchers note that they have been able to clearly uncover imprints of these environmental mutagens on DNA, which occur years before the tumor becomes evident.
Some of these somatic alterations, called driver mutations, confer selective clonal growth advantage and are implicated in cancer development, say the researchers. The remaining mutations are "passengers," in that they do not contribute to oncogenesis. However, these passenger mutations have the imprints of the mutational mechanisms that have generated them and thus can provide valuable insights into the cause and pathogenesis of cancer.
That is fundamental to understanding the evolution of each cancer
The key thing that we really need to be moving toward is to identify all the driver mutations for individual cancers, explained Michael R. Stratton, FRCPath, FMedSci, FRS, deputy director of the Wellcome Trust Sanger Institute, and who is a coauthor of both studies. "That is fundamental to understanding the evolution of each cancer and will become fundamental to understanding how we should treat them."
Malignant melanoma and lung cancer are 2 common cancers in industrialized nations, for which the primary carcinogenic exposure is known. For lung cancer, it is cigarette smoke; for malignant melanoma, it is exposure to ultraviolet light. "We studied these two cancers in particular at this stage, because we were interested in knowing whether having a complete catalogue of somatic mutations would allow us to see the effects of ultraviolet light and tobacco smoke on DNA of the cancer," Dr. Stratton told Medscape Oncology.
"It turned out that we could see the effects of these two external mutagens with remarkable acuity in the different patterns of somatic mutation that were found in the two cancers," said Dr. Stratton, who is also joint head of the Cancer Genome Project. "Now, we can go on to other cancer types in which the environmental exposure is not known and see whether there are mysterious patterns that have no explanation."
Uncovering this information will divulge a great deal of information about the origins and development of cancer. "The mutations found will also tell us about the cancer genes that are mutated and that are driving each individual cancer," he said. "Knowing all the cancer genes in future, in each case, will allow us to make much more informed choices as to which drugs will work in the individual patient and which ones will not."
Knowing all the cancer genes in future...will allow us to make much more informed choices
Lung Cancer Genome
Smokers have more than 20 times the risk for the development of lung cancer than nonsmokers, according to the study authors, as well as an increased risk for other types of malignant diseases. Tobacco smoke contains more than 60 mutagens that will bind to and, eventually, chemically modify DNA and thus brand the lung cancer genome with characteristic mutational patterns.
In this analysis, Dr. Stratton and colleagues sequenced NCI-H209, a small-cell lung cancer cell line derived from a bone marrow metastasis of a 55-year-old man before he was treated with chemotherapy. The goal was to explore the mutational burden associated with tobacco smoking. Although the smoking history of the patient was not available, the researchers point out that the sample showed "histologically typical small cells with classic neuroendocrine features," and more than 97% of tumors with these characteristics are associated with tobacco smoking.
With use of massively parallel sequencing technology, a total of 22,910 somatic substitutions were identified, including 134 in coding exons. The investigators were able to identify many distinct point mutation patterns, which reflects the "cocktail of carcinogens present in cigarette smoke," along with signatures of the partially successful attempts made by the cell's surveillance mechanisms to repair DNA damage.
an average of one mutation for every 15 cigarettes smoked,
Lung cancer typically develops after 50 pack-years of smoking (pack-year = 7300 cigarettes). If the majority of mutations are derived from the combination of mutagens present in tobacco smoke, then the clone of cells that ultimately becomes malignant would acquire, during its lifetime, "an average of one mutation for every 15 cigarettes smoked," the study authors note. "And if this is the case for a localized cluster of cells, then the number of mutations acquired across the whole bronchial tree from even one cigarette must be substantial."
Sequencing Malignant Melanoma
The second cancer that the researchers sequenced was malignant melanoma, which comprises only 3% of skin cancer cases but causes three quarters of death due to skin cancer. In this analysis, they sequenced COLO-829, an immortal, publicly available cancer cell line that was derived, before therapy, from a metastasis of a malignant melanoma in a 43-year-old man.
A total of 33,345 base somatic substitutions were identified, providing "the first comprehensive catalogue of somatic mutations from an individual cancer." The catalogue of somatic mutations represents a cumulative record of all mutational events that have occurred during the lineage of cell divisions, beginning with the fertilized egg and ending in the cancer cell, according to the study authors.
This catalogue included the overwhelming majority of mutations present in COLO-829 and also carried the imprint of past ultraviolet-light–induced DNA damage along with evidence for auxiliary, independent mechanisms of damage.
Ultraviolet light exposure is a known environmental risk factor for the development of melanoma and the dominant mutational signature reflected DNA damage due to this factor, the study authors write. There was also evidence of attempts to repair the DNA, and "buried within it are most of the driver mutations that have conferred selective growth advantage on this melanoma."
Dr. Stratton noted that the plan is to continue sequencing cancers. "We intend to continue these studies ultimately doing thousands of cancers in the same way ourselves and together with colleagues around the globe," he said.
The authors in the lung cancer study have disclosed various financial relationships. A complete description is available in the original article. The authors in the melanoma study have disclosed no relevant financial relationships.
