scientists have charted the most complete cancer genomes to date, according to two studies published in Nature this week, providing a catalog of some 90% of all the somatic mutations in melanoma and a type of lung cancer, as well as a starting point for identifying potentially causal mutations common to these types of cancer.
"For the first time we have a really quite comprehensive view of two different common tumor types," said Bert Vogelstein of Johns Hopkins Medicine, who was not involved in the research. "That information will form the foundation for subsequent studies."
Previously, scientists studying cancer genomes had identified a handful of so-called driver mutations -- those that have a causative effect on the cancerous growth. But these two papers are the first to also analyze the noncoding regions of the genome, which may also contain driver mutations that could act by altering gene expression, Vogelstein said.
Using shotgun sequencing techniques, Michael Stratton of the Wellcome Trust Sanger Institute and the Institute of Cancer Research in the UK and his colleagues compiled a list of more than 50,000 somatic mutations in a small-cell lung cancer metastasis and a malignant melanoma cell line. Comparing them to known mutations in these cancer types, the researchers determined they had identified approximately 90% of all the mutations in the cancer cell lines, Stratton said. Finally, using traditional PCR techniques to search the genomes for newly identified mutations, the shotgun sequencing appeared to result in only about a 3% false positive rate. "That's a high quality catalog," Stratton said.
From these catalogs, the researchers further identified the types of mutations that were most prominent in each cancer type and found them to be consistent with their known causes of ultraviolet light and tobacco carcinogens. The lung cancer genome, for example, was riddled with G to T substitutions, while the melanoma cell line carried predominately C to T mutations.
Gerd Pfeifer, a molecular biologist at the City of Hope clinical research hospital in California, found the similarity among the mutation types within a particular cancer genome "quite surprising." While scientists had previously identified a handful of mutations found in these particular cancer types, "people thought that was maybe a unique situation," said Pfeifer, who was not involved in the research. "But it seems to be a much more general phenomenon that affects the entire genome."
Thus, by knowing the complete genomes of a variety of cancer types, Pfeifer added, "we might understand [something] about the etiology of these cancers." For melanoma and lung cancer, scientists have a pretty good understanding of what causes the mutations, but for many other cancer types, such as breast or pancreatic cancer, the "mutational signatures" revealed by these types of sequencing studies may get scientists "closer to understanding the origin of the tumors," he said.
"I think over the next year you can be absolutely confident there will be dozens if not hundreds of different tumors looked at," Vogelstein said.
In addition to sequencing more different kinds of cancers, there will be a "profound benefit" of sequencing more cell lines from the same tumor type, said Stratton. By identifying mutations that show up consistently in hundreds of different tumors of the same type, he said, scientists will be able to pinpoint additional driver mutations of specific cancers. These genes may present new drug targets for cancer therapies.
A complete list of the driver mutations in any particular cancer type can then serve as the ultimate diagnostic tool, Stratton added. Looking at a particular tumor in a particular patient and being able to identify which driver mutations it carries "will give us a good indication of which drugs the patient will respond to," he said, "[giving] us a much more refined way of applying cancer therapy to the benefit of patients."
"This is a landmark moment in cancer research," Stratton said. "From this moment on, this is going to be our expectation for what we want to know about individual cancers -- it resets our ambitions for cancer."
"For the first time we have a really quite comprehensive view of two different common tumor types," said Bert Vogelstein of Johns Hopkins Medicine, who was not involved in the research. "That information will form the foundation for subsequent studies."Previously, scientists studying cancer genomes had identified a handful of so-called driver mutations -- those that have a causative effect on the cancerous growth. But these two papers are the first to also analyze the noncoding regions of the genome, which may also contain driver mutations that could act by altering gene expression, Vogelstein said.
Using shotgun sequencing techniques, Michael Stratton of the Wellcome Trust Sanger Institute and the Institute of Cancer Research in the UK and his colleagues compiled a list of more than 50,000 somatic mutations in a small-cell lung cancer metastasis and a malignant melanoma cell line. Comparing them to known mutations in these cancer types, the researchers determined they had identified approximately 90% of all the mutations in the cancer cell lines, Stratton said. Finally, using traditional PCR techniques to search the genomes for newly identified mutations, the shotgun sequencing appeared to result in only about a 3% false positive rate. "That's a high quality catalog," Stratton said.
From these catalogs, the researchers further identified the types of mutations that were most prominent in each cancer type and found them to be consistent with their known causes of ultraviolet light and tobacco carcinogens. The lung cancer genome, for example, was riddled with G to T substitutions, while the melanoma cell line carried predominately C to T mutations.
Gerd Pfeifer, a molecular biologist at the City of Hope clinical research hospital in California, found the similarity among the mutation types within a particular cancer genome "quite surprising." While scientists had previously identified a handful of mutations found in these particular cancer types, "people thought that was maybe a unique situation," said Pfeifer, who was not involved in the research. "But it seems to be a much more general phenomenon that affects the entire genome."
Thus, by knowing the complete genomes of a variety of cancer types, Pfeifer added, "we might understand [something] about the etiology of these cancers." For melanoma and lung cancer, scientists have a pretty good understanding of what causes the mutations, but for many other cancer types, such as breast or pancreatic cancer, the "mutational signatures" revealed by these types of sequencing studies may get scientists "closer to understanding the origin of the tumors," he said.
"I think over the next year you can be absolutely confident there will be dozens if not hundreds of different tumors looked at," Vogelstein said.
In addition to sequencing more different kinds of cancers, there will be a "profound benefit" of sequencing more cell lines from the same tumor type, said Stratton. By identifying mutations that show up consistently in hundreds of different tumors of the same type, he said, scientists will be able to pinpoint additional driver mutations of specific cancers. These genes may present new drug targets for cancer therapies.
A complete list of the driver mutations in any particular cancer type can then serve as the ultimate diagnostic tool, Stratton added. Looking at a particular tumor in a particular patient and being able to identify which driver mutations it carries "will give us a good indication of which drugs the patient will respond to," he said, "[giving] us a much more refined way of applying cancer therapy to the benefit of patients."
"This is a landmark moment in cancer research," Stratton said. "From this moment on, this is going to be our expectation for what we want to know about individual cancers -- it resets our ambitions for cancer."
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