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AML genome answers no longer MIA
BETHESDA, Md.—The Cancer Genome Atlas (TCGA) Research Network, a massive effort to increase molecular knowledge of cancer through identification of the genetic mutations that lead to its various subtypes, has announced the release of a detailed classification of the genomic alterations and mutations that lead to acute myeloid leukemia (AML). TCGA is jointly supported and managed by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute, both of which are part of the U.S. National Institutes of Health.
AML is the most common acute form of adult leukemia, and occurs when immature white blood cells do not mature, but instead collect in the bone marrow, reducing the production of healthy blood cells and leading to anemia, abnormal bleeding, infections and, if untreated, death.
The researchers' work, which appeared online May 1 in the New England Journal of Medicine, results from their study of the tumor genomes of specimens from 200 adult cases of spontaneously occurring, newly diagnosed AML, representing all known subtypes of the cancer (in roughly the same proportion as is seen in the general population). Each patient's AML tumor genome was compared to a normal genome derived from their skin sample. Fifty of the 200 samples were analyzed with whole-genome sequencing, while the protein-coding regions of the genome were analyzed in the other samples. In each case, the researchers also used sequencing to examine RNA as well.
"Rather than just random snapshots about individual patients, this study provides a more detailed look at the aberrant genomes of AML than we have ever had before," NHGRI Director Dr. Eric D. Green said in a press release. "It has the potential to open up new directions in AML research, and perhaps, in the design of new therapeutics, its impact could be felt in the near future."
The results of the study, in addition to being informative, were also surprising. The size of the sample allowed researchers to predict that they had identified nearly all mutations that occur in at least 5 percent of AML patients—and that in general, there are comparatively few mutations, making AML tumors some of the least mutated among adult cancers. Solid tumors seen in breast, lung or pancreatic cancer generally present with hundreds of genetic mutations, but the average number for each AML genome in the TCGA's work was 13.
The team found more than 1,600 genes that were mutated at least once in the sampled tumors, and classified the recurrently mutated genes into nine categories based on the involved pathways and the genes' functions. Of the observed mutated genes, epigenetic modifiers represented the most frequently mutated class of genes.
Though relatively few recurrently mutated genes were found, the discovery of frequent alterations in genes that control gene expression stands to help highlight new potential drug targets and disease markers. Abnormal chromosome arrangement and gene fusions are often used to provide diagnoses and prognosis for AML patients, and the study not only revealed that nearly half of all the examined samples displayed gene fusions, it also drew attention to many fusions that had not previously been identified.
"Although gene fusions resulting from chromosomal rearrangements have been studied in AML for many years, this study uncovered many previously unknown, some which could be new targets," says Brad Ozenberger, Ph.D., TCGA program director. "An important message from this study and other TCGA reports is that each tumor is different. It is now quite clear that drug regimens for cancer will increasingly be customized for the particular patient, based on the specific spectrum of mutations in his/her cancer."
Previously, it had been known that signaling gene mutations were very common in AML and assumed that all tumor samples would display at least one such mutation, but the study showed that these genes are mutated in only 60 percent of cases. Mutations of the FLT3 gene, which plays a role in blood cell development, are seen in roughly a third of cases. FLT3, NPM1 and DNMT3A are commonly mutated genes in AML, and the researchers found that many AML patients present with concurrent mutations of these genes. Recurring mutations were also found in cohesin genes, which play an important role in cell division.
"This data set helps to integrate what was previously fragmented information," said Dr. Timothy J. Ley, associate director for cancer genomics at The Genome Institute at Washington University School of Medicine in St. Louis and co-leader of the study. "We didn't realize how few recurrent mutations there were, and no one was thinking even five years ago that AML was associated with a high frequency of mutations in genes that encode epigenetic modifiers."
Ozenberger says an important result of these findings "is a much better stratification of patients based on their specific mutational patterns," noting that the results "begin to describe which genetic markers should direct a physician to treat a patient more aggressively."
He says that he "absolutely" sees epigenetics, like genomics, playing a larger role in cancer study, pointing out that by performing multiple genomic analyses—such as "mutation, methylation, gene expression, rearrangements"—on the same samples, TCGA can then integrate the data "to reveal the correlations between gene sequence disruption and effects on gene expression." Methylation patterns also represent potential biomarkers, Ozenberger adds, as this work identified "particular methylation signatures associated with increased risk for recurrence."
AML is not the first type of cancer the TCGA Research Network has published such an analysis on; the group has also released reports on glioblastoma multiforme, ovarian serious adenocarcinoma, colorectal adenocarcinoma, lung squamous cell carcinoma and invasive breast cancer. And other analyses are on the way: Ozenberger says the group "has a paper in press on kidney clear cell carcinoma," and will be releasing reports soon on lung adenocarcinoma, melanoma and thyroid carcinoma. He adds that "with data now generated in TCGA on 8,000 cancer specimens in 26 different diseases, the Network has begun working hard on pan-cancer analyses," and later this year TCGA plans to publish "comparisons of the genomes across 1000s of tumors, revealing unanticipated similarities between tumor types previously not known to have the same genomic drivers."
"Elucidation of the genetic cause of disease cannot happen effectively without the basic atlas of possible changes that occur in that disease," says Ozenberger. "Each TCGA paper is historic, similar to the completion of the first representation of the human genome only 10 years ago. Each TCGA tumor report provides the essential parts list that then allows for the informed application of research dollars, private and public, to translate that information to therapies. That process cannot be started efficiently without the comprehensive views that TCGA is providing."
"We've never had such a complete picture of AML, and this data set will be mined by researchers for years," Dr. Richard Wilson, director of Washington University's Genome Institute and a co-leader of the study, commented in a statement. "These findings have probably identified every pathway in which a modification—and perhaps new drugs—might be beneficial. They also further refine our understanding of the importance of individual mutations for disease classification and prognostication, and will help us build better disease models."