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Study Suggests Blood Stem Cell Aging is Source of Background Mutations in AML

NEW YORK (GenomeWeb News) – Almost all of the mutations detected in acute myeloid leukemia genomes result from blood stem cell aging, with just a few mutations spurring development of the disease, according to a study in today's issue of Cell.

"It's not hundreds of mutations that are important but only a few in each patient that push a normal cell to become a cancer cell," senior author Richard Wilson, director of the Genome Institute at Washington University in St. Louis, said in a statement. "Finding these mutations will be important for identifying targeted therapies that can knock down a patient's cancer."

Given the extent of the mutations found in past AML studies, the relatively low recurrence of these mutations, and the types of genes affected, Wilson and colleagues from Washington University and the MD Anderson Cancer Center suspected that some, or even many, of these alterations might have been present in blood stem cells prior to the introduction of AML-causing mutations.

"Many of the mutations we were seeing didn't seem like obvious sorts of genes that might be involved in cancer development, nor were they common across several patients with the same disease," Wilson told GenomeWeb Daily News. "So the question was: what really goes on in these stem cells in the course of a lifetime?"

To explore this further, they used Illumina GAII or GAIIx instruments to sequence tumor and matched normal skin sample genomes from two-dozen individuals with AML to an average haploid coverage of 28 times. These samples represented 12 cases of "M3" AML, in which tumors contain a fusion between the PML and RARA genes that's thought to help spur AML development. The remaining 12 samples belonged to the "M1" form of AML, which lacks the PML-RARA fusion.

Consistent with previous AML sequencing studies, the tumor samples contained a wide range of single base mutations, small insertions and deletions, and structural variants affecting coding, regulatory, and uncharacterized regions in the genome.

After using targeted Illumina sequencing and custom, patient-specific NimbleGen capture arrays to verify apparent mutations, the researchers found that each AML genome contained 440 validated mutations, on average. But, as shown in the past, the number of somatic single nucleotide glitches present in each tumor climbed with increasing patient age.

And coding sequences generated from healthy volunteers' blood stem cell samples contained age-associated mutations too. When the team did exome sequencing on blood stem cell samples from seven individuals ranging in age from infancy to more than 70 years old, it uncovered an age-related rise in mutations in hematopoietic stem/progenitor cells — cells found in the bone marrow that give rise to various blood cells, including those that become over-represented in individuals with AML.

"It really fit quite perfectly with what we were seeing in the tumors," Wilson said.

Based on their findings, the study authors proposed that these hematopoietic stem/progenitor cell mutations accumulate over time as a consequence of glitches introduced during cell division.

Their prevalence in healthy individuals indicates that most are harmless on their own. On the other hand, if a cancer-causing mutation gets added to the mix, some of these existing mutations may contribute to the success of clones containing cancer drivers.

"We accumulate mutations and, at some point, the odds fail you and you take a hit in a part of your genome that's really critical for good health," Wilson explained.

This new model for understanding AML mutations can offer a context for figuring out which are required to drive disease development, he said.

That information, in turn, is expected to be useful for not only clarifying the pathways that can lead to cancer, but also in helping to define mutations that are useful for classifying disease or guiding treatment decisions.

"In leukemia, you typically see about a dozen coding mutations in a patient's tumor. And a small number of those tend to be recurrent," he said. "The question has always been, 'How many events does it take to drive development of the cancer and which mutations and which genes are key in establishing the disease?'"

From the mutations present in the 24 AML M1 and M3 genomes and in other AML samples assessed in follow-up stages of the study, the team narrowed in on mutations in a few key genes suspected of initiating AML in each subtype.

In the M1 AML tumors missing the PML-RARA fusion, for example, researchers found recurrent mutations in 13 genes, including NPM1, DNMT3A, and IDH1, which were often mutated together in the M1 tumors and appear to be promising driver candidates.

They also started putting together a preliminary list of genes with mutations that don't appear to cause AML on their own, but which might interact with cancer-initiating changes to improve a tumor's chance of success.

"It gives us a good first glimpse," Wilson said. "There are obviously some patterns, but there are still some questions that are left by not being able to find obvious cooperating events in some of these patients."

"One thing this screams out for is a much deeper dataset," he added.

Indeed, the team is already doing genomic analyses on 200 more AML tumors collected for the Cancer Genome Atlas, or TCGA, study. In addition to DNA sequencing, those samples are being tested using other approaches such as RNA sequencing and epigenetic analyses.

More broadly, it remains to be seen whether the model of mutation accumulation identified in blood stem cells holds in the tissues that give rise to other kinds of cancer, particularly solid tumors.

"I think there are lessons from this for solid tumors, but I think at the same time you have to come at [these cancers] a little differently," Wilson said. "It really is going to depend on what tumor type we're talking about."