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Team Finds Few Abnormalities in AML Genomes

NEW YORK (GenomeWeb News) – Relatively few genetic changes are involved in the development of acute myeloid leukemia, or AML, according to a paper scheduled to appear online this week in the Proceedings of the National Academy of Sciences.

A team of researchers from St. Jude Children's Research Hospital and the National Cancer Institute used SNP microarrays and selective resequencing to find copy number alterations, loss of heterozygosity, and point mutations contributing to AML pathogenesis. The research suggests that most types of AML involve just a few genetic changes per genome — though many of these changes affect known cancer-related genes.

"These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML," senior author James Downing, director of molecular pathology at St. Jude Children's Research Hospital, and his co-authors wrote, "which is in stark contrast to most other human malignancies."

AML is an aggressive form of cancer that affects myeloid stem cells and gives rise to irregular white blood cells. Although there are treatments available, the AML cure rate is only 60 percent or so, the researchers noted, partly due to the heterogeneous nature of the disease. Previous SNP microarray and array CGH studies have started identifying copy number changes in AML genomes. And AML genome sequencing projects are ongoing.

To continue characterizing the genomic changes underlying AML, Downing and his team first used Affymetrix SNP microarrays to assess leukemia samples from 111 children from several AML subtypes.

"The identification of the complete complement of genetic lesions within AML will not only improve our understanding of the molecular pathology of acute leukemia, but should also directly impact diagnosis and risk stratification, and may lead to the identification of new targets against which novel therapies can be developed," the authors explained.

Altogether, they detected 217 copy number alterations — roughly 2.4 per leukemia genome, on average.

But one AML subtype, FAB-M7, had far more copy number changes than the other subtypes tested. Whereas most subtypes involved nearly 1.8 copy number changes per AML genome, on average, those in the FAB-M7 subtype contained 9.3 such changes per patient.

"The complement of genetic lesions varies across the different genetic subtypes of AML, but there are very few lesions in total," Downing said in a statement. "That is surprising. Most cancers have lots of alterations."

The number of copy number alterations per leukemia genome did not correspond to treatment outcomes, they found, though the pathways affected may offer clues about the biological pathways affected in each AML subtype.

Using the genomic identification of significant targets in cancer, or GISTIC, algorithm, the researchers pinpointed five areas in the genome with significantly more gains than expected by chance and 13 that contained significantly more deletions. They also identified 24 recurrent lesions involving less than 20 million bases.

Of the nearly 1,200 genes contained in these 41 areas, just 30 overlapped with genes cataloged in the Cancer Gene Census. And of these, 21 were genes linked to AML in past studies.

The group's genomic analyses also turned up chromosomal translocations in the AML samples, including several that weren't accompanied by obvious sequence or copy number changes.

When they explored copy neutral loss of heterozygosity in AML samples, first looking at matched samples for 60 of the children and then applying these results to look at CN-LOH patterns in the other 51 patients, for whom matched samples weren't available, the researchers found that 13 percent of subjects carried detectable CN-LOH changes.

Next, the researchers re-sequenced 25 genes — 13 implicated in previous studies and a dozen from areas of interest in this study — to find point mutations involved in AML. On average, the team detected less than one non-synonymous change per leukemia.

"These data reflect a low burden of genomic alterations in pediatric de novo AML, which is in stark contrast to most other cancers." Downing and his co-authors wrote. "[O]ur data raise the possibility that the development of AML may require fewer genetic alterations than other cancers and that a very limited number of biological processes may need to be altered in hematopoietic stem cells, multi-potential progenitors, or committed myeloid progenitors to convert them from a normal into an acute myeloid leukemic cell."

In the future, Downing and his colleagues noted that it will likely be important to do more extensive genomic studies of AML as well as additional work on specific AML subtypes.

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