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Genomic Studies Provide Details on AML Evolution, Prognosis

NEW YORK (GenomeWeb News) – A pair of genomic studies online today in the New England Journal of Medicine by independent research groups are offering insights into the genetic patterns associated with acute myeloid leukemia development and prognosis, respectfully.

In the first of these, researchers from Washington University in St. Louis did whole-genome sequencing on matched normal and AML samples from seven individuals who had had a pre-cancerous condition called myelodysplastic syndrome prior to developing secondary AML.

After identifying potential mutations in the tumor genomes, the investigators targeted these in patient samples and used deep sequencing to look at the mutational patterns in each individual's bone marrow during secondary AML compared to those in bone marrow samples collected in the earlier, myelodysplastic syndrome stage of disease.

In the process, they found sub-populations of cells or sub-clones within the acute AML tumor that had originated in myelodysplastic syndrome. These "founding clones" took on additional mutations in AML, evolving into other clones in some cases.

"This tells us that the secondary clones were not distinct cancers, but that they all evolved from the founding clone," first author Matthew Walter, an oncology and genetics researcher at Washington University, said in a statement.

From a treatment perspective, study authors explained, that suggests that it may be possible to get a therapeutic edge on AML by targeting the mutations present in the original clonal population.

"It's probably not enough to know that a particular mutation exists in cancer cells," Washington University oncology researcher Timothy Graubert, the study's senior author, said in a statement. "We likely will need to dig deeper to find out whether a mutation is in the founding clone that initiated the cancer or in a later-evolving clone."

He and his team did paired-end sequencing with either the Illumina GAIIx or HiSeq to sequence the genomes of matched normal-bone marrow samples from seven individuals with secondary AML. Before developing AML, all seven individuals had been diagnosed with myelodysplastic syndrome, a group of blood disorders known to progress to secondary AML in around one third of cases.

From the potential point mutations and small insertions and deletions present in each patient's AML genome, the team designed custom solid-phase long-oligonucleotide arrays targeting these regions. They then captured those sequences from matched normal, AML, and myelodysplastic syndrome samples and sequenced them to an average of more than 600 times coverage.

When they compared the mutations, indels, and allele frequency patterns for AML tumor and associated myelodysplastic syndrome samples, the researchers found that each of the AML cases stemmed from a founding clone present in myelodysplastic bone marrow samples. For the individuals tested, these founding clones contained between 182 and 660 somatic mutations.

"These results clearly establish that myelodysplastic syndromes are truly an early form of cancer," Walter said. "But until now, there were a lot of people — patients and physicians included — who questioned this."

In addition to highlighting the progressive nature of the disease, analyses of genomic data for the seven AML patients — and sequences for 200 more AML tumors assessed by whole-genome or whole-exome sequencing — uncovered 11 genes that were recurrently mutated in the AML tumors. These included four genes that had not been tied to AML or myelodysplastic syndrome in the past.

In another NEJM study, a Memorial Sloan-Kettering Cancer Center-led team analyzed mutations in 18 genes in tumors from individuals with AML, looking also at how alterations in these genes related to survival rates and response to elevated chemotherapy dose.

Using data on more than 500 AML patients under the age of 60 years old who were assessed for the discovery or validation stage of that study, the researchers classified AML patients into high-, medium-, and low-risk groups.

They also found that in patients whose tumors contained alterations to either DNMT3A or NPM1, survival rates improved when higher-than-usual doses of the chemotherapy drug daunorubicin were used. The same was true for individuals whose tumors harbored MLL gene translocations.

"Information of this type could be used by a clinician for treatment planning at diagnosis and the start of therapy," co-author Hillard Lazarus, a hematology and oncology researcher at Case Western Reserve University and director of the Seidman Cancer Center's novel cell therapy program, said in a statement.

"[I]f the patient has the mutation in question, the clinician can go ahead and give the higher chemotherapy dose," he added. "If the patient does not have the mutation, a higher dose may not be of benefit."

A study published in NEJM in 2009 by researchers involved in the Eastern Cooperative Oncology Group clinical trial, including Lazarus and other authors on the new study, indicated that elevating the dose of daunorubicin used in combination with cytarabine during induction chemotherapy could improve outcomes for AML patients under 60 years old.

Using samples collected for ECOG from 398 AML patients younger than 60 years old, researchers used targeted sequencing to look at the mutation patterns in 18 genes, looking at which mutations offered prognostic information and which might help predict tumor response to the higher daunorubicin dose.

Results of the study indicated that higher daunorubicin dose is linked to a survival edge for AML patients whose tumors contained MLL translocations or mutations in DNMT3 or NPM1.

The team also described mutations that corresponded to better and worse outcomes in AML more generally. For example, consistent with past studies, they saw that individuals with certain FLT3, MLL, ASXL1 and PHF6 mutations had worse survival rates than those without, while mutations in CEBPA or IDH2 alone or mutations in NPM1 in conjunction with changes to IDH1 or IDH2 heralded more promising outcomes.

By bringing together cytogenetic and gene mutation information, the study authors came up with a prognostic scheme for classifying individuals with AML into favorable-, intermediate-, or adverse-risk groups.

In a related NEJM editorial, University of Chicago hematology and oncology researcher Lucy Godley discussed findings from both new studies and how they relate to the types of tumor profiling currently done for AML in the clinic.

As genomics-based tumor profiling becomes more commonplace in the clinic, she suggested that care will be needed to appropriately interpret the information and determine which genes are most relevant for diagnosing AML and trying to predict patient outcomes and select appropriate treatments.

"It is exciting to think that the goal of personalized medicine is quickly approaching, but it will require careful thought to implement genomic-based clinical evaluation in a way that is meaningful for patients," she concluded.

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