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This Week in NEJM: Mar 15, 2012


UPDATE: The links for the second AML article as well as the prostate cancer article have been corrected.

In NEJM this week, researchers at Washington University in St. Louis report their study of the genetic changes that underlie a patient's progression from myelodysplastic syndrome to secondary acute myeloid leukemia. The team performed whole-genome sequencing of paired skin and bone marrow samples from seven AML patients to identify the somatic mutations they carry, and then genotyped bone marrow samples obtained from the patients during their previous myelodysplastic-syndrome stage. They found that about 85 percent of bone marrow cells in these patients were clonal both in the myelodysplastic and AML stages, and that the AML samples contained mutations in 11 recurrently mutated genes, including four novel genes. "In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations," the authors write. "All founding clones and subclones contained at least one mutation in a coding gene."

In a related post at his MassGenomics blog, study co-author Dan Koboldt says the results suggest "a linear model of clonal evolution. … In other words, a single population of MDS cells underwent multiple rounds of mutation and selection, giving rise to multiple subpopulations present in full-blow secondary AML." In addition, Koboldt says, while it may in the future become possible to perform whole-genome sequencing on thousands of tumors of a certain type to absolutely determine the mutations involved, "WGS of a discovery cohort followed by extension screening in a larger cohort offers a powerful and cost-effective strategy" in the meantime.

Also in NEJM this week, researchers from across the US team up to report on the prognostic relevance of integrated genetic profiling in AML patients. The researchers performed a mutational analysis of 18 genes in 398 AML patients that were randomly assigned to received induction therapy with either high-dose or standard-dose daunorubicin. They identified at least one somatic mutation in 97.3 percent of the patients and found several mutations that were associated with reduced overall survival or improved overall survival. "We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort," the authors write. "High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations but not among patients with wild-type DNMT3A, NPM1, and MLL."

For more on the AML studies in this week's NEJM, go to Cancer Minute's sister publication GenomeWeb Daily News.

Finally in NEJM this week, a team of European researchers assess prostate cancer mortality at 11 years of follow-up. The team analyzed data from 182,160 men between the ages of 50 and 74 who were randomly assigned to receive either PSA-based screening or no screening at all. After a median follow-up of 11 years, the team found that the relative reduction in risk of death from prostate cancer was 21 percent in the screening group. "Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality," the team adds.

The Scan

Genome Sequences Reveal Range Mutations in Induced Pluripotent Stem Cells

Researchers in Nature Genetics detect somatic mutation variation across iPSCs generated from blood or skin fibroblast cell sources, along with selection for BCOR gene mutations.

Researchers Reprogram Plant Roots With Synthetic Genetic Circuit Strategy

Root gene expression was altered with the help of genetic circuits built around a series of synthetic transcriptional regulators in the Nicotiana benthamiana plant in a Science paper.

Infectious Disease Tracking Study Compares Genome Sequencing Approaches

Researchers in BMC Genomics see advantages for capture-based Illumina sequencing and amplicon-based sequencing on the Nanopore instrument, depending on the situation or samples available.

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.