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This Week in NEJM: Mar 8, 2012


In NEJM this week, a team led by researchers from Cancer Research UK report on intra-tumor heterogeneity as revealed by multi-region sequencing, and its implications for personalized medicine. The team performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple samples from primary renal carcinomas and associated metastatic sites of four patients. "Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region," the authors write. "Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution." These findings suggest that such heterogeneity can lead to underestimation of the landscape of a tumor genome, the team adds, and may present an additional challenge for personalized medicine.

In a related editorial, NIH's Dan Longo says that although intra-tumor heterogeneity is not a new idea, previous studies had not identified the branching evolution of these mutations, nor had they shown widespread aneuploidy and allelic imbalances at the chromosome level, as this study has done. But, he adds, this is not terrible news for personalized medicine. "The findings confirm that the genetic lesions that are found in the original tumor cells, the trunk of the evolutionary tree, are consistently expressed," Longo says. "In addition, given that the tumor will do whatever is necessary to activate certain genes and inactivate others, the genes that are affected by convergent evolution may be suitable targets for functional inhibition or restoration." What this study does, he adds, is change the "simple view of directing therapy on the basis of genetic tumor markers." Cancer Minute has more on the heterogeneity study here.

Also in NEJM this week, the University of Chicago's Lucy Godley and Michelle Le Beau write a commentary about the importance of the histone code in creating treatments for acute myeloid leukemia. "The discovery that cytogenetic abnormalities were recurrent in patients with hematologic malignant lesions led to the first application of gene-based risk stratification," the researchers say. "More recently, there has been a growing appreciation of the role of chromatin structure in the biology of acute myeloid leukemia. Both covalent cytosine modifications in DNA and post-translational modifications of the histone proteins that pack DNA into nucleosomes can be altered in acute myeloid leukemia." Work is continuing in this area, they add, and new treatments are being devised.

The Scan

Single-Cell Sequencing Points to Embryo Mosaicism

Mosaicism may affect preimplantation genetic tests for aneuploidy, a single-cell sequencing-based analysis of almost three dozen embryos in PLOS Genetics finds.

Rett Syndrome Mouse Model Study Points to RNA Editing Possibilities

Investigators targeted MECP2 in mutant mouse models of Rett syndrome, showing in PNAS that they could restore its expression and dial down symptoms.

Investigators Find Shared, Distinct Genetic Contributors to Childhood Hodgkin Lymphoma

An association study in JAMA Network Open uncovers risk variants within and beyond the human leukocyte antigen locus.

Transcriptomic, Epigenetic Study Appears to Explain Anti-Viral Effects of TB Vaccine

Researchers report in Science Advances on an interferon signature and long-term shifts in monocyte cell DNA methylation in Bacille Calmette-Guérin-vaccinated infant samples.