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Genomics In The Journals: Dec 15, 2011

NEW YORK (GenomeWeb News) – Using a multi-stage meta-analysis approach, a large team has tracked down eight new loci linked to type 2 diabetes risk in east Asian populations — findings they report online in Nature Genetics.

After searching for T2D-associated variants in 6,952 T2D cases and 11,865 unaffected controls enrolled through eight past genome-wide association studies, the researchers replicated initial results from this discovery set using in silico data for more than 5,800 cases and nearly 4,600 controls. They then went on to verify T2D associations at eight sites in the genome in tens of thousands more individuals with or without the disease.

"Findings from this study highlight not only previously unknown biological pathways but also population-specific loci for T2D," co-corresponding author Mark Seielstad, a researcher affiliated with the University of California at San Francisco and the Genome Institute of Singapore, and colleagues wrote.


In agreement with a whole-genome and whole-exome sequencing study in the New England Journal of Medicine this week, Spanish researchers participating in the International Cancer Genome Consortium identified mutations in the splicing gene SF3B1 in a subset of chronic lymphocytic leukemia tumors. Recurrent mutations predicted to alter the function of proteins encoded by SF3B1 and dozens of other genes were identified through an exome sequencing study in which researchers sequenced matched tumor and normal samples from 105 individuals with CLL. In their subsequent analyses, which included targeted testing on samples from almost 300 more CLL patients, investigators found evidence for ties between SF3B1 alterations and more aggressive and deadly forms of the CLL.

Meanwhile, researchers from the US and the UK provided even more evidence that mutations to RNA splicing genes can contribute to blood cancer in their study of myelodysplastic syndromes, a set of hematopoietic stem cell disorders that can lead to treatment resistant secondary acute myeloid leukemia, or sAML.

Investigators uncovered a missense mutation in the RNA splicing gene U2AF1 when they sequenced and compared matched tumor-normal genomes from a man with MDS who developed sAML. Mutations in the same U2AF1 codon also turned up in two more MDS-derived sAML tumor genomes — and in nearly 9 percent of the 150 individuals with MDS who the researchers tested by targeted sequencing. The mutation was especially common amongst MDS patients who went on to develop leukemia.

"In many cases, the diagnosis of myelodysplastic syndromes is unclear because there isn't a straightforward diagnostic test," Washington University researcher Matthew Walter, the study's senior author, said in a statement. "By understanding at the genetic level what is contributing to this disease, we hope to eventually improve the diagnosis and treatment of this disorder."

Both the CLL and MDS studies appear in the online version of Nature Genetics.


A study in the Journal of Experimental Medicine outlines the gene expression analysis approach that a team from the US, Israel, and Spain used to study a form of leukemia called T-cell acute lymphoblastic leukemia. When they used microarrays to gauge genome-wide expression patterns in 57 adult T-ALL samples, the researchers found that the samples clustered into different disease subsets based on transcription patterns. For instance, roughly half of T-ALL tumors had expression patterns reminiscent of those found in another blood cancer, acute myeloid leukemia, or in stem cells.

The group's subsequent analyses pointed to mutations in the ETV6 genes in early immature forms of T-ALL. Meanwhile, some tumors sharing expression patterns with those in AML harbored mutations affecting genes implicated in that disease, such as IDH1, IDH2, FLT3, or DNMT3A.

"Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL characteristics," Columbia University researcher and study leader Adolfo Ferrando and co-authors wrote, "and highlight the potential role of ETV6 mutations in these tumors."


In the new, open-access Cell Press journal Cell Reports, an international team describes how it used genome sequencing to pin down PRRT2 gene mutations in a movement disorder called paroxysmal kinesigenic dyskinesia. When researchers sifted through mutation, copy number, and structural variant patterns in whole-genome sequence data generated at Complete Genomics for six individuals with PKD, they saw that all six individuals carried mutations abbreviating PRRT2, a gene coding for a transmembrane protein related to nerve cell communication. Affected individuals from all but one of the 25 best-characterized PKD families also had truncating mutations in the gene — as did individuals from 28 of 78 more PKD-affected families that were screened.

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