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Genomics In The Journals: Nov 15, 2012

NEW YORK (GenomeWeb News) – Two new Nature Genetics studies implicate mutations in same gene — ID3 — as contributors to Burkitt lymphoma, a form of B-cell lymphoma.

For their part, researchers with the International Cancer Genome Consortium's Molecular Mechanisms in Malignant Lymphomas Sequencing, or ICGC MMML-Seq, project tell of how they uncovered recurrent mutations in ID3 using integrated genome, exome, and transcriptome sequence data from four Burkitt lymphoma tumors known to harbor a translocation involving an immunoglobulin gene and a MYC oncogene.

From the seven recurrently mutated genes identified in their integrated analysis, investigators focused in on ID3, determining that the gene was mutated in 68 percent of the IG-MYC translocation-containing Burkitt lymphomas. On the other hand, just 13 percent of the other IG-MYC translocation-positive B-cell lymphomas tested had ID3 alterations, prompting the study's authors to propose that "the combination of ID3 inactivation and IG-MYC translocation is a characteristic property of Burkitt lymphoma pathogenesis."

Mutations affecting ID3 were also discovered by a team from the US, UK, and China. For that study, researchers performed whole-genome sequencing on matched tumor and normal samples from one individual with Burkitt lymphoma, along with exome sequencing on dozens more Burkitt lymphoma tumors. When they sifted through this sequence data and compared it to exome sequences from a set of diffuse large B-cell lymphomas, or DLBCLs, that group uncovered 70 genes recurrently mutated in Burkitt lymphoma. Among them was ID3, which was mutated in around one-third of Burkitt lymphoma cases, but not in the DLBCL tumors. Together, the researchers say, such findings support the notion that ID3 may act normally as a tumor suppressor in Burkitt lymphoma, while mutations in the gene spur on cell cycle progression and cellular proliferation.

Earlier this year, a National Institutes of Health-led team reported on pathways that appeared to be recurrently mutated in Burkitt lymphoma based on analyses of RNA sequence data from Burkitt lymphoma tumors and cell lines. That work also highlighted the potential importance of mutations to ID3 — and a related transcription factor called TCF3 — in Burkitt lymphoma risk.

A team that includes members of the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project has identified a gene fusion that appears to act as a driver mutation in some cases of non-Down syndrome-associated pediatric acute megakaryoblastic leukemia, or AMKL, a form of childhood acute myeloid leukemia.

As they report in Cancer Cell, researchers found that the fusion — which involves the CBFA2T3 and GLIS2 genes — via transcriptome sequencing of matched tumor and normal samples from 14 children with non-Down syndrome-AMKL and whole-genome sequencing on samples from four children with the disease. The CBFA2T3-GLIS2 fusion subsequently turned up in nearly 30 percent of pediatric AMKL cases assessed, including those with some of the most aggressive and treatment resistant tumors. In contrast, the fusion was not found in adult AMKL tumors.

"The discovery of the CBFA2T3-GLIS2 fusion gene in a subset of patients with AMKL paves the way for improved diagnostic testing, better risk stratification to help guide treatment and more effective therapeutic interventions for this aggressive childhood cancer," senior author James Downing, deputy director, scientific director and executive vice president at St. Jude's Children's Research Hospital, said in a statement.

The University of Washington's Jay Shendure, Evan Eichler, and their colleagues has described a targeted sequencing approach for finding genes recurrently altered by de novo mutations in individuals with autism spectrum disorder for a new study in the early, online version of Science.

The team used this modified molecular inversion probe technique to capture and sequence 44 genes suspected of having a role in idiopathic ASD based on previous studies of syndromic ASD and/or other neurodevelopmental and neuropsychiatric conditions. When they sequenced this gene set in nearly 2,500 individuals with ASD from the Simons Simplex Collection, for instance, investigators tracked down 27 de novo mutation events affecting 16 genes. From findings so far, they estimated that recurrent glitches in half a dozen of these genes are at play in around 1 percent of sporadic ASD cases. The work also provided new clues about how some ASD phenotypes such as head size may relate to mutations in certain genes.

Moreover, Shendure, Eichler, and co-authors wrote in the paper that the "analytical framework described here can be applied to any other disorder — simple or complex — for which de novo coding mutations are suspected to contribute to risk."

"Additionally, the experimental methods presented here are broadly useful for the rapid and economical resequencing of candidate genes in extremely large cohorts," they added, "as may be required for the definitive implication or rare variants or de novo mutations in any genetically complex disorder."

Members of a large China- and Mongolia-led consortium have sequenced draft versions of the wild and domestic Bactrian camel genomes — work that they describe in Nature Communications.

The team used DNA from an eight-year-old male Bactrian camel from Mongolia to generate data for the wild Bactrian camel genome, sequenced to average effective depth of 76-fold over roughly 84 percent of its estimated 2.38 billion bases. DNA from a six-year-old male camel from Inner Mongolia, China, was used to generate sequences for the domestic Bactrian camel, sequenced to a depth of 27-fold, on average. By comparing the wild and domestic Bactrian camel sequences to one another and to sequences from other vertebrates, researchers began identifying Bactrian camel genes and genetic polymorphisms, exploring the animals' evolutionary history and domestication and delving into the genetic features contributing to Bactrian camel metabolism, salt tolerance, and immune system function.

"Our comparative analysis based on the genome sequences provides important insights into the evolution and domestication of Bactrian camels," the study's authors say. "In addition, the identified genes and pathways may enhance our understanding of the genetic mechanisms that enable camels to survive in extreme environments."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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