Volume 46 Issue 2, February 2014

A new study shows that HOXB13 is preferentially recruited to the risk allele of a prostate cancer–associated SNP, enhancing the expression of RFX6, a driver of prostate cancer cell migration and predictor of disease progression. The work illustrates how a single risk locus contributes both to prostate cancer incidence and, through functional follow-up, to disease progression.

Although dozens of common variants have been associated with increased risk of type 2 diabetes (T2D), the mechanisms by which these variants increase disease susceptibility are largely unknown. A new study mapping the human pancreatic islet cistrome provides a roadmap for exploring the effects of these variants and suggests that altered enhancer function might be a common contributor to the genetic risk of T2D.

Genomic aberrations affecting genes in B cell differentiation are hallmarks of B-precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1–positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism.

Alkes Price, Peter Visscher and colleagues provide recommendations on the application of mixed-linear-model association methods across a range of study designs.

Community microattribution review of the evidence for colon cancer risk conferred by constitutional variants in MLH1, MSH2, MSH6 and PMS2 has resulted in the reclassification of two-thirds of the variants reported in existing databases and led to clinical recommendations for the interpretation of 1,370 variants that do not result in obvious protein truncation.

Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the ETV6-RUNX1 fusion gene. They find that RAG-mediated deletions are the dominant mutational process.

Gong-Hong Wei, Jussi Taipale and colleagues show that a prostate cancer risk allele at 6q22 enhances HOXB13 chromatin binding at this locus, leading to increased allele-specific expression of RFX6. They further show that RFX6 suppression reduces the proliferation, migration and invasion of prostate cancer cells and that RFX6 expression in clinical samples correlates with tumor progression and metastasis.

Jorge Ferrer and colleagues have mapped regulatory SNP variants associated in GWAS with type 2 diabetes risk and glycemic traits to large clusters of enhancer elements regulating the transcriptional identity of pancreatic β cells via a highly connected transcription factor network.

Boaz Cook and colleagues show that dominant disease-causing mutations in genes encoding P-type ATPases result in a gain-of-function ionic leakage phenotype that is exacerbated at elevated temperatures. The authors propose that the mutations promote leakage by disrupting the tight coupling of ATPase activity and transmembrane gating control.

Nancy Bonini and colleagues performed a genome-wide yeast screen for modifiers of TDP-43 toxicity and identified genes in RNA metabolism, including several RNA-binding proteins with connections to stress granules. They determined that therapeutic modulation of stress granule–associated eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models in flies and primary mammalian neurons.

Sandro Santagata, Gad Getz and colleagues report the discovery of a recurrent mutation in the oncogene BRAF in papillary craniopharyngiomas that does not occur in the histologically related adamantinomatous form. Their results have the potential to aid in diagnosis and treatment of these intracranial tumors.

Adolfo Ferrando and colleagues report the exome sequencing of peripheral T cell lymphomas. They identified recurrent mutations in RHOA, TET2, DNMT3A, IDH2, FYN, ATM, B2M and CD58.

Shigeru Chiba and colleagues report exome sequencing of angioimmunoblastic T cell lymphoma (AITL) and other peripheral T cell lymphomas and identify a recurrent somatic RHOA mutation encoding a p.Gly17Val alteration in 68% of AITL samples.

Jessica Okosun, Csaba Bödör and colleagues performed whole-genome or whole-exome sequencing on 10 follicular lymphoma and transformed follicular lymphoma pairs, followed by deep sequencing of 28 target genes in an additional 122 cases. They identify recurrent mutations in linker histone genes and genes involved in JAK-STAT signaling, NF-κB signaling and B cell development.

Ludwine Messiaen and colleagues report the identification of constitutional LZTR1 mutations in individuals with schwannomatosis, an autosomal dominant inherited disorder of multiple schwannomas.

Michael Duchen, Francesco Muntoni, Eamonn Sheridan and colleagues show that loss-of-function mutations in MICU1 cause a recessive disorder characterized by proximal myopathy, learning difficulties and progressive extrapyramidal motor deficits. The mutations alter mitochondrial calcium homeostasis, leading to mitochondrial damage and dysfunction.

Neil Hunter and colleagues show that the HEI10 ubiquitin ligase regulates meiotic recombination by limiting the colocalization of RNF212 and MSH4-MSH5 to future crossover sites. At later stages, they find that HEI10 accumulates stably at designated crossover sites and facilitates clearance of RNF212 and MSH4-MSH5 complexes to promote the final steps of meiotic recombination.

Gonçalo Abecasis, Dajiang Liu and colleagues report a meta-analysis framework to identify rare variant associations based on gene-level tests and the use of shared summary statistics provided by individual studies. They demonstrate their approach on a meta-analysis of blood lipid levels including 18,699 individuals, drawn from across 7 studies and genotyped with exome arrays.

Douglas Higgs and colleagues report a high-throughput approach, called Capture-C, to analyze interactions between cis regulatory elements. Using Capture-C, the authors interrogated hundreds of specific interactions at high resolution in a single experiment.