Volume 42 Issue 8, August 2010

A new study reports that androgen signaling induces DNA double-strand breaks and TMPRSS2-ERG rearrangements through androgen receptor–mediated recruitment of topoisomerase 2B. These findings shed light on the generation of the most common fusion oncogene in human cancer.

A new study finds that individuals with high plasma triglyceride levels carry approximately twice as many rare, coding genetic variants within four candidate genes identified through genome-wide association studies than individuals without these high levels. This study demonstrates the overlap of rare and common variant signals at loci associated with lipid levels and shows the value of efforts to extend susceptibility variant discovery to embrace the full allele-frequency spectrum.

A new study reports that susceptibility to drug-induced liver injury by the cyclooxygenase 2 (COX-2) inhibitor lumiracoxib is associated with a human lymphocyte antigen (HLA) class II haplotype. This finding suggests that those at risk of hepatotoxicity can be identified by HLA genotyping, raising the possibility that lumiracoxib can be resurrected as a useful drug.

Katherine Siminovitch and colleagues report replication and fine-mapping studies for primary biliary cirrhosis. They identify three loci newly associated with susceptibility to this autoimmune liver disease.

Michael Seldin and colleagues report a genome-wide association study and meta-analyses for primary biliary cirrhosis. They identify three loci newly associated with susceptibility to this autoimmune liver disease.

Christine Skibola and colleagues identify variants at 6p21.32 associated with risk of follicular lymphoma, providing further support that variation in the MHC region influences risk of this disease. They also replicate previously reported risk variants for chronic lymphocytic leukemia.

Joop Jansen and colleagues report the identification of somatic mutations altering the histone methyltransferase EZH2 in myelodysplastic syndromes. They find EZH2 deletions, missense and frameshift mutations in about 23% of myelodysplastic syndrome samples.

Srinivasan Yegnasubramanian and colleagues show that androgen signaling promotes recruitment of androgen receptor and TOP2B to sites of TMPRSS2-ERG genomic breakpoints, triggering TOP2B-mediated double-strand breaks. These findings provide insights into the mechanism underlying this common prostate cancer gene fusion event.

Thomas Bugge and colleagues report that the matriptase protease initiates an epidermal kallikrein proteolytic cascade in mice lacking Spink5, which encodes the serine protease inhibitor LEKTI. Loss of matriptase rescued some features of excessive proteolytic degradation of corneodesmosomes and inflammatory activation in LEKTI-deficient mice, which are a model of human Netherton syndrome.

Robert Hegele and colleagues report a genome-wide association study for hypertriglyceridemia, followed by resequencing of the coding regions of candidate genes. They identify an excess of rare variants in affected individuals at four genes within the associated loci.

Connie Bezzina and colleagues report a genome-wide association study for ventricular fibrillation in individuals with acute myocardial infarction, a leading cause of total and cardiovascular mortality.

Solveig Gretarsdottir, Kari Stefansson and colleagues report a genome-wide association study for abdominal aortic aneurysm. They identified a variant located within the DAB2IP gene on 9q33 associated with risk of developing abdominal aortic aneurysm.

Elaine Remmers and colleagues report a genome-wide association study for Behçet's Disease in a Turkish population. They identify associations in the Class I region of the MHC, IL10 and IL23R-IL12RB2.

Nobuhisa Mizuki and colleagues report a genome-wide association study for Behçet's disease, a chronic systemic inflammatory disorder, in a Japanese population. They identify variants at IL23R-IL12RB2 and IL10 associated with Behçet's disease.

Yusuke Nakamura and colleagues report a genome-wide association study for endometriosis in Japanese. The authors find that genetic variants in the CDKN2BAS locus at chromosome 9p21 are significantly associated with endometriosis.

Charles Paulding and colleagues report a genome-wide association study for susceptibility to lumiracoxib-induced liver injury. The study utilized lumiracoxib-treated cases with liver injury and lumiracoxib-treated controls, and included independent replication. The authors identify an association to a common HLA haplotype.

Samuel Singer and colleagues report an integrative genomic analysis of soft-tissue sarcomas. They survey sequence, copy number and mRNA expression in 207 individuals diagnosed with one of seven major high-grade sarcoma subtypes, and highlight subtype-specific alternations.

Nicholas Cross and colleagues report the identification of somatic mutations altering the histone methyltransferase EZH2 in myeloid disorders. They identify monoallelic and biallelic EZH2 mutations in 7% of myeloid disorders, most commonly myelodysplastic and/or myeloproliferative neoplasms and myelofibrosis.