Volume 41 Issue 5, May 2009

Two studies show that the common recurrent gene fusion between TMPRSS2 and ERG promotes prostate cancer in both mouse and humans when PTEN is concurrently lost. In human prostate cancer, the presence of both these aberrations may be indicative of poor prognosis, suggesting that preclinical therapeutic research should target both of these pathways.

A new study reports large-scale systematic resequencing of the coding exons of the X chromosome in males with X-linked mental retardation (XLMR), illustrating the challenge of sorting through large amounts of benign variation in order to identify disease-causing sequence changes.

A new study defines the flaky tail mouse as a model for human atopic dermatitis caused by a null mutation in the gene encoding filaggrin, a key component of the epidermal barrier. Research in these mice will help explain how a disrupted barrier contributes to the pathogenesis of atopic dermatitis and to asthma arising in the context of atopic skin disease.

Yardena Samuels and colleagues report a mutational analysis of the matrix metalloproteinase gene family in cutaneous metastatic melanoma. They find frequent somatic mutations in MMP8 and present functional evidence that wild-type MMP-8 inhibits melanoma progression.

Andrew Futreal and colleagues report inactivating somatic mutations in the histone lysine demethylase gene UTX in human cancers, including multiple myelomas, esophageal squamous carcinomas, renal clear cell carcinomas, acute and chronic myeloid leukemias, breast and colorectal cancers and glioblastomas, identifying UTX as a new tumor suppressor gene.

Charles Sawyers and colleagues report that mice expressing a TMPRSS2-ERG fusion develop prostatic intraepithelial neoplasia, but only in the context of PI3-kinase pathway activation mediated by either Pten loss or Akt activation. They also find that human TMPRSS2-ERG–positive tumors are enriched for PTEN loss, suggesting that these two events cooperate in human prostate tumorigenesis.

Hyung-Lae Kim and colleagues report a genome-wide association study of quantitative traits of biomedical importance in Koreans. Although some loci were previously detected in European populations, others are new.

Tarpey et al. carry out a large-scale systematic sequencing of the majority of X-chromosome coding exons from 208 families with multiple individuals with mental retardation and a pattern of transmission compatible with X linkage in order to identify XLMR-causative mutations. They find several mutations that appear to be causative in loci already known to be involved in XLMR, as well as new data about those loci, and make inferences about the role of the different classes of variants in these diseases.

Martin McMahon and colleagues have generated a new mouse model of metastatic melanoma by generating mice with an activating mutation of Braf and deletion of Pten. The mice show metastatic melanoma with 100% penetrance and short latency, and should serve as a useful pre-clinical model in which to evaluate new therapies.

The FANTOM4 study identified transcriptional start sites active during proliferation arrest and differentiation of the human monocytic cell line THP-1. Systematic knockdown of 52 transcription factors provide support for their model in which a complex transcriptional network regulates the differentiation process.

Piero Carninci and colleagues report that 6–30% of cap-selected mouse and human RNA transcripts initiate within repetitive elements. They conclude that retrotransposon transcription is far more widespread than first thought and has a major influence on the transcriptional output of mammalian genomes.

John Mattick and Yoshihide Hayashizaki and colleagues report the identifcation of tiny RNAs approximately 18 nucleotides in length that map near transcription start sites in human, chicken and Drosophila genomes. They call them transcription initiation RNAs (tiRNAs) and show that they associate with highly expressed transcripts and sites of RNA polymerase II binding.

David Hunter and colleagues report results of the CGEMS multistage genome-wide association study of breast cancer. They identify two new risk variants on chromosomes 1p11.2 and 14q24.1, and confirm several previously reported breast cancer risk loci.

Douglas Easton and colleagues report results of a large multistage genome-wide association study of breast cancer. The study identifies two new breast cancer risk loci on chromosomes 3p24 and 17q23.2.

Yusuke Nakamura and colleagues report results of a genome-wide association study for chronic hepatitis B in East Asians. They discover strong association with markers in the HLA-DP region, suggesting an important role for this locus in modulating the course of HBV infection.

Young-Ae Lee and colleagues report results of a genome-wide association study for atopic dermatitis. They identify a risk locus on chromosome 11q13 in a region previously associated with risk of Crohn's disease.

Irwin McLean and colleagues show that the flaky tail mouse mutant has a frameshift mutation in the gene encoding filaggrin. Topical application of allergen to flaky tail mice results in skin inflammation and enhanced cutaneous allergen priming, shedding light on the mechanisms underlying filaggrin-related atopic disease.

Miguel Moreno-Pelayo and colleagues report mutations in the seed region of human miR-96 segregating with progressive hearing loss in two families. In an accompanying paper, Karen Steel and colleagues show that the mouse diminuendo mutant, which also shows progressive hearing loss, carries a similar mutation in the seed region of mouse miR-96.

Karen Steel and colleagues report that the mouse diminuendo mutant, which shows progressive hearing loss, carries a mutation in the seed region of mouse miR-96. In an accompanying paper, Miguel Moreno-Pelayo and colleagues report similar mutations in the seed region of human miR-96 segregating with progressive hearing loss in two families.

Pier Paolo Pandolfi and colleagues report that prostate-specific overexpression of ERG in transgenic mice results in no overt phenotype on its own but promotes progression of intraepithelial neoplasia to adenocarcinoma in a PTEN heterozygous background. They also find that human TMPRSS2-ERG–positive tumors are enriched for PTEN loss, suggesting that these two events cooperate in human prostate tumorigenesis.

Alec Jeffreys and Rita Neumann identify a polymorphic recombination hot spot that was activated by a single base change roughly 70,000 years ago and has persisted in the human population despite its systematic elimination by biased gene conversion. The work provides the first example of a highly transient recombination hot spot in the human population.

Craig Pikaard and colleagues show that AGO4 is recruited to target loci through physical interactions with nascent RNA polymerase V transcripts. They also show that the SMC hinge-domain protein DMS3 functions in the assembly of Pol V transcription complexes.