Letters in 2015

Jessica Okosun, David Sabatini and colleagues identify recurrent RRAGC mutations in follicular lymphoma, resulting in activated mTORC1 signaling. The activating nature of the mutations, their existence within the dominant clone and their stability during disease progression support the potential of these mutations as promising candidates for targeted therapy.

Matthew Meyerson and colleagues identify focal amplifications of regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC in epithelial cancers. CRISPR/Cas9-mediated repression or deletion of a MYC enhancer in a lung adenocarcinoma cell line with the enhancer amplification results in downregulation of MYC and its target genes and impaired anchorage-independent and clonogenic growth.

Ivona Aksentijevich and colleagues identify heterozygous loss-of-function mutations in TNFAIP3 (encoding A20) in six unrelated families with early-onset systemic inflammation. Affected individuals exhibit increased expression of NF-κB–mediated proinflammatory cytokines, consistent with the established role of A20 as a potent inhibitor of the NF-κB signaling pathway.

Raif Geha, Louis Kunkel, Waleed Al-Herz and colleagues report a mutation in TFRC (encoding transferrin receptor 1, TfR1) that causes combined immunodeficiency characterized by impaired function of T and B cells in homozygous patients. Iron citrate rescued the lymphocyte defects in patient-derived cells and in a mouse model, demonstrating the importance of TfR1-mediated iron internalization in adaptive immunity.

Murat Günel and colleagues use an integrated genomic approach to analyze the malignant progression of IDH1-mutant gliomas. They observe nonlinear clonal expansion of the original tumors and identify oncogenic pathways driving progression, including activation of MYC and RTK-RAS-PI3K pathways and epigenetic silencing of developmental transcription factors.

Paul Khavari and colleagues analyze tumor genomes to identify snoRNAs showing frequent copy number loss of adjacently encoded snoRNAs SNORD50A and SNORD50B. These snoRNAs directly bound K-Ras and their loss leads to increased activity of both wild-type and oncogenic K-Ras and is associated with reduced survival.

Terry Burke, Mark Blaxter, David Lank and colleagues report a reference genome sequence of the ruff and analysis of the three distinct male morphs of this bird species. They identify a ‘supergene’ consisting of a fixed inversion in two of the morphs and identify candidate reproductive trait genes in this region.

José M. Jiménez-Gómez and colleagues report that the circadian clock of cultivated tomato was quantitatively slowed during domestication compared to its wild relatives, based on measurements of circadian leaf movements. They map QTL for phase and period, and identify the causal gene, EID1, underlying the phase QTL.

Leif Andersson and colleagues report the genome sequence of the ruff, a bird species with three male morphs with different reproductive strategies. Satellite and faeder morphs differ from the common independent morph by a 4.5-Mb inversion that occurred approximately 3.8 million years ago, and multiple genetic changes within this inverted region are associated with the satellite and faeder morphs.

Evans Lagudah and colleagues report that variation in a gene encoding a hexose transporter confers resistance to multiple pathogens in wheat. They further show that the variant protein encoded by the resistance allele exerts a dominant-negative effect by heterodimerizing with functional hexose transporters, resulting in reduced glucose uptake.

Nazneen Rahman and colleagues identify inactivating germline mutations in the gene encoding the transcriptional repressor REST in familial and non-familial cases of Wilms tumor. The mutations cluster in the DNA-binding domain of REST and compromise REST transcriptional repression.

Teresa Palomero, Adolfo Ferrando, Raul Rabadan and colleagues report the results of an exome sequencing study of cutaneous T cell lymphoma (CTCL). They identify highly recurrent chromosomal deletions along with a broad spectrum of somatic mutations in genes involved in epigenetic regulation and signaling.

Davide Sosso and colleagues show that SWEET4 hexose transporters are essential for grain filling in both maize and rice, and were likely selected during domestication to enhance sugar import into the endosperm.

Timothy Vyse and colleagues report the results of a large-scale association study of systemic lupus erythematosus (SLE). They identify ten new susceptibility loci and implicate aberrant regulation of innate and adaptive immunity genes in disease pathogenesis.

Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2.

Lewis Cantley and colleagues report an integrated metabolic and transcriptomic study of non–small cell lung cancer (NSCLC) cell lines. They show that the activity of the serine/glycine biosynthetic pathway in NSCLC is highly heterogeneous and is regulated by NRF2 and that elevated expression of genes in this pathway confers poor prognosis in human NSCLC.

Suneet Agarwal and colleagues use somatic cells and induced pluripotent stem cells from patients with PARN mutations to show that PARN is required for the 3′-end maturation of the telomerase RNA component TERC. Their findings provide a mechanism linking PARN mutations to telomere diseases.

Lavinia Paternoster and colleagues report the results of a large, multi-ancestry genome-wide association study of atopic dermatitis. They identify ten new susceptibility loci harboring candidate genes involved in innate host defense and T cell function.

Matthew Freedman and colleagues show that androgen receptor (AR) binding sites undergo extensive reprogramming during prostate epithelial transformation. They further show that FOXA1 and HOXB13 colocalize at reprogrammed AR binding sites in human tumor tissue and are able to reprogram the AR cistrome of an immortalized prostate cell line to resemble that of prostate tumors.

Hélène Cavé and colleagues genetically profile a cohort of 118 juvenile myelomonocytic leukemia (JMML) samples and uncover mutations in multiple components of the RAS signaling pathway and the PRC2 network. Their study demonstrates an association between JMML clinical outcome and mutational profile and suggests a dose-dependent effect for RAS pathway activation.