Articles in 2014

De-Chen Lin, Ming-Rong Wang and colleagues report exome sequencing, RNA sequencing, and copy number analyses of esophageal squamous cell carcinoma. They identified recurrent mutations in FAT1, FAT2, ZNF750, EP300 and KMT2D.

Maria Teresa Landi and colleagues identify a rare missense variant in POT1 shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in POT1 and find a significant excess of rare exonic POT1 variants in melanoma cases compared to controls, implicating POT1 variants in melanoma susceptibility.

Mario Falchi, Philippe Froguel and colleagues report association of a multi-allelic copy number variant encompassing the salivary amylase gene AMY1 with body mass index and risk of obesity.

David Adams, Julia Newton-Bishop, Timothy Bishop, Nicholas Hayward and colleagues identify loss-of-function variants in POT1 in several families with early onset multiple primary melanoma. They further show that these variants disrupt telomere binding by POT1 and are associated with increased telomere length.

Genome-wide association studies have previously identified variants in SLC30A8, encoding the zinc transporter ZnT8, associated with diabetes risk. A rare variant association study has now established the direction of effect, surprisingly showing that loss-of-function mutations in SLC30A8 are protective against diabetes.

Diverse neurodegenerative diseases share a common pathological feature, namely the accumulation of misfolded proteins. However, both drug development and research need more standardization of the biomarkers for the protein types involved. The bold strategy of integrating high-throughput genetic and chemical screens in yeast with experiments in neurons derived from genetically modified human induced pluripotent stem cells (iPSCs) is producing many significant new molecular insights into disease mechanisms.

Peripheral T cell lymphomas are rare but aggressive non-Hodgkin lymphomas derived from mature T lymphocytes or natural killer (NK) cells. New studies identify recurrent dominant-negative mutation of the RHOA GTPase gene in these lymphomas.

A new study explores the ancient oral microbiome from the well-preserved dental calculus samples of four human individuals who lived during medieval times, using a suite of genomic, proteomic and microscopic approaches. The authors investigate the evolution of dental pathogens by reconstructing the genome of the periodontal pathogen Tannerella forsythia and also identify antibiotic resistance genes, bacterial virulence factors and host immune defense proteins.

Douglas Levine and colleagues identify recurrent inactivating mutations in the SWI/SNF complex member SMARCA4 in 12 of 12 samples of small cell carcinoma of the ovary, hypercalcemic type. These findings open the door for the development of targeted therapies to treat this rare but deadly cancer.

Jeffrey Trent, David Huntsman and colleagues identify the SWI/SNF chromatin-remodeling gene SMARCA4 as commonly mutated in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Their results implicate SMARCA4 as a crucial factor in the oncogenesis of SCCOHT, a rare but highly malignant cancer.

Karolin Nord and colleagues report that GRM1 recombines with multiple genes in promoter swapping and gene fusion events in 90% of the chondromyxoid fibroma cases analyzed, resulting in GRM1 overexpression. These results implicate GRM1 rearrangement as a driver of CMF and a biomarker for this tumor type.

William Foulkes and colleagues identify germline inactivating mutations in familial cases of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Through additional analysis of non-familial tumors, the authors find that nearly 100% of tumors carry SMARCA4 mutations and 38 of 40 lack protein expression, implicating SMARCA4 loss as the major cause of SCCOHT.

Keith Caldecott, Bert de Vries, Sherif El-Khamisy, Gianpiero Cavalleri and colleagues identify homozygous TDP2 mutations in individuals with intellectual disability, seizures and ataxia. Their follow-up studies suggest that TDP2 is required to maintain normal transcription in response to the DNA double-strand breaks induced by abortive TOP2 activity.

Peter Campbell and colleagues identify PLCG1 and PTPRB as new driver genes for angiosarcoma through whole-exome sequencing of tumor samples. They find somatic PTPRB mutations in 10 of 39 cases and PLCG1 mutations in 3 of 34 cases, along with mutations in known cancer-related genes.