Volume 44 Issue 10, October 2012

Genomic characterization efforts in small-cell lung cancer have been complicated by the paucity of high-quality surgical resection specimens for this aggressive lung cancer subtype that is usually diagnosed at unresectable stages in small biopsies or cytology specimens. Now, two papers report genomic analyses of small-cell lung cancer, highlighting subsets of tumors driven by amplification of FGFR1, SOX2 or MYC family members or by a MYCL1 fusion oncogene, among many other recurrent alterations.

A new exome sequencing study of individuals with hepatocellular carcinoma (HCC) reveals imprints of mutagenic exposure and identifies new genes contributing to tumorigenesis. This work joins several recent publications reporting whole-genome, exome and RNA sequencing in HCC, which together provide a comprehensive genomic landscape and new insights into the etiology of liver cancer.

Gene expression is under partial genetic regulation, which may vary between different cell types and tissues. A new study finds that there is substantial but incomplete overlap among regulatory variants located near the regulated genes in three human tissues.

Albena Jordanova and colleagues report mutations in HINT1 in autosomal recessive axonal neuropathy with neuromyotonia. Using linkage analysis and whole-genome sequencing, they identify 8 mutations in 33 affected families.

The MuTHER Consortium reports an analysis of the genetics of gene expression in three tissues from approximately 850 mono- and dizygotic twins. They systematically dissect cis and trans genetic effects and estimate non-genetic effects on gene expression.

Dongxin Lin and colleagues report a genome-wide association study for esophageal squamous cell carcinoma (ESCC) in Chinese populations, identifying nine new susceptibility loci. They also perform a genome-wide gene-environment interaction analysis with alcohol consumption, a known risk factor for ESCC.

Yuxian Zhu and colleagues report the draft genome of a diploid cotton Gossypium raimondii. This species is a wild South American cotton, whose progenitor is thought to have been the contributor of the D subgenome of the allotetraploid commercial species Gossypium hirsutum and Gossypium barbadense, which account for ~95% of the worldwide cotton crop.

Roman Thomas and colleagues report exome sequencing of 29 small-cell lung cancers (SCLCs), 2 SCLC genomes and transcriptomes of 15 SCLCs. They identify recurrent mutations in the CREBBP, EP300 and MLL genes encoding histone modifiers. They identify mutations in SLIT2 and EPHA7, which have a role in axon guidance and cell migration, and focal amplifications of FGFR1.

Sekar Seshagiri and colleagues report exome, transcriptome and copy-number alteration data in small-cell lung cancer. The authors find SOX2 amplification in 27% of samples and also identify a recurrent RFL-MYCL1 fusion.

Ze-Guang Han and colleagues report exome sequencing of ten hepatitis B virus–positive hepatocellular carcinomas. They identify recurrent somatic mutations in ARID1A and mutation signatures that may reflect mutagenic exposures.

Robert Jenkins and colleagues report fine mapping of the glioma risk region at 8q24.21. They identify a new low-frequency variant in the region that is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation.

John Maris and colleagues identify common variants at 6q16 associated with neuroblastoma susceptibility. The risk variants are located near the HACE1 and LIN28B genes, both of which show altered expression in advanced neuroblastomas.

Peter Donnelly and colleagues report a genome-wide association study for Barrett's esophagus, a common premalignant condition associated with stomach acid reflux and predisposing to esophageal adenocarcinoma. They identify two loci associated with susceptibility to Barrett's esophagus.

Carl Anderson and colleagues report dense genotyping, using the Immunochip array, of 2,861 primary biliary cirrhosis (PBC) cases and 8,514 controls. They identify three loci newly associated with PBC, and their fine-mapping of previous susceptibility loci identifies five regions with multiple independent common, low-frequency and rare variant associations.

Ningli Wang, Tin Aung and colleagues report genome-wide association analyses for primary angle closure glaucoma, a major cause of blindness worldwide. They identify three loci newly associated with this disease.

Elizabeth Holliday and colleagues report a genome-wide association study for ischemic stroke. They identify common variants at 6p21.1 associated with large artery atherosclerosis (LAA), a major subtype of ischemic stroke.

Brian Fowler, David Rosenblatt and colleagues show that mutations in the ABC transporter gene ABCD4 cause a new inborn error of vitamin B₁₂ metabolism. ABCD4 colocalizes with the lysosomal proteins LAMP1 and LMBD1 and may be involved in intracellular processing of vitamin B₁₂.

Xue-Jun Zhang, Jun Wang and colleagues identify mutations in MVK in disseminated superficial actinic porokeratosis, a disorder characterized by defects in epidermal keratinization. MVK encodes mevalonate kinase, an enzyme involved in the biosynthesis of cholesterol and isoprenoids.

David Reich and colleagues report direct characterization of the human mutation rate based on analysis of 85,289 Icelandic individuals genotyped at 2,477 autosomal microsatellite loci. They use this mutation rate to build a model of microsatellite evolution and estimate key evolutionary parameters.

Yurii Aulchenko and colleagues report a variance components–based method, GRAMMAR-Gamma, for genome-wide association studies including a large number of individuals and genetic markers. They demonstrate, using simulations as well as human and Arabidopsis thaliana data sets, that their method provides unbiased estimates of SNP effect and increases computational efficiency, which may facilitate analysis of human whole-genome resequencing studies.