Volume 45 Issue 10, October 2013

The transcription factor PAX5 is required for normal B cell development and is frequently mutated or deleted in B cell precursor acute lymphoblastic leukemia (B-ALL). A new study demonstrates that germline hypomorphic mutations of PAX5 are associated with susceptibility to B-ALL, implicating PAX5 in a growing list of hematopoietic transcription factors mutated in familial leukemia predisposition syndromes.

Identifying genomic alterations in cancer does not guarantee therapeutic benefit. A new study combining DNA and RNA sequencing with functional validation uncovers new genetic driver alterations in glioblastoma with potential for clinical translation.

Three new studies have used whole-genome sequencing of M. tuberculosis to demonstrate unexpected complexity in the modern evolution of drug-resistant tuberculosis, and a fourth study suggests a close evolutionary relationship between the pathogen and its human host over a period of 70,000 years. Collectively, the observations in these studies suggest that future strategies to tackle drug-resistant tuberculosis must integrate host genetics with detailed strain epidemiology.

Current clinical practice is organized according to tissue or organ of origin of tumors. Now, The Cancer Genome Atlas (TCGA) Research Network has started to identify genomic and other molecular commonalities among a dozen different types of cancer. Emerging similarities and contrasts will form the basis for targeted therapies of the future and for repurposing existing therapies by molecular rather than histological similarities of the diseases.

Larsson Omberg and colleagues write a Commentary describing the collaborative model used by the Pan-Cancer Working Group of The Cancer Genome Atlas. Pan-Cancer members used the Synapse software platform to share and evolve data, results and methods to perform integrative analyses of genome-wide molecular data for 12 cancer types.

Chris Sander and colleagues have extracted significant functional events from 12 tumor types. Tumors can be classified as being driven largely by either mutation or copy number changes, and, within this division, subclasses of cross-tissue patterns of events are discerned that suggest sets of combinatorial therapies.

Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation. Fifteen new significantly mutated candidate driver genes were found associated with recurrently amplified or deleted regions.

Anna Lasorella, Raul Rabadan, Antonio Iavarone and colleagues report an integrated analysis of genomic alterations in glioblastoma. They identify and functionally validate several new driver events, including loss-of-function mutations in CTNND2 and recurrent EGFR fusions.

Patrick Sullivan and colleagues report a multi-stage genome-wide association study for schizophrenia in a Swedish population. They identify 13 loci newly associated with schizophrenia.

Garry Cutting and colleagues report a comprehensive functional and clinical analysis of CFTR variants reported in cystic fibrosis. They determine that 128 of 160 CFTR variants with an allele frequency of >0.01% are causal for disease.

Shengyue Wang and colleagues report the draft genome sequence and transcriptome analysis for Echinococcus granulosus, a parasitic helminth and cause of human hydatid disease. Their comparative genomic analysis identifies genes acquired by E. granulosus that are associated with host immune response, parasite survival and growth.

Iñaki Comas and colleagues report whole-genome sequencing and analysis of 259 Mycobacterium tuberculosis complex strains, providing a survey of global diversity and facilitating evolutionary analyses. Their phylogeographic analysis suggests the emergence of M. tuberculosis complex strains about 70,000 years ago in Africa, with expansion correlated with increased human population density during the Neolithic Demographic Transition.

Maha Farhat, Megan Murray and colleagues report whole-genome sequencing of 116 Mycobacterium tuberculosis strains selected to be representative of both global diversity and drug resistance. The authors develop a new method to search for resistance markers in microbial genomes based on reconstructing a genome-wide phylogeny and identifying regions showing convergent evolution, and they use this method to identify 39 new candidate drug resistance regions in the M. tuberculosis genome.

David Alland and colleagues report sequencing of Mycobacterium tuberculosis strains under ethambutol drug selection. They follow the multistep progression in acquisition of ethambutol resistance in clinical isolates, finding that an interaction of mutations in several genes in DPA biosynthetic and utilization pathways influence the level of resistance as measured by the minimal inhibitory concentration.

Bing Ren and colleagues generate base-resolution maps of DNA methylation in 17 adult mouse tissues. They identify tissue-specific differentially methylated regions and show that they occur at distal cis-regulatory elements, many of which bear enhancer features.

Sebastian Maerkl and colleagues use single-cell measurements to show that the output of the yeast PHO5 promoter can be precisely tuned by subtle changes in binding-site affinity for the Pho4 transcription factor. These results provide insights into how transcription-factor binding sites regulate gene expression and demonstrate the feasibility of developing quantitative models of transcriptional regulatory networks.

Heiko Witt, Miklós Sahin-Tóth and colleagues show that loss-of-function variants in CPA1 are strongly associated with early onset chronic pancreatitis. On the basis of their findings, they propose that the mechanism may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity.

Richard Houlston and colleagues report a genome-wide association study of multiple myeloma and identify four loci associated with susceptibility to this malignancy.

Marshall Horwitz, Charles Mullighan, Kenneth Offit and colleagues report the identification of a recurrent germline PAX5 mutation in families with pre–B cell acute lymphoblastic leukemia. They also identify sporadic cases of this leukemia with the same mutation that arose somatically.

The cohesin complex mediates sister chromatid cohesion during cell division. Now, Seishi Ogawa and colleagues report largely mutually exclusive mutations in multiple members of the cohesin complex in acute myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, chronic myelogenous leukemia and classical myeloproliferative neoplasms.

Lude Franke and colleagues report the results of a large expression QTL study performed on peripheral blood samples from 5,311 individuals. They identify trans-eQTL effects for 103 independent loci that were previously associated with complex traits at genome-wide significance, suggesting that this approach can provide insights into the downstream effects of many trait-associated variants.

Eli Sprecher, Kathleen Green and colleagues show that biallelic mutations in DSG1 cause a syndrome featuring severe dermatitis, multiple allergies and metabolic wasting. The mutations abolish expression of desmoglein 1, resulting in loss of cell adhesion accompanied by increased expression of several allergy-related cytokines.

Flaviano Giorgini and colleagues perform an overexpression screen in yeast to identify genes that can suppress the toxic effects of the mutant Huntington's disease protein Htt. They identify glutathione peroxidase activity as a robust suppressor of mutant Htt toxicity and validate these protective effects in Drosophila and in mammalian cell models.

Lijun Bi and colleagues report sequencing of 161 tuberculosis strains from China, including 44 drug-sensitive, 94 MDR and 23 XDR isolates. They identify 72 new genes and 28 new intergenic regions significantly associated with drug resistance.

Genomic alterations in diverse cell types at different sites in the body give rise to hundreds of different forms of cancer and the ways in which these changes give rise to tumors with different biology, pathology and treatment strategies are beginning to be characterized. The Cancer Genome Atlas Research Network has catalogued the aberrations in the DNA, chromatin and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Here, the Pan-cancer initiative examines the similarities and differences among the genomic and cellular alterations found in the first dozen tumor types to be profiled by TCGA. This first look across cancer offers new tools in genomics and bioinformatics and the prospect of repurposing targeted therapies directed by the molecular pathology of the tumors in addition to their clinical classification.