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Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

Analysis of genomic data from 981 colorectal cancers from participants in 11 countries reveals variations in mutational signatures of microsatellite-stable cancers that are dependent on geographical origin and age at which the cancer was diagnosed.

Whole-genome sequencing and mutational signature analysis of 265 head and neck cancer samples collected from eight different countries provide insight into the vital contribution of tobacco smoke in disease etiology.

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.

Whole-genome sequencing of 962 clear cell renal cell carcinomas from 11 countries shows geographic variations in somatic mutation profiles, including a mutational signature of unknown cause in 70% of cases from Japan.

Clear cell renal carcinoma, the most common form of adult kidney cancer, is often characterized by the presence of inactivating mutations in the VHL gene. A large survey for somatic mutations now identifies inactivating mutations in two genes encoding enzymes involved in histone modification, highlighting the role of mutations in components of the chromatin modification machinery in human cancer.

Pancreatic cancer is highly aggressive, usually because of widespread metastasis. Here, next-generation DNA sequencing has been used to detect genomic rearrangements in 13 patients with pancreatic cancer and to explore clonal relationships among metastases. The results reveal not only considerable inter-patient heterogeneity, but also ongoing genomic instability and evolution during the development of metastases.

Using large-scale exome sequencing, this study identifies a second (after VHL) frequently mutated gene in clear cell renal cell carcinomas, the most frequent type of kidney cancer. PBRM1, a member of the SWI/SNF complex involved in transcriptional regulation, is mutated in about 40% of cases and shown to function as tumour suppressor gene. PBRM1 was independently found as a putative cancer gene involved in pancreatic cancer in a mouse transposon screen.

Andrew Futreal and colleagues identify the major cartilage collagen gene COL2A1 as a frequent target of somatic mutation in chondrosarcoma. The mutation patterns are consistent with selection for variants likely to impair normal collagen biosynthesis.

Tobacco smoke contains more than sixty carcinogens that bind and mutate DNA. Here, massively parallel sequencing technology is used to sequence a small-cell lung cancer cell line, exploring the mutational burden associated with tobacco smoking. Multiple mutation signatures from the cocktail of carcinogens in tobacco smoke are found, as well as evidence of transcription-coupled repair and another, more general, expression-linked repair pathway.

Multiple somatic rearrangements are often found in cancer genomes, but the underlying processes of rearrangement and the effects of this are unclear. A paired-end sequencing strategy is now used to map somatic rearrangements in human breast cancer genomes. More rearrangements in some breast cancers are found than previously recognized, including frequent tandem duplications that may reflect a specific defect in DNA maintenance.

The incidence of esophageal squamous cell carcinoma varies significantly across different geographical regions. Mutational signature analysis of tumors sampled from high- and low-incidence areas suggests that these variations may not be explained by mutagenic exposures.

The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, the authors sequence childhood and adult osteosarcomas, identifying mutations in insulin-like growth factor signalling genes and distinct genomic rearrangement profiles characterized by chromothripsis-amplification.

Homozygous gene deletions in cancer cells occur over recessive cancer genes (where they can confer selective growth advantage) or over genes at fragile sites of the genome (where they are thought to reflect increased DNA breakage). Here, a large number of homozygous deletions in a collection of cancer cell lines are identified and analysed to derive structural signatures for the two different types of deletion. More deletions are found in inherently fragile regions, and fewer overlying recessive genes.

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.

Individuals who are at high risk of developing acute myeloid leukaemia can be identified years before diagnosis using genetic information from blood samples.

The subclonal composition of human prostate tumours and their metastases has been mapped by whole-genome sequencing, thus establishing the evolutionary trees behind the development and spread of these cancers; an important observation was that metastases could be re-seeded multiple times, and spread from one tumour to another was frequently seen.

A study of breast cancers shows that the number of somatic mutations in each varies markedly and is strongly correlated with age at diagnosis and cancer histological grade.