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Tumors vary in their ratio of normal to cancerous cells and in their genomic copy number. Carter et al . describe an analytic method for inferring the purity and ploidy of a tumor sample, enabling longitudinal studies of subclonal mutations and tumor evolution. We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12 . We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.

Levi Garraway and colleagues report exome sequencing of 112 prostate adenocarcinomas and matched normal tissues. They identify novel recurrent mutations in several genes, including MED12 , FOXA1 and SPOP . They find that tumors harboring SPOP mutations lack the TMPRSS2 - ERG fusion or other ETS rearrangements, supporting the hypothesis that SPOP mutation is an early driver event in prostate tumorigenesis. Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year 1 . Overtreatment of indolent disease also results in significant morbidity 2 . Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) 3 , 4 and PTEN (10q23) 5 , 6 , gains of AR (the androgen receptor gene) 7 , 8 and fusion of ETS family transcription factor genes with androgen-responsive promoters 9 , 10 , 11 . Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis 12 , 13 but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1 . SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.

Samuel Singer and colleagues report an integrative genomic analysis of soft-tissue sarcomas. They survey sequence, copy number and mRNA expression in 207 individuals diagnosed with one of seven major high-grade sarcoma subtypes, and highlight subtype-specific alternations. Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States 1 , show remarkable histologic diversity, with more than 50 recognized subtypes 2 . However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1 . Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4 , decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

This paper reports one of the largest breast cancer whole-exome and whole-genome sequencing efforts so far, identifying previously unknown recurrent mutations in CBFB , deletions of RUNX1 and recurrent MAGI1 – AKT3 fusion; the fusion suggests that the use of ATP-competitive AKT inhibitors should be evaluated in clinical trials. Mutations and translocations in breast cancer This paper reports one of the largest whole-exome sequencing efforts in human breast cancers so far, complemented by whole-genome sequences of 22 breast cancer/normal pairs. The authors analysed diverse subtypes from patients in Mexico and Vietnam and identified recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1 , as well as a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancers (those lacking oestrogen and progesterone receptors and ERBB2 expression). The fusion leads to constitutive activation of AKT kinase, which can be counteracted by treatment with a small-molecule inhibitor. Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone 1 . This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy 2 , 3 , 4 . Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration 5 . Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements 6 , 7 , 8 , 9 , 10 . Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA 11 , TP53 6 , AKT1 12 , GATA3 13 and MAP3K1 10 , we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1 . Furthermore, we have identified a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3–AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.

Adam Bass, Gad Getz and colleagues report whole-exome sequencing of 149 esophageal adenocarcinomas (EACs) and whole-genome sequencing of 15 EACs. They identify a mutational signature defined by a high prevalence of A>C transversions, as well as 26 genes mutated at high frequency in EACs. The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five ( TP53 , CDKN2A , SMAD4 , ARID1A and PIK3CA ) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20 , TLR4 , ELMO1 and DOCK2 . Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4 ; multiple ephrin receptor genes, notably EPHA3 ; vascular endothelial growth factor receptor KDR ; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers—including NF1 , APC , RB1 and ATM —and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment. Mutations involved in lung cancer In large-sale genomics study, mutations associated with lung cancer, the leading cause of cancer death, were examined in 188 primary tumour samples. More than 600 genes with known or potential links to lung adenocarcinoma were sequenced, of which 26 were mutated at high frequency suggestive of a direct role in carcinogenesis. Sequencing of over 600 genes in a large collection of lung adenocarcinoma samples provides an overview of somatic mutations and signalling pathways altered in cancer genes in this tumour type.

HapMap2 raises the bar The International HapMap Consortium has produced a second-generation version of its remarkable haplotype map of the human genome. The Phase II HapMap charts human genetic variation even more extensively than the original, tripling of the number of genetic markers included. The original HapMap was instrumental in making large-scale genome-wide association studies possible. An indication of how this type of work will be extended with 'HapMap2' is presented in this issue: Sabeti et al . build on previous work detecting signs of positive natural selection on human genes. With many more markers now available, they have discovered three examples of apparent population-specific selection based on geographic area — involving gene pairs linked to Lassa virus in West Africa, skin pigmentation in Europe and hair follicle development in Asia — and they speculate on how these may relate to human biology. Sabeti et al . build on their This paper builds on previous work of detecting selection on human genes, using the many more markers available in the Phase II HapMap project. Three examples of apparent population-specific selection based on geographic area are described, and how these may relate to human biology is discussed. With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2) 1 . We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection 2 , and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population: LARGE and DMD , both related to infection by the Lassa virus 3 , in West Africa; SLC24A5 and SLC45A2 , both involved in skin pigmentation 4 , 5 , in Europe; and EDAR and EDA2R , both involved in development of hair follicles 6 , in Asia.