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Showing papers by "Chris Sander published in 2013"


Journal ArticleDOI
TL;DR: A practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics, which makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries.
Abstract: The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

10,947 citations


Journal ArticleDOI
TL;DR: The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA with a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages.
Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

5,294 citations


Journal Article
01 Sep 2013-Nature
TL;DR: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels as mentioned in this paper.
Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

4,634 citations


Journal ArticleDOI
Gad Getz1, Stacey Gabriel1, Kristian Cibulskis1, Eric S. Lander1  +280 moreInstitutions (31)
02 May 2013-Nature
TL;DR: In this paper, the authors performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and-sequencing-based technologies, and classified them into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy number high.
Abstract: We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

3,719 citations


Journal ArticleDOI
10 Oct 2013-Cell
TL;DR: Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM.

3,593 citations


01 Jan 2013
TL;DR: In this article, the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs) was described, including several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA.
Abstract: We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

2,616 citations


Journal ArticleDOI
28 Aug 2013-Nature
TL;DR: Remodelling cellular metabolism constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
Abstract: Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.

2,548 citations


01 Jan 2013
TL;DR: The genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours, and these features are classified into four categories: POLE ultramutated, microsatellite instability hypermutated, copy- number low, and copy-number high.
Abstract: We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

2,448 citations


Journal ArticleDOI
TL;DR: This work distilled thousands of genetic and epigenetic features altered in cancers to ∼500 selected functional events (SFEs) and derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types, indicating the presence of different oncogenic processes.
Abstract: Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ~500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies.

1,212 citations


Journal ArticleDOI
TL;DR: The results indicate that the gap between cell lines and tumours can be bridged by genomically informed choices of cell line models for all tumour types.
Abstract: Cancer cell lines are frequently used as in vitro tumour models. Recent molecular profiles of hundreds of cell lines from The Cancer Cell Line Encyclopedia and thousands of tumour samples from the Cancer Genome Atlas now allow a systematic genomic comparison of cell lines and tumours. Here we analyse a panel of 47 ovarian cancer cell lines and identify those that have the highest genetic similarity to ovarian tumours. Our comparison of copy-number changes, mutations and mRNA expression profiles reveals pronounced differences in molecular profiles between commonly used ovarian cancer cell lines and high-grade serous ovarian cancer tumour samples. We identify several rarely used cell lines that more closely resemble cognate tumour profiles than commonly used cell lines, and we propose these lines as the most suitable models of ovarian cancer. Our results indicate that the gap between cell lines and tumours can be bridged by genomically informed choices of cell line models for all tumour types.

1,150 citations


Journal ArticleDOI
TL;DR: A novel method to infer microbial community ecology directly from time-resolved metagenomics is presented, extending generalized Lotka–Volterra dynamics to account for external perturbations and suggests a subnetwork of bacterial groups implicated in protection against C. difficile.
Abstract: The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka–Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli.

Journal ArticleDOI
TL;DR: The ACC mutational landscape is determined and the exome or whole-genome sequences of 60 ACC tumor-normal pairs are reported, finding mutations in genes encoding chromatin-state regulators, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis.
Abstract: Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

Journal ArticleDOI
TL;DR: This work proposes a framework for joint modeling of discrete and continuous variables that arise from integrated genomic, epigenomic, and transcriptomic profiling, motivated by the hypothesis that diverse molecular phenotypes can be predicted by a set of orthogonal latent variables that represent distinct molecular drivers, and thus can reveal tumor subgroups of biological and clinical importance.
Abstract: Large-scale integrated cancer genome characterization efforts including the cancer genome atlas and the cancer cell line encyclopedia have created unprecedented opportunities to study cancer biology in the context of knowing the entire catalog of genetic alterations. A clinically important challenge is to discover cancer subtypes and their molecular drivers in a comprehensive genetic context. Curtis et al. [Nature (2012) 486(7403):346-352] has recently shown that integrative clustering of copy number and gene expression in 2,000 breast tumors reveals novel subgroups beyond the classic expression subtypes that show distinct clinical outcomes. To extend the scope of integrative analysis for the inclusion of somatic mutation data by massively parallel sequencing, we propose a framework for joint modeling of discrete and continuous variables that arise from integrated genomic, epigenomic, and transcriptomic profiling. The core idea is motivated by the hypothesis that diverse molecular phenotypes can be predicted by a set of orthogonal latent variables that represent distinct molecular drivers, and thus can reveal tumor subgroups of biological and clinical importance. Using the cancer cell line encyclopedia dataset, we demonstrate our method can accurately group cell lines by their cell-of-origin for several cancer types, and precisely pinpoint their known and potential cancer driver genes. Our integrative analysis also demonstrates the power for revealing subgroups that are not lineage-dependent, but consist of different cancer types driven by a common genetic alteration. Application of the cancer genome atlas colorectal cancer data reveals distinct integrated tumor subtypes, suggesting different genetic pathways in colon cancer progression.

Journal ArticleDOI
TL;DR: The chromosome 3p21 locus harbors 3 frequently mutated ccRCC tumor suppressor genes, and BAP1 and SETD2 mutations are associated with worse CSS, suggesting their roles in disease progression.
Abstract: Purpose: To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1 , SETD2 , and BAP1 on cancer-specific survival (CSS) of 609 patients with clear cell renal cell carcinoma (ccRCC) from 2 distinct cohorts. Experimental Design: Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was conducted to interrogate the genotype–phenotype associations. These findings were compared with analyses of the genomic and clinical dataset from our nonoverlapping The Cancer Genome Atlas (TCGA) cohort of 421 patients with primary ccRCC. Results: 3p21 tumor suppressors are frequently mutated in both the MSKCC ( PBRM1 , 30.3%; SETD2 , 7.4%; BAP1 , 6.4%) and the TCGA ( PBRM1 , 33.5%; SETD2 , 11.6%; BAP1 , 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts [MSKCC, P = 0.002; HR 7.71; 95% confidence interval (CI)2.08–28.6; TCGA, P = 0.002; HR 2.21; 95% CI 1.35–3.63]. SETD2 are associated with worse CSS in the TCGA cohort ( P = 0.036; HR 1.68; 95% CI 1.04–2.73). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusion: The chromosome 3p21 locus harbors 3 frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6%–12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30%–34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic, and molecular interrogation of this novel class of tumor suppressors. Clin Cancer Res; 19(12); 3259–67. ©2013 AACR .

Journal ArticleDOI
TL;DR: The prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer are defined to serve as a platform for therapeutic drug discovery and optimal development of target-specific agents will require pretreatment genomic characterization.
Abstract: Purpose We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. Patients and Methods An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing. Results Sixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin p...

Journal ArticleDOI
TL;DR: This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in oncology.
Abstract: This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

Journal ArticleDOI
TL;DR: The findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.
Abstract: Renal cell carcinoma (RCC) comprises 85% of kidney cancer and its incidence is increasing, potentially because of more widespread use of diagnostic imagining, with a trend toward smaller tumors being diagnosed (1). Mortality from RCC, however, has not decreased in parallel, suggesting that perhaps not all small tumors are indolent. More than 40% of RCC is attributable to obesity as measured by body mass index (BMI). Recent meta-analyses from prospective observational studies estimate that RCC risk increases by 24% for men and 34% for women for every 5kg/m2 rise in BMI (2). Putative mechanisms through which larger body size increases risk of kidney cancer include chronic tissue hypoxia, altered hormonal milieu, and increased inflammatory response (3). Because these processes can both induce and promote carcinogenesis (4,5), one might expect higher BMI to be an adverse prognostic factor for kidney cancer. Remarkably, a recent systematic review and meta-analysis found overweight and obese kidney cancer patients experienced statistically significantly longer survival than normal-weight patients (6). This phenomenon, known as the “obesity paradox,” has been described among patients on dialysis (7) and with other hemodynamic and metabolic disorders such as heart failure (8), hypertension (9), coronary heart disease (10), diabetes (11), and chronic kidney disease (12), but not among other obesity-related cancers including prostate, colorectal, and postmenopausal breast cancer (13). The impact of obesity on RCC survival has not been adequately examined, and mechanisms underlying the associations have not been explored. It is not clear whether the obesity paradox is spurious and influenced by detection bias or whether tumors developing in heavier patients are less aggressive and therefore confer a survival advantage. Given that one in three American adults is obese (14) and the incidence of kidney cancer is increasing (1), a better understanding of the obesity paradox is critical to inform secondary prevention efforts and maximize weight management strategies for kidney cancer patients. The purpose of this analysis was to examine the influence of presurgical BMI on stage at presentation and cancer-specific mortality (CSM), while considering the impact of detection bias, nutritional status, and molecular tumor features.

Journal ArticleDOI
TL;DR: The inferred relationships were consistent with sequence-based predictions and published data from miRNA perturbation experiments, and miRNAs with recurrent target relationships were frequently regulated by genetic and epigenetic alterations across the studied cancer types.
Abstract: Little is known about the extent to which individual microRNAs (miRNAs) regulate common processes of tumor biology across diverse cancer types. Using molecular profiles of >3,000 tumors from 11 human cancer types in The Cancer Genome Atlas, we systematically analyzed expression of miRNAs and mRNAs across cancer types to infer recurrent cancer-associated miRNA-target relationships. As we expected, the inferred relationships were consistent with sequence-based predictions and published data from miRNA perturbation experiments. Notably, miRNAs with recurrent target relationships were frequently regulated by genetic and epigenetic alterations across the studied cancer types. We also identify new examples of miRNAs that coordinately regulate cancer pathways, including the miR-29 family, which recurrently regulates active DNA demethylation pathway members TET1 and TDG. The online resource http://cancerminer.org allows exploration and prioritization of miRNA-target interactions that potentially regulate tumorigenesis.

Journal ArticleDOI
TL;DR: A powerful experimental-computational technology for inferring network models that predict the response of cells to perturbations, and that may be useful in the design of combinatorial therapy against cancer, is presented.
Abstract: We present a powerful experimental-computational technology for inferring network models that predict the response of cells to perturbations, and that may be useful in the design of combinatorial therapy against cancer The experiments are systematic series of perturbations of cancer cell lines by targeted drugs, singly or in combination The response to perturbation is quantified in terms of relative changes in the measured levels of proteins, phospho-proteins and cellular phenotypes such as viability Computational network models are derived de novo, ie, without prior knowledge of signaling pathways, and are based on simple non-linear differential equations The prohibitively large solution space of all possible network models is explored efficiently using a probabilistic algorithm, Belief Propagation (BP), which is three orders of magnitude faster than standard Monte Carlo methods Explicit executable models are derived for a set of perturbation experiments in SKMEL-133 melanoma cell lines, which are resistant to the therapeutically important inhibitor of RAF kinase The resulting network models reproduce and extend known pathway biology They empower potential discoveries of new molecular interactions and predict efficacious novel drug perturbations, such as the inhibition of PLK1, which is verified experimentally This technology is suitable for application to larger systems in diverse areas of molecular biology

Journal ArticleDOI
TL;DR: The result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy is presented, and computational techniques to annotate somatic variants and predict their impact on cancer phenotype are recommended.
Abstract: International Cancer Genome Consortium members review and recommend computational approaches for identifying mutations that drive cancer progression from among the many sequence variants present in tumor genomes.

Journal ArticleDOI
TL;DR: It is shown that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors, and the selection pressure to amplify 5q inccRCC is driven, at least partly, by SQ STM1.

Journal ArticleDOI
S. Chatrchyan, Vardan Khachatryan, Albert M. Sirunyan, A. Tumasyan  +2195 moreInstitutions (142)
TL;DR: In this article, the mass limits for the Randall-Sundrum graviton model in the dijet channel were established at the 95% confidence level on the production cross-section of hypothetical new particles decaying to quark-quark, quarkgluon, or gluon-gluon final states.
Abstract: Results are presented of a search for the production of new particles decaying to pairs of partons (quarks, antiquarks, or gluons), in the dijet mass spectrum in proton-proton collisions at sqrt(s) = 8 TeV. The data sample corresponds to an integrated luminosity of 4.0 inverse femtobarns, collected with the CMS detector at the LHC in 2012. No significant evidence for narrow resonance production is observed. Upper limits are set at the 95% confidence level on the production cross section of hypothetical new particles decaying to quark-quark, quark-gluon, or gluon-gluon final states. These limits are then translated into lower limits on the masses of new resonances in specific scenarios of physics beyond the standard model. The limits reach up to 4.8 TeV, depending on the model, and extend previous exclusions from similar searches performed at lower collision energies. For the first time mass limits are set for the Randall-Sundrum graviton model in the dijet channel.

Journal ArticleDOI
TL;DR: This work identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis.
Abstract: Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options Luminal A breast cancer is the most heterogeneous, both molecularly and clinically Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications

S. Chatrchyan, Vardan Khachatryan, Albert M. Sirunyan, A. Tumasyan  +2195 moreInstitutions (142)
01 Jun 2013
TL;DR: In this paper, the mass limits for the Randall-Sundrum graviton model in the dijet channel were established at the 95% confidence level on the production cross-section of hypothetical new particles decaying to quark-quark, quarkgluon, or gluon-gluon final states.
Abstract: Results are presented of a search for the production of new particles decaying to pairs of partons (quarks, antiquarks, or gluons), in the dijet mass spectrum in proton-proton collisions at sqrt(s) = 8 TeV. The data sample corresponds to an integrated luminosity of 4.0 inverse femtobarns, collected with the CMS detector at the LHC in 2012. No significant evidence for narrow resonance production is observed. Upper limits are set at the 95% confidence level on the production cross section of hypothetical new particles decaying to quark-quark, quark-gluon, or gluon-gluon final states. These limits are then translated into lower limits on the masses of new resonances in specific scenarios of physics beyond the standard model. The limits reach up to 4.8 TeV, depending on the model, and extend previous exclusions from similar searches performed at lower collision energies. For the first time mass limits are set for the Randall-Sundrum graviton model in the dijet channel.

Journal ArticleDOI
TL;DR: Network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.
Abstract: Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.

Journal ArticleDOI
12 Nov 2013-PLOS ONE
TL;DR: A genomic analysis of GENCODE lnc RNAs in high-grade serous ovarian adenocarcinoma based on The Cancer Genome Atlas (TCGA) molecular profiles shows that intergenic lncRNAs can be specifically targeted by somatic copy-number amplification, suggestive of functional involvement in tumor initiation or progression.
Abstract: Long non-coding RNAs (lncRNAs) are emerging as potent regulators of cell physiology, and recent studies highlight their role in tumor development. However, while established protein-coding oncogenes and tumor suppressors often display striking patterns of focal DNA copy-number alteration in tumors, similar evidence is largely lacking for lncRNAs. Here, we report on a genomic analysis of GENCODE lncRNAs in high-grade serous ovarian adenocarcinoma, based on The Cancer Genome Atlas (TCGA) molecular profiles. Using genomic copy-number data and deep coverage transcriptome sequencing, we derived dual copy-number and expression data for 10,419 lncRNAs across 407 primary tumors. We describe global correlations between lncRNA copy-number and expression, and associate established expression subtypes with distinct lncRNA signatures. By examining regions of focal copy-number change that lack protein-coding targets, we identified an intergenic lncRNA on chromosome 1, OVAL, that shows narrow focal genomic amplification in a subset of tumors. While weakly expressed in most tumors, focal amplification coincided with strong OVAL transcriptional activation. Screening of 16 other cancer types revealed similar patterns in serous endometrial carcinomas. This shows that intergenic lncRNAs can be specifically targeted by somatic copy-number amplification, suggestive of functional involvement in tumor initiation or progression. Our analysis provides testable hypotheses and paves the way for further study of lncRNAs based on TCGA and other large-scale cancer genomics datasets.

Journal ArticleDOI
TL;DR: Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions.
Abstract: Approximately 15% of colorectal carcinomas (CRC) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumors, unlike the majority of colorectal carcinomas, are often diploid, exhibit frequent epigenetic silencing of the MLH1 DNA mismatch repair gene, and have a better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analyzed 224 colorectal cancers by whole exome sequencing, we compared the 35 CRC (15.6%) with a hypermutated genotype to those with a non-hypermutated genotype. We found that 22 (63%) of hypermutated CRC exhibited transcriptional silencing of the MLH1 gene, a high frequency of BRAF V600E gene mutations and infrequent APC and KRAS mutations, a mutational pattern significantly different from their non-hypermutated counterparts. However, the remaining 13 (37%) hypermutated CRC lacked MLH1 silencing, contained tumors with the highest mutation rates (“ultramutated” CRC), and exhibited higher incidences of APC and KRAS mutations, but infrequent BRAF mutations. These patterns were confirmed in an independent validation set of 250 exome-sequenced CRC. Analysis of mRNA and microRNA expression signatures revealed that hypermutated CRC with MLH1 silencing had greatly reduced levels of WNT signaling and increased BRAF signaling relative non-hypermutated CRC. Our findings suggest that hypermutated CRC include one subgroup with fundamentally different pathways to malignancy than the majority of CRC. Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions.

Journal ArticleDOI
TL;DR: Paxtools is a Java library that contains algorithms, software components and converters for biological pathways represented in the standard BioPAX language that allows scientists to focus on their scientific problem by removing technical barriers to access and analyse pathway information.
Abstract: A rapidly growing corpus of formal, computable pathway information can be used to answer important biological questions including finding non-trivial connections between cellular processes, identifying significantly altered portions of the cellular network in a disease state and building predictive models that can be used for precision medicine Due to its complexity and fragmented nature, however, working with pathway data is still difficult We present Paxtools, a Java library that contains algorithms, software components and converters for biological pathways represented in the standard BioPAX language Paxtools allows scientists to focus on their scientific problem by removing technical barriers to access and analyse pathway information Paxtools can run on any platform that has a Java Runtime Environment and was tested on most modern operating systems Paxtools is open source and is available under the Lesser GNU public license (LGPL), which allows users to freely use the code in their software systems with a requirement for attribution Source code for the current release (420) can be found in Software S1 A detailed manual for obtaining and using Paxtools can be found in Protocol S1 The latest sources and release bundles can be obtained from biopaxorg/paxtools

Journal ArticleDOI
S. Chatrchyan, Vardan Khachatryan, Albert M. Sirunyan, A. Tumasyan  +2176 moreInstitutions (141)
TL;DR: In this article, a search is presented for free heavy long-lived fractionally charged particles produced in pp collisions at √s=7 TeV, where the data sample was recorded by the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0
Abstract: A search is presented for free heavy long-lived fractionally charged particles produced in pp collisions at √s=7 TeV. The data sample was recorded by the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb-1. Candidate fractionally charged particles are identified by selecting tracks with associated low charge measurements in the silicon tracking detector. Observations are found to be consistent with expectations for background processes. The results of the search are used to set upper limits on the cross section for pair production of fractionally charged, massive spin-1/2 particles that are neutral under SU(3)C and SU(2)L. We exclude at 95% confidence level such particles with electric charge ±2e/3 with masses below 310 GeV, and those with charge ±e/3 with masses below 140 GeV.