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1. RAD52 resolves transcription-replication conflicts to mitigate R-loop induced genome instability

Author

Manisha Jalan, Aman Sharma, Xin Pei, Nils Weinhold, Erika S. Buechelmaier, Yingjie Zhu, Sana Ahmed-Seghir, Abhirami Ratnakumar, Melody Di Bona, Niamh McDermott, Joan Gomez-Aguilar, Kyrie S. Anderson, Charlotte K. Y. Ng, Pier Selenica, Samuel F. Bakhoum, Jorge S. Reis-Filho, Nadeem Riaz, and Simon N. Powell

Subjects
Science
Abstract

Abstract Collisions of the transcription and replication machineries on the same DNA strand can pose a significant threat to genomic stability. These collisions occur in part due to the formation of RNA-DNA hybrids termed R-loops, in which a newly transcribed RNA molecule hybridizes with the DNA template strand. This study investigated the role of RAD52, a known DNA repair factor, in preventing collisions by directing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Furthermore, RAD52’s ability to interact with the transcription machinery, coupled with its capacity to facilitate R-loop dissolution, highlights its role in preventing collisions. Lastly, we provide evidence of an increased mutational burden from double-strand breaks at conserved R-loop sites in human tumor samples, which is increased in tumors with low RAD52 expression. In summary, this study underscores the importance of RAD52 in orchestrating the balance between replication and transcription processes to prevent collisions and maintain genome stability.

Published
2024
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2. p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino

Author

Christina B. Marney, Erik S. Anderson, Mutayyaba Adnan, Kai-Lin Peng, Ya Hu, Nils Weinhold, and Adam M. Schmitt

Subjects
DINO, long noncoding RNA, p53, tumor suppression, cancer, DNA methylation, Biology (General), QH301-705.5
Abstract

Summary: Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.

Published
2021
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3. Protein-Protein interactions uncover candidate 'core genes' within omnigenic disease networks.

Author

Abhirami Ratnakumar, Nils Weinhold, Jessica C Mar, and Nadeem Riaz

Subjects
Genetics, QH426-470
Abstract

Genome wide association studies (GWAS) of human diseases have generally identified many loci associated with risk with relatively small effect sizes. The omnigenic model attempts to explain this observation by suggesting that diseases can be thought of as networks, where genes with direct involvement in disease-relevant biological pathways are named 'core genes', while peripheral genes influence disease risk via their interactions or regulatory effects on core genes. Here, we demonstrate a method for identifying candidate core genes solely from genes in or near disease-associated SNPs (GWAS hits) in conjunction with protein-protein interaction network data. Applied to 1,381 GWAS studies from 5 ancestries, we identify a total of 1,865 candidate core genes in 343 GWAS studies. Our analysis identifies several well-known disease-related genes that are not identified by GWAS, including BRCA1 in Breast Cancer, Amyloid Precursor Protein (APP) in Alzheimer's Disease, INS in A1C measurement and Type 2 Diabetes, and PCSK9 in LDL cholesterol, amongst others. Notably candidate core genes are preferentially enriched for disease relevance over GWAS hits and are enriched for both Clinvar pathogenic variants and known drug targets-consistent with the predictions of the omnigenic model. We subsequently use parent term annotations provided by the GWAS catalog, to merge related GWAS studies and identify candidate core genes in over-arching disease processes such as cancer-where we identify 109 candidate core genes.

Published
2020
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4. Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes

Author

Nadeem Riaz, Pedro Blecua, Raymond S. Lim, Ronglai Shen, Daniel S. Higginson, Nils Weinhold, Larry Norton, Britta Weigelt, Simon N. Powell, and Jorge S. Reis-Filho

Subjects
Science
Abstract

Germline mutations in homologous recombination (HR) DNA repair genes are linked to breast and ovarian cancer. Here, the authors show that mutually exclusive bi-allelic inactivation of HR genes are present in other cancer types and associated with genomic features of HR deficiency, expanding the potential use of HR-directed therapies.

Published
2017
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5. The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Author

Amrita M. Nargund, Can G. Pham, Yiyu Dong, Patricia I. Wang, Hatice U. Osmangeyoglu, Yuchen Xie, Omer Aras, Song Han, Toshinao Oyama, Shugaku Takeda, Chelsea E. Ray, Zhenghong Dong, Mathieu Berge, A. Ari Hakimi, Sebastien Monette, Carl L. Lekaye, Jason A. Koutcher, Christina S. Leslie, Chad J. Creighton, Nils Weinhold, William Lee, Satish K. Tickoo, Zhong Wang, Emily H. Cheng, and James J. Hsieh

Subjects
kidney cancer, ccRCC, mouse tumor model, VHL, PBRM1, HIF1, STAT3, MTOR, genetics, epigenetics, Biology (General), QH301-705.5
Abstract

PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.

Published
2017
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6. The impact of the protein interactome on the syntenic structure of mammalian genomes.

Author

Isa Kristina Kirk, Nils Weinhold, Søren Brunak, and Kirstine Belling

Subjects
Medicine, Science
Abstract

Conserved synteny denotes evolutionary preserved gene order across species. It is not well understood to which degree functional relationships between genes are preserved in syntenic blocks. Here we investigate whether protein-coding genes conserved in mammalian syntenic blocks encode gene products that serve the common functional purpose of interacting at protein level, i.e. connectivity. High connectivity among protein-protein interactions (PPIs) was only moderately associated with conserved synteny on a genome-wide scale. However, we observed a smaller subset of 3.6% of all syntenic blocks with high-confidence PPIs that had significantly higher connectivity than expected by random. Additionally, syntenic blocks with high-confidence PPIs contained significantly more chromatin loops than the remaining blocks, indicating functional preservation among these syntenic blocks. Conserved synteny is typically defined by sequence similarity. In this study, we also examined whether a functional relationship, here PPI connectivity, can identify syntenic blocks independently of orthology. While orthology-based syntenic blocks with high-confident PPIs and the connectivity-based syntenic blocks largely overlapped, the connectivity-based approach identified additional syntenic blocks that were not found by conventional sequence-based methods alone. Additionally, the connectivity-based approach enabled identification of potential orthologous genes between species. Our analyses demonstrate that subsets of syntenic blocks are associated with highly connected proteins, and that PPI connectivity can be used to detect conserved synteny even if sequence conservation drifts beyond what orthology algorithms normally can identify.

Published
2017
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7. Deciphering diseases and biological targets for environmental chemicals using toxicogenomics networks.

Author

Karine Audouze, Agnieszka Sierakowska Juncker, Francisco J S S A Roque, Konrad Krysiak-Baltyn, Nils Weinhold, Olivier Taboureau, Thomas Skøt Jensen, and Søren Brunak

Subjects
Biology (General), QH301-705.5
Abstract

Exposure to environmental chemicals and drugs may have a negative effect on human health. A better understanding of the molecular mechanism of such compounds is needed to determine the risk. We present a high confidence human protein-protein association network built upon the integration of chemical toxicology and systems biology. This computational systems chemical biology model reveals uncharacterized connections between compounds and diseases, thus predicting which compounds may be risk factors for human health. Additionally, the network can be used to identify unexpected potential associations between chemicals and proteins. Examples are shown for chemicals associated with breast cancer, lung cancer and necrosis, and potential protein targets for di-ethylhexyl-phthalate, 2,3,7,8-tetrachlorodibenzo-p-dioxin, pirinixic acid and permethrine. The chemical-protein associations are supported through recent published studies, which illustrate the power of our approach that integrates toxicogenomics data with other data types.

Published
2010
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8. Systematic characterisation of cellular localisation and expression profiles of proteins containing MHC ligands.

Author

Agnieszka S Juncker, Mette V Larsen, Nils Weinhold, Morten Nielsen, Søren Brunak, and Ole Lund

Subjects
Medicine, Science
Abstract

Presentation of peptides on Major Histocompatibility Complex (MHC) molecules is the cornerstone in immune system activation and increased knowledge of the characteristics of MHC ligands and their source proteins is highly desirable.In the present large-scale study, we used a large data set of proteins containing experimentally identified MHC class I or II ligands and examined the proteins according to their expression profiles at the mRNA level and their Gene Ontology (GO) classification within the cellular component ontology. Proteins encoded by highly abundant mRNA were found to be much more likely to be the source of MHC ligands. Of the 2.5% most abundant mRNAs as much as 41% of the proteins encoded by these mRNAs contained MHC class I ligands. For proteins containing MHC class II ligands, the corresponding percentage was 11%. Furthermore, we found that most proteins containing MHC class I ligands were localised to the intracellular parts of the cell including the cytoplasm and nucleus. MHC class II ligand donors were, on the other hand, mostly membrane proteins.The results contribute to the ongoing debate concerning the nature of MHC ligand-containing proteins and can be used to extend the existing methods for MHC ligand predictions by including the source protein's localisation and expression profile. Improving the current methods is important in the growing quest for epitopes that can be used for vaccine or diagnostic purposes, especially when it comes to large DNA viruses and cancer.

Published
2009
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9. Local function conservation in sequence and structure space.

Author

Nils Weinhold, Oliver Sander, Francisco S Domingues, Thomas Lengauer, and Ingolf Sommer

Subjects
Biology (General), QH301-705.5
Abstract

We assess the variability of protein function in protein sequence and structure space. Various regions in this space exhibit considerable difference in the local conservation of molecular function. We analyze and capture local function conservation by means of logistic curves. Based on this analysis, we propose a method for predicting molecular function of a query protein with known structure but unknown function. The prediction method is rigorously assessed and compared with a previously published function predictor. Furthermore, we apply the method to 500 functionally unannotated PDB structures and discuss selected examples. The proposed approach provides a simple yet consistent statistical model for the complex relations between protein sequence, structure, and function. The GOdot method is available online (http://godot.bioinf.mpi-inf.mpg.de).

Published
2008
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10. Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases

Author

N. Ari Wijetunga, Alexander G. Goglia, Nils Weinhold, Michael F. Berger, Michael Cislo, Daniel S. Higginson, Kiana Chabot, Ahmed M. Osman, Lauren Schaff, Elena Pentsova, Alexandra M. Miller, Simon N. Powell, Adrienne Boire, and Jonathan T. Yang

Subjects
Cancer Research, Oncology
Abstract

Purpose:Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response.Experimental Design:We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan–Meier analysis was used to associate genomic changes with survival.Results:The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5–21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre ≥ 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05).Conclusions:In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response.

Published
2022

12. Data from Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer

Author

Daniel S. Higginson, Shen Yin, Nils Weinhold, Atif J. Khan, Simon N. Powell, Rahul Majumdar, and Grace Moore

Abstract

Cancer cells defective in homologous recombination (HR) are responsive to DNA-crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta (Pol θ), a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic biallelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single-base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we used what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor Pol θ to design and test novel signatures of polymerase theta–mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions (TINS). We find that TINS consistent with TMEJ repair are highly specific to tumors with pathogenic biallelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. In addition, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared with current state-of-the-art signatures.Implications:Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency.

Published
2023

14. Supplementary fig 5 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases

Author

Jonathan T. Yang, Adrienne Boire, Simon N. Powell, Alexandra M. Miller, Elena Pentsova, Lauren Schaff, Ahmed M. Osman, Kiana Chabot, Daniel S. Higginson, Michael Cislo, Michael F. Berger, Nils Weinhold, Alexander G. Goglia, and N. Ari Wijetunga

Abstract

Supplemental Figure 5. Concordance between plasma and CSF ctDNA variants over time.

Published
2023

15. Supplementary fig 1 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases

Author

Jonathan T. Yang, Adrienne Boire, Simon N. Powell, Alexandra M. Miller, Elena Pentsova, Lauren Schaff, Ahmed M. Osman, Kiana Chabot, Daniel S. Higginson, Michael Cislo, Michael F. Berger, Nils Weinhold, Alexander G. Goglia, and N. Ari Wijetunga

Abstract

Supplement Figure 1. Survival analysis for cohort. Overall survival (median=9 months) for the whole cohort is shown with a 95% confidence interval (blue).

Published
2023

16. Supplementary fig 2 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases

Author

Jonathan T. Yang, Adrienne Boire, Simon N. Powell, Alexandra M. Miller, Elena Pentsova, Lauren Schaff, Ahmed M. Osman, Kiana Chabot, Daniel S. Higginson, Michael Cislo, Michael F. Berger, Nils Weinhold, Alexander G. Goglia, and N. Ari Wijetunga

Abstract

Supplemental Figure 2. Compartment analysis comparing altered genes in solid tumors, plasma ctDNA, and CSF ctDNA, pre and post-pCSI.

Published
2023

17. Supplementary fig 3 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases

Author

Jonathan T. Yang, Adrienne Boire, Simon N. Powell, Alexandra M. Miller, Elena Pentsova, Lauren Schaff, Ahmed M. Osman, Kiana Chabot, Daniel S. Higginson, Michael Cislo, Michael F. Berger, Nils Weinhold, Alexander G. Goglia, and N. Ari Wijetunga

Abstract

Supplemental Figure 3. Tumor purity estimates by FACETS in plasma and CSF samples (n=11, plasma; n=32, CSF, Wilcoxon rank sum test p=0.001)

Published
2023

18. Supplementary fig 4 from Dynamic Mutational Landscape of Cerebrospinal Fluid Circulating Tumor DNA and Predictors of Survival after Proton Craniospinal Irradiation for Leptomeningeal Metastases

Author

Jonathan T. Yang, Adrienne Boire, Simon N. Powell, Alexandra M. Miller, Elena Pentsova, Lauren Schaff, Ahmed M. Osman, Kiana Chabot, Daniel S. Higginson, Michael Cislo, Michael F. Berger, Nils Weinhold, Alexander G. Goglia, and N. Ari Wijetunga

Abstract

Supplemental Figure 4. The distribution of clonal and subclonal alterations in CSF ctDNA pre and post-pCSI.

Published
2023

19. Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer

Author

Grace Moore, Rahul Majumdar, Simon N. Powell, Atif J. Khan, Nils Weinhold, Shen Yin, and Daniel S. Higginson

Subjects
BRCA2 Protein, Ovarian Neoplasms, Cancer Research, Oncology, Mutation, Humans, Female, Poly(ADP-ribose) Polymerase Inhibitors, Homologous Recombination, Molecular Biology, Article
Abstract

Cancer cells defective in homologous recombination (HR) are responsive to DNA-crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta (Pol θ), a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic biallelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single-base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we used what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor Pol θ to design and test novel signatures of polymerase theta–mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions (TINS). We find that TINS consistent with TMEJ repair are highly specific to tumors with pathogenic biallelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. In addition, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared with current state-of-the-art signatures. Implications: Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency.

Published
2021

20. p53-Intact Cancers Escape Tumor Suppression Through Loss of Long Noncoding RNA Dino

Author

Nils Weinhold, Adam M. Schmitt, Ya Hu, Christina B. Marney, Mutayyaba Adnan, Kai-Lin Peng, and E.S. Anderson

Subjects
Cancer, Locus (genetics), Biology, medicine.disease, medicine.disease_cause, Long non-coding RNA, law.invention, law, DNA methylation, medicine, Cancer research, Suppressor, Gene silencing, Carcinogenesis, Gene
Abstract

Many long noncoding RNA (lncRNA) genes are located near cancer-associated loci, suggesting potential roles in cancer development. However, conclusive evidence connecting the function of lncRNAs to the mechanism by which these genetic alterations impact cancer are largely lacking. Here we report that DINO, the long noncoding RNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation in a phenotype that does not require the protein encoded at the locus, p21. In rigorous, genetically-defined mouse models, Dino is a haplo-insufficient tumor suppressor of B cell lymphoma in which p21 does not suppress tumorigenesis. In human cancers, a discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO to impair the p53 signaling pathway in trans and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a long noncoding RNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.

Published
2020

21. p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino

Author

Mutayyaba Adnan, Ya Hu, Adam M. Schmitt, E.S. Anderson, Christina B. Marney, Nils Weinhold, and Kai-Lin Peng

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Male, p53, 0301 basic medicine, QH301-705.5, Apoptosis, Locus (genetics), Haploinsufficiency, Biology, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, cancer, Gene silencing, Genes, Tumor Suppressor, Genetic Predisposition to Disease, long noncoding RNA, Biology (General), Allele, Gene, Alleles, DNA methylation, Epistasis, Genetic, Phenotype, Long non-coding RNA, Mice, Inbred C57BL, 030104 developmental biology, Genetic Loci, Mutation, Cancer research, RNA, Long Noncoding, Tumor Suppressor Protein p53, tumor suppression, Carcinogenesis, DINO, 030217 neurology & neurosurgery
Abstract

SUMMARY Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression., Graphical Abstract, In brief Tumorigenesis requires escape from the p53 tumor suppressor protein. How 50% of cancers develop despite an intact p53 pathway remains largely unknown. Marney et al. report here that loss of the lncRNA DINO provides a route to tumorigenesis in p53-intact cells, and DINO is recurrently silenced in human cancers.

Published
2021

22. Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes

Author

Ronglai Shen, Larry Norton, Daniel S. Higginson, Jorge S. Reis-Filho, Nadeem Riaz, Nils Weinhold, Simon N. Powell, Raymond S. Lim, Britta Weigelt, and Pedro Blecua

Subjects
0301 basic medicine, DNA repair, Science, Mutation, Missense, General Physics and Astronomy, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Germline mutation, Neoplasms, medicine, Humans, Allele, lcsh:Science, Gene, Genetics, Multidisciplinary, Recombinational DNA Repair, General Chemistry, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, lcsh:Q, Homologous recombination, Ovarian cancer, DNA, Genes, Neoplasm
Abstract

BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair and are germ-line cancer pre-disposition genes that result in a syndrome of hereditary breast and ovarian cancer (HBOC). Whether germ-line or somatic alterations in these genes or other members of the HR pathway and if mono- or bi-allelic alterations of HR-related genes have a phenotypic impact on other cancers remains to be fully elucidated. Here, we perform a pan-cancer analysis of The Cancer Genome Atlas (TCGA) data set and observe that bi-allelic pathogenic alterations in homologous recombination (HR) DNA repair-related genes are prevalent across many malignancies. These bi-allelic alterations often associate with genomic features of HR deficiency. Further, in ovarian, breast and prostate cancers, bi-allelic alterations are mutually exclusive of each other. The combination of these two properties facilitates reclassification of variants of unknown significance affecting DNA repair genes, and may help personalize HR directed therapies in the clinic., Germline mutations in homologous recombination (HR) DNA repair genes are linked to breast and ovarian cancer. Here, the authors show that mutually exclusive bi-allelic inactivation of HR genes are present in other cancer types and associated with genomic features of HR deficiency, expanding the potential use of HR-directed therapies.

Published
2017

23. Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

Author

Helen Won, S. Duygu Selcuklu, A. Ari Hakimi, David Chen, Michael F. Berger, Patrizia Pinciroli, Agnes Viale, Nancy Bouvier, Patricia Wang, Ying-Bei Chen, Umesh Bhanot, Parul Patel, Michael Chevinsky, William Lee, Nicholas D. Socci, Jennifer J. Knox, Almedina Redzematovic, Maurizio Voi, Emily H. Cheng, Nils Weinhold, Mahtab Marker, Robert J. Motzer, James J. Hsieh, Martin H. Voss, Daoqi You, and Kety Huberman

Subjects
Male, 0301 basic medicine, Oncology, Pathology, Indoles, medicine.medical_treatment, Targeted therapy, 0302 clinical medicine, Renal cell carcinoma, Sunitinib, Randomized Controlled Trials as Topic, Aged, 80 and over, Histone Demethylases, BAP1, Nuclear Proteins, Middle Aged, Prognosis, Kidney Neoplasms, DNA-Binding Proteins, Survival Rate, Von Hippel-Lindau Tumor Suppressor Protein, 030220 oncology & carcinogenesis, Female, Ubiquitin Thiolesterase, medicine.drug, Adult, medicine.medical_specialty, Urology, Antineoplastic Agents, Disease-Free Survival, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Pyrroles, Everolimus, Progression-free survival, Carcinoma, Renal Cell, Aged, Proportional Hazards Models, business.industry, Tumor Suppressor Proteins, PTEN Phosphohydrolase, Histone-Lysine N-Methyltransferase, medicine.disease, Clear cell renal cell carcinoma, 030104 developmental biology, Mutation, business, Kidney cancer, Transcription Factors
Abstract

Background Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. Objective To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participants Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysis Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitations Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1 , BAP1 , and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. Conclusions PBRM1 , BAP1 , and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summary Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Published
2017

24. The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Author

Christina S. Leslie, Mathieu Berge, Toshinao Oyama, A. Ari Hakimi, Patricia Wang, Song Han, Hatice U. Osmangeyoglu, Amrita M. Nargund, Zhenghong Dong, Emily H. Cheng, Chad J. Creighton, James J. Hsieh, Yiyu Dong, Omer Aras, Yuchen Xie, Shugaku Takeda, Nils Weinhold, Satish K. Tickoo, Can G. Pham, Carl Lekaye, Jason A. Koutcher, Zhong Wang, Chelsea E. Ray, William Lee, and Sebastien Monette

Subjects
0301 basic medicine, Transcription, Genetic, Somatic cell, Hydronephrosis, Kidney, medicine.disease_cause, Oxidative Phosphorylation, PBRM1, STAT3, Mice, genetics, lcsh:QH301-705.5, MTOR, Nuclear Proteins, kidney cancer, Kidney Neoplasms, SWI/SNF, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Von Hippel-Lindau Tumor Suppressor Protein, Signal Transduction, STAT3 Transcription Factor, HIF1, Down-Regulation, mouse tumor model, Mechanistic Target of Rapamycin Complex 1, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, HMGB Proteins, VHL, medicine, Animals, Humans, Epigenetics, Carcinoma, Renal Cell, PI3K/AKT/mTOR pathway, Integrases, epigenetics, Gene Expression Profiling, ccRCC, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Clear cell renal cell carcinoma, 030104 developmental biology, lcsh:Biology (General), Cancer research, Carcinogenesis, Gene Deletion, Clear cell, Transcription Factors
Abstract

PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.

Published
2017

25. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Author

Noreen Dhalla, Saianand Balu, Alexander Potapov, Yiling Lu, Antonio Iavarone, Roel G.W. Verhaak, Alessandro Perin, Bradley A. Murray, Lee Lichtenstein, Nils Gehlenborg, Zhenlin Ju, Simon G. Coetzee, Stephanie Weaver, Gaetano Finocchiaro, Susan M. Staugaitis, Scott Morris, Da Yang, Rosy Singh, Erik Zmuda, Wei Zhang, Aaron D. Black, Roger E. McLendon, J. Bradley Elder, J. Todd Auman, Arvind Rao, Harshad S. Mahadeshwar, Yunhu Wan, Liming Yang, Stacey Gabriel, Andreas Unterberg, Adam E. Flanders, Piotr A. Mieczkowski, Jianjiong Gao, Robert Penny, Andrew Wei Xu, Peter W. Laird, Gad Getz, Cynthia Taylor, Adrian Ally, Ilya Shmulevich, Tina Wong, Christopher M. McPherson, Heidi J. Sofia, Matthew G. Soloway, Jonna Grimsby, Caterina Giannini, Mark L. Cohen, Johanna Gardner, Semin Lee, Alan P. Hoyle, Jianhua Zhang, Thais S. Sabedot, Felicia Williams, Mia Grifford, Daniela Pretti da Cunha Tirapelli, David Van Den Berg, Margi Sheth, Ye Wu, Jenny Eschbacher, Marco A. Marra, Katherine A. Hoadley, Angeliki Pantazi, Chris Benz, Michael S. Noble, Christopher R. Pierson, Kristen M. Leraas, Roy Tarnuzzer, Suzanne Sifri, Huandong Sun, Greg Eley, Eyas M. Hattab, David I. Heiman, Rehan Akbani, Todd Pihl, Michael Parfenov, Erwin G. Van Meir, Jill S. Barnholtz-Sloan, Peggy Yena, Josh Stuart, Richard A. Moore, Toshinori Hinoue, Kelly Senecal, Andrew D. Cherniack, Donald W. Parsons, Rileen Sinha, Dennis T. Maglinte, Timothy A. Chan, Reanne Bowlby, Phuong L. Nguyen, Juok Cho, Andrew E. Sloan, Alexei Protopopov, Matthew Schniederjan, Yun Wang, Yuexin Liu, Rameen Beroukhim, Kristian Cibulskis, Ty Abel, Ronald E. Warnick, Sahil Seth, Richard A. Gibbs, Rebecca Duell, W. Kimryn Rathmell, Jay Bowen, Michael S. Lawrence, Darell D. Bigner, Mary McGraw, Wen-Bin Liu, Xiaojia Ren, Umadevi Veluvolu, Erin Curley, Lynda Chin, Andy Chu, Laila M. Poisson, Harindra Arachchi, Jean C. Zenklusen, Ardene Noss, Sue E. Bell, Karen Devine, Moiz S. Bootwalla, Rebecca Carlsen, David Mallery, Eric S. Lipp, Hailei Zhang, Bradley A. Ozenberger, Andrew J. Mungall, Amie Radenbaugh, Luciano Neder, Sol Katzman, Lisa Iype, Shaowu Meng, Wendi Barrett, S. Onur Sumer, Katie Dicostanzo, Mark Vitucci, Phillip H. Lai, Vsevolod Shurkhay, D. Neil Hayes, Jiabin Tang, Hui Shen, Christopher A. Bristow, Stefania Cuzzubbo, Quinn T. Ostrom, Yasin Senbabaoglu, Ruth Steele, Peter J. Park, Jacqueline E. Schein, Lior Pachter, Jia Liu, Payal Sipahimalani, Angela Hadjipanayis, Scott L. Carter, Donghui Tan, Travis I. Zack, Kristen Shimmel, Steven E. Schumacher, Leigh B. Thorne, Kenna R. Mills Shaw, Troy Shelton, Julien Baboud, Jianan Zhang, Olga Potapova, Stuart R. Jefferys, Andreas von Deimling, B. Arman Aksoy, Carrie Sougnez, Howard Colman, Tom Mikkelsen, Amanda Clarke, Houtan Noushmehr, Daniel Crain, Mark A. Jensen, D L Rotin, Stephen B. Baylin, Barry S. Taylor, Gordon Saksena, Benito Campos, Sudha Chudamani, Ouida Liu, Lisle E. Mose, Jonathan G. Seidman, Corbin D. Jones, Norman L. Lehman, Eric S. Lander, David Haussler, Franklin W. Huang, Nina Thiessen, Charles M. Perou, Gregory N. Fuller, Kosuke Yoshihara, C. Ryan Miller, Brenda Ayala, Dina Aziz, Sara Sadeghi, Cameron Brennan, Randy Mandt, Aditya Raghunathan, Jeffrey Roach, Robert A. Holt, Timothy J. Triche, Barbara Tabak, Kenneth Aldape, John N. Weinstein, Kevin Lau, Ady Kendler, Lee Cooper, Carlos Gilberto Carlotti, Siyuan Zheng, Isaac Joseph, Jason T. Huse, Steven J.M. Jones, Brady Bernard, Chip Stewart, Lixing Yang, Lisa Wise, A. Gordon Robertson, Ronglai Shen, Lisa Scarpace, Richard Kreisberg, Shiyun Ling, Michael Mayo, Jordonna Fulop, Cathy Brewer, Denise Brooks, Daniel E. Carlin, Nils Weinhold, Angela Tam, Beth Hermes, Kalle Leinonen, Giovanni Ciriello, Mahitha Vallurupalli, John A. Demchok, Bianca Pollo, Christel Herold-Mende, Rajan Jain, Liu Xi, Francesco DiMeco, Nilsa C. Ramirez, Tara M. Lichtenberg, Ashley Fehrenbach, Yingchun Liu, Miruna Balasundaram, Sofie R. Salama, Rivka R. Colen, Olena Morozova, Yussanne Ma, Zhining Wang, W. K. Alfred Yung, Scott R. VandenBerg, Esther Rheinbay, Junyuan Wu, Katayoon Kasaian, Tanja M. Davidsen, William A. Friedman, Kathy Smolenski, Yichao Sun, Anders Jacobsen, Chiara Calatozzolo, Matthew D. Wilkerson, Lucia Cuppini, Gordon B. Mills, Xingzhi Song, Joseph Paulauskis, Jaegil Kim, Pei Lin, Scott Frazer, William M. Lee, Evan O. Paull, Sheila A. Fisher, Carolyn M. Hutter, Janae V. Simons, Gene Barnett, Mara Rosenberg, Scot Waring, Timothy R. Fennell, Raju Kucherlapati, Christine Jungk, Martin L. Ferguson, Julie M. Gastier-Foster, Cathy Schilero, Yingli Wolinsky, Rohini Raman, Zack Sanborn, Ranabir Guin, Matthew Meyerson, Daniel J. Brat, Cheryl A. Palmer, Nikolaus Schultz, Erik P. Sulman, Eric Chuah, Mark E. Sherman, Theo A. Knijnenburg, Mitchel S. Berger, Lihua Zou, Hoon Kim, Daniel DiCara, Sam Ng, Joel S. Parker, Sheila Reynolds, Raffaele Nunziata, Daniel J. Weisenberger, Natalie Tasman, Chris Sander, Doug Voet, Yaron S.N. Butterfield, Brian P. O'Neill, Lori Boice, Brat D.J., Verhaak R.G.W., Aldape K.D., Yung W.K.A., Salama S.R., Cooper L.A.D., Rheinbay E., Miller C.R., Vitucci M., Morozova O., Robertson A.G., Noushmehr H., Laird P.W., Cherniack A.D., Akbani R., Huse J.T., Ciriello G., Poisson L.M., Barnholtz-Sloan J.S., Berger M.S., Brennan C., Colen R.R., Colman H., Flanders A.E., Giannini C., Grifford M., Iavarone A., Jain R., Joseph I., Kim J., Kasaian K., Mikkelsen T., Murray B.A., O'Neill B.P., Pachter L., Parsons D.W., Sougnez C., Sulman E.P., Vandenberg S.R., Van Meir E.G., Von Deimling A., Zhang H., Crain D., Lau K., Mallery D., Morris S., Paulauskis J., Penny R., Shelton T., Sherman M., Yena P., Black A., Bowen J., Dicostanzo K., Gastier-Foster J., Leraas K.M., Lichtenberg T.M., Pierson C.R., Ramirez N.C., Taylor C., Weaver S., Wise L., Zmuda E., Davidsen T., Demchok J.A., Eley G., Ferguson M.L., Hutter C.M., Shaw K.R.M., Ozenberger B.A., Sheth M., Sofia H.J., Tarnuzzer R., Wang Z., Yang L., Zenklusen J.C., Ayala B., Baboud J., Chudamani S., Jensen M.A., Liu J., Pihl T., Raman R., Wan Y., Wu Y., Ally A., Auman J.T., Balasundaram M., Balu S., Baylin S.B., Beroukhim R., Bootwalla M.S., Bowlby R., Bristow C.A., Brooks D., Butterfield Y., Carlsen R., Carter S., Chin L., Chu A., Chuah E., Cibulskis K., Clarke A., Coetzee S.G., Dhalla N., Fennell T., Fisher S., Gabriel S., Getz G., Gibbs R., Guin R., Hadjipanayis A., Hayes D.N., Hinoue T., Hoadley K., Holt R.A., Hoyle A.P., Jefferys S.R., Jones S., Jones C.D., Kucherlapati R., Lai P.H., Lander E., Lee S., Lichtenstein L., Ma Y., Maglinte D.T., Mahadeshwar H.S., Marra M.A., Mayo M., Meng S., Meyerson M.L., Mieczkowski P.A., Moore R.A., Mose L.E., Mungall A.J., Pantazi A., Parfenov M., Park P.J., Parker J.S., Perou C.M., Protopopov A., Ren X., Roach J., Sabedot T.S., Schein J., Schumacher S.E., Seidman J.G., Seth S., Shen H., Simons J.V., Sipahimalani P., Soloway M.G., Song X., Sun H., Tabak B., Tam A., Tan D., Tang J., Thiessen N., Triche T., Van Den Berg D.J., Veluvolu U., Waring S., Weisenberger D.J., Wilkerson M.D., Wong T., Wu J., Xi L., Xu A.W., Zack T.I., Zhang J., Aksoy B.A., Arachchi H., Benz C., Bernard B., Carlin D., Cho J., DiCara D., Frazer S., Fuller G.N., Gao J., Gehlenborg N., Haussler D., Heiman D.I., Iype L., Jacobsen A., Ju Z., Katzman S., Kim H., Knijnenburg T., Kreisberg R.B., Lawrence M.S., Lee W., Leinonen K., Lin P., Ling S., Liu W., Liu Y., Lu Y., Mills G., Ng S., Noble M.S., Paull E., Rao A., Reynolds S., Saksena G., Sanborn Z., Sander C., Schultz N., Senbabaoglu Y., Shen R., Shmulevich I., Sinha R., Stuart J., Sumer S.O., Sun Y., Tasman N., Taylor B.S., Voet D., Weinhold N., Weinstein J.N., Yang D., Yoshihara K., Zheng S., Zhang W., Zou L., Abel T., Sadeghi S., Cohen M.L., Eschbacher J., Hattab E.M., Raghunathan A., Schniederjan M.J., Aziz D., Barnett G., Barrett W., Bigner D.D., Boice L., Brewer C., Calatozzolo C., Campos B., Carlotti C.G., Chan T.A., Cuppini L., Curley E., Cuzzubbo S., Devine K., DiMeco F., Duell R., Elder J.B., Fehrenbach A., Finocchiaro G., Friedman W., Fulop J., Gardner J., Hermes B., Herold-Mende C., Jungk C., Kendler A., Lehman N.L., Lipp E., Liu O., Mandt R., McGraw M., Mclendon R., McPherson C., Neder L., Nguyen P., Noss A., Nunziata R., Ostrom Q.T., Palmer C., Perin A., Pollo B., Potapov A., Potapova O., Rathmell W.K., Rotin D., Scarpace L., Schilero C., Senecal K., Shimmel K., Shurkhay V., Sifri S., Singh R., Sloan A.E., Smolenski K., Staugaitis S.M., Steele R., Thorne L., Tirapelli D.P.C., Unterberg A., Vallurupalli M., Wang Y., Warnick R., Williams F., Wolinsky Y., Bell S., Rosenberg M., Stewart C., Huang F., Grimsby J.L., and Radenbaugh A.J.

Subjects
Adult, Male, Pathology, medicine.medical_specialty, IDH1, Adolescent, Kaplan-Meier Estimate, 1p/19q Codeletion, Biology, Article, Glioma, Molecular genetics, Grade II Glioma, medicine, Cluster Analysis, Humans, neoplasms, Exome, ATRX, Proportional Hazards Models, Aged, Cluster Analysi, DNA, Neoplasm, Sequence Analysis, DNA, General Medicine, Middle Aged, Genes, p53, medicine.disease, Chromosomes, Human, Pair 1, Mutation, Proportional Hazards Model, Cancer research, GLIOMA, Female, Oligodendroglioma, Neoplasm Grading, Glioblastoma, Chromosomes, Human, Pair 19, Human, Signal Transduction
Abstract

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)

Published
2015

26. Comprehensive genomic characterization of head and neck squamous cell carcinomas

Author

Ni Zhao, Carter Van Waes, Lori Boice, Ashley H. Salazar, Petar Stojanov, Michael B. Prystowsky, Akinyemi I. Ojesina, Tara M. Lichtenberg, Nikolaus Schultz, Joshua M. Stuart, Mitchell J. Frederick, Julie M. Gastier-Foster, Jeffrey N. Myers, Bradley A. Ozenberger, Margaret L. Gulley, Jean C. Zenklusen, Inanc Birol, Christina Yau, Mark E. Sherman, Saianand Balu, Angela Hadjipanayis, Barry S. Taylor, Piotr A. Mieczkowski, Anthony Saleh, Carol G. Shores, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Lisa Wise, Peter S. Hammerman, Pei Lin, Marc Ladanyi, Mark C. Weissler, Scott L. Carter, Michele C. Hayward, Rehan Akbani, Todd Pihl, J. Jack Lee, Sophie C. Egea, Harshad S. Mahadeshwar, Leigh B. Thorne, Matthew G. Soloway, Troy Shelton, Andrea Haddad, William N. William, Wiktoria Maria Suchorska, Johanna Gardner, Marco A. Marra, Julie Ahn, Travis I. Zack, Lihua Zou, Bayardo Perez-Ordonez, David A. Wheeler, Daniel Crain, Adrian Ally, Deepak Srinivasan, Jay Bowen, Aaron D. Black, Jing Wang, Ludmila Danilova, Roy Tarnuzzer, Brenda Diergaarde, Tod D. Casasent, Dean Cheng, Giovanni Ciriello, Ken Burnett, Jeff Bruce, Wojciech Golusiński, Jonathan G. Seidman, Corbin D. Jones, Daniel J. Weisenberger, Lisa A. Peterson, Thomas M. Harris, Angeliki Pantazi, Nina Thiessen, Curtis R. Pickering, Chandra Sekhar Pedamallu, Yingchun Liu, William Lee, Andrzej Mackiewicz, Hailei Zhang, Ronglai Shen, B. Arman Aksoy, Lixing Yang, Jeffrey Roach, Simion I. Chiosea, John Waldron, David Van Den Berg, James Stephen Marron, Tanja Davidsen, Liming Yang, Maciej Wiznerowicz, Benjamin Gross, Paul M. Weinberger, Yufeng Liu, Reanne Bowlby, Zhixiang Zuo, Bartosz Szybiak, Roni J. Bollag, Samuel S. Freeman, Heather M. Walline, Gad Getz, Scott Morris, Michael S. Noble, Charles Saller, Sahil Seth, Richard A. Gibbs, Jonathan C. Irish, Hollie A. Harper, George E. Sandusky, S. Onur Sumer, Trevor Hackman, Gordon B. Mills, Carol R. Bradford, Payal Sipahimalani, Nipun Kakkar, Robert Penny, Jennifer Drummond, Adam M. Zanation, Rebecca Carlsen, Andrew J. Mungall, Harshavardhan Doddapaneni, James G. Herman, Sylvia Wrenn, Andy Chu, Nilsa C. Ramirez, Patrick Kwok Shing Ng, Patrick K. Kimes, Tina Wong, Mark E. Prince, Han Si, Kristian Cibulskis, Katherine Tarvin, Peter W. Laird, Jiabin Tang, Raja R. Seethala, Michael Parfenov, Jan F. Prins, Erin Curley, Hui Cheng, Donna M. Muzny, Lynda Chin, D. Neil Hayes, Margi Sheth, Carmen Gomez-Fernandez, Jessica Walton, Paul C. Boutros, Ariane Nguyen, Kristen M. Leraas, Robert L. Ferris, Greg Eley, Christopher C. Benz, Jaegil Kim, Thomas E. Carey, Douglas B. Chepeha, Janae V. Simons, Jiexin Zhang, Laura S. Rozek, Maureen A. Sartor, Christopher A. Bristow, Justin A. Bishop, Adel K. El-Naggar, Nishant Agrawal, Yiling Lu, Carrie Sougnez, Evan G. Taylor, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Wendell G. Yarbrough, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Michael Mayo, Wenbin Liu, Ranabir Guin, W. Kimryn Rathmell, Mayya Malakh, Jessica Frick, John N. Weinstein, Kevin Lau, Michelle Q. Pham, Gideon Dresdner, Luc G. T. Morris, David Mallery, Zhining Wang, Yichao Sun, Lynn M. Herbert, Christine M. Komarck, Lauren Averett Byers, Angela Tam, Thomas Bodenheimer, Doug Voet, Christie Kovar, Junyuan Wu, Walker Hale, Charles M. Perou, Angela B.Y. Hui, Kenna R. Mills Shaw, Timothy J. Triche, Dong Zeng, Steven J.M. Jones, Matthew D. Wilkerson, Jinze Liu, Yan Guo, Hsu Chao, Tamara R. Jones, Katherine A. Hoadley, Stuart R. Jefferys, Thomas C. Motter, Matthew Meyerson, Konstanty Korski, Timothy A. Chan, Mark A. Jensen, Julien Baboud, Alexei Protopopov, David I. Heiman, Nils Gehlenborg, Heidi J. Sofia, Aaron D. Tward, Eric S. Lander, Yunhu Wan, Scot Waring, Peggy Yena, Robert I. Haddad, Daniel DiCara, Gordon Saksena, Juok Cho, Richard A. Moore, Darshan Singh, Peter J. Park, Matthew Ibbs, Robert A. Holt, Andrew D. Cherniack, Tanguy Y. Seiwert, Lee Lichtenstein, Anders Jacobsen, Rameen Beroukhim, Brandee T. Brown, Stephen C. Benz, Paweł Golusiński, Vonn Walter, Lixia Diao, Erik Zmuda, Scott Frazer, Michael S. Lawrence, Nils Weinhold, Jacqueline E. Schein, Xiaojia Ren, Denise Brooks, Elizabeth Buda, Jianjiong Gao, Jianhua Zhang, William W. Shockley, J. Todd Auman, Xingzhi Song, Jennifer R. Grandis, Jonathan B. McHugh, Stacey Gabriel, Martin L. Ferguson, Jeffrey S. Reid, Joseph Paulauskis, Umadevi Veluvolu, John A. Demchok, Moiz S. Bootwalla, Fei-Fei Liu, Alan P. Hoyle, Shaowu Meng, Mei Huang, Ann Marie Egloff, Christina Beard, Liu Xi, Ricardo Ramirez, Donna Morton, Lisle E. Mose, Leslie Cope, Marjorie Romkes, Zubair Khan, Noreen Dhalla, Candace Shelton, Boris Reva, Stephen B. Baylin, Miruna Balasundaram, Psalm Haseley, Andrew Wei Xu, Yan Shi, A. Gordon Robertson, Gregory T. Wolf, Darlene Lee, Steven E. Schumacher, Semin Lee, Rileen Sinha, Dennis T. Maglinte, Haiyan I. Li, William K. Funkhouser, Yi Han, Sam Ng, Joel S. Parker, Kai Wang, Zhong Chen, You Hong Fan, Yaron S.N. Butterfield, Jeffrey S. Moyer, Robert A. Burton, David Pot, Chris Sander, Daryl Waggott, Joseph A. Califano, Netty Santoso, and Kyle Chang

Subjects
Male, DNA Copy Number Variations, Somatic cell, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, CDKN2A, Humans, HRAS, Molecular Targeted Therapy, RNA, Neoplasm, Gene, neoplasms, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Oncogene, Genome, Human, Squamous Cell Carcinoma of Head and Neck, Wnt signaling pathway, DNA, Neoplasm, Genomics, Oncogenes, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, FAT1, Signal Transduction, Transcription Factors
Abstract

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Published
2015

27. Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy

Author

Timothy A. Chan, Sviatoslav M. Kendall, Logan A. Walsh, Jonathan J. Havel, Nadeem Riaz, Alexis Desrichard, Vladimir Makarov, and Nils Weinhold

Subjects
0301 basic medicine, medicine.medical_treatment, Ipilimumab, medicine.disease_cause, Article, Autoimmunity, Cohort Studies, 03 medical and health sciences, Antigen, Antigens, Neoplasm, Genetics, medicine, Humans, Melanoma, Serpins, biology, Antibodies, Monoclonal, Immunotherapy, medicine.disease, Survival Analysis, Immune checkpoint, Blockade, Ovalbumin, 030104 developmental biology, Mutation, Immunology, biology.protein, medicine.drug
Abstract

Immune checkpoint blockade has shown significant promise as an anti-cancer treatment, yet the determinants of response are not completely understood. Here, we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival following anti-CTLA4 immunotherapy in two independent cohorts of melanoma patients (n=174). Interestingly, serpins are homologues of the well-known ovalbumin antigen and are associated with autoimmunity. Our findings have implications for the personalization of immunotherapy.

Published
2016

28. Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

Author

Gouri Nanjangud, Gunes Gundem, Emily H. Cheng, William Lee, Almedina Redzematovic, Allan J. Pantuck, Emily C. Zabor, Patricia Wang, Irina Ostrovnaya, John C. Cheville, Elli Papaemmanuil, Paul Russo, Brandon J. Manley, Amrita M. Nargund, Maria E. Arcila, Nicholas M. Donin, Chad J. Creighton, A. Ari Hakimi, Esther Drill, Lu Wang, James J. Hsieh, R. Houston Thompson, Nils Weinhold, Venkatraman E. Seshan, Satish K. Tickoo, and Jozefina Casuscelli

Subjects
0301 basic medicine, Oncology, Kidney, medicine.medical_specialty, Somatic cell, Chromophobe Renal Cell Carcinoma, Chromosome, General Medicine, Chromophobe cell, Biology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Internal medicine, Gene duplication, medicine, biology.protein, Cancer gene, PTEN, Research Article
Abstract

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.

Published
2017

29. Chromosome-wise Protein Interaction Patterns and Their Impact on Functional Implications of Large-Scale Genomic Aberrations

Author

Anders Juul, Nils Weinhold, Søren Brunak, Thomas Skøt Jensen, Isa Kristina Kirk, Niels E. Skakkebæk, Kirstine Belling, and Henrik Leffers

Subjects
0301 basic medicine, Histology, Chromosomes, Human, Pair 21, Gene Dosage, Aneuploidy, Trisomy, Biology, Chromosomes, Pathology and Forensic Medicine, Protein–protein interaction, Transcriptome, Mice, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Protein Interaction Mapping, Gene expression, medicine, Animals, Humans, Protein function prediction, Gene, Oligonucleotide Array Sequence Analysis, Chromosome Aberrations, Genetics, Gene Expression Profiling, Chromosome, Genomics, Cell Biology, medicine.disease, 030104 developmental biology, Down Syndrome, Chromosome 21
Abstract

Gene copy-number changes influence phenotypes through gene-dosage alteration and subsequent changes of protein complex stoichiometry. Human trisomies where gene copy numbers are increased uniformly over entire chromosomes provide generic cases for studying these relationships. In most trisomies, gene and protein level alterations have fatal consequences. We used genome-wide protein-protein interaction data to identify chromosome-specific patterns of protein interactions. We found that some chromosomes encode proteins that interact infrequently with each other, chromosome 21 in particular. We combined the protein interaction data with transcriptome data from human brain tissue to investigate how this pattern of global interactions may affect cellular function. We identified highly connected proteins that also had coordinated gene expression. These proteins were associated with important neurological functions affecting the characteristic phenotypes for Down syndrome and have previously been validated in mouse knockout experiments. Our approach is general and applicable to other gene-dosage changes, such as arm-level amplifications in cancer.

Published
2017
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30. The impact of the protein interactome on the syntenic structure of mammalian genomes

Author

Kirstine Belling, Nils Weinhold, Søren Brunak, and Isa Kristina Kirk

Subjects
0301 basic medicine, Genetic Linkage, Swine, Gene Expression, lcsh:Medicine, Interactome, Genome, Mice, Gene Order, Protein Interaction Maps, lcsh:Science, Conserved Sequence, Genetics, Mammals, Multidisciplinary, Mammalian Genomics, Chromosome Biology, Chromosome Mapping, Genomics, Chromatin, Order (biology), Vertebrates, Apes, Epigenetics, Algorithms, Research Article, Primates, Pan troglodytes, Computational biology, Biology, ENCODE, Synteny, Human Genomics, Chromosomes, Evolution, Molecular, 03 medical and health sciences, Dogs, Animals, Humans, Chimpanzees, Gene, Sequence (medicine), 030102 biochemistry & molecular biology, lcsh:R, Organisms, Biology and Life Sciences, Computational Biology, Cell Biology, Sequence Analysis, DNA, Comparative Genomics, Genome Analysis, 030104 developmental biology, Animal Genomics, Amniotes, lcsh:Q
Abstract

Conserved synteny denotes evolutionary preserved gene order across species. It is not well understood to which degree functional relationships between genes are preserved in syntenic blocks. Here we investigate whether protein-coding genes conserved in mammalian syntenic blocks encode gene products that serve the common functional purpose of interacting at protein level, i.e. connectivity. High connectivity among protein-protein interactions (PPIs) was only moderately associated with conserved synteny on a genome-wide scale. However, we observed a smaller subset of 3.6% of all syntenic blocks with high-confidence PPIs that had significantly higher connectivity than expected by random. Additionally, syntenic blocks with high-confidence PPIs contained significantly more chromatin loops than the remaining blocks, indicating functional preservation among these syntenic blocks. Conserved synteny is typically defined by sequence similarity. In this study, we also examined whether a functional relationship, here PPI connectivity, can identify syntenic blocks independently of orthology. While orthology-based syntenic blocks with high-confident PPIs and the connectivity-based syntenic blocks largely overlapped, the connectivity-based approach identified additional syntenic blocks that were not found by conventional sequence-based methods alone. Additionally, the connectivity-based approach enabled identification of potential orthologous genes between species. Our analyses demonstrate that subsets of syntenic blocks are associated with highly connected proteins, and that PPI connectivity can be used to detect conserved synteny even if sequence conservation drifts beyond what orthology algorithms normally can identify.

Published
2017

31. Genome-wide analysis of noncoding regulatory mutations in cancer

Author

Nikolaus Schultz, William Lee, Anders Jacobsen, Chris Sander, and Nils Weinhold

Subjects
Genetics, Cancer genome sequencing, Comparative genomics, Genome evolution, Gene Expression Profiling, Computational Biology, Molecular Sequence Annotation, Genomics, Genome project, Biology, Genome, Article, 3. Good health, Gene Expression Regulation, Neoplastic, Succinate Dehydrogenase, Neoplasms, Mutation, Humans, Regulatory Elements, Transcriptional, Telomerase, Exome, Exome sequencing
Abstract

Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes.

Published
2014

32. Abstract PD8-09: Bi-allelic alterations in homologous recombination (HR) DNA repair-related genes as the basis for HR defects in human cancers: A pan-cancer genomics and functional analysis

Author

Britta Weigelt, Ronglai Shen, Daniel S. Higginson, Larry Norton, Nadeem Riaz, Raymond S. Lim, Jorge S. Reis-Filho, Simon N. Powell, Nils Weinhold, and Pedro Blecua

Subjects
Cancer Research, DNA repair, PALB2, RAD51, Biology, medicine.disease, Germline mutation, Breast cancer, Oncology, medicine, Cancer research, Ovarian cancer, Homologous recombination, Gene
Abstract

Background: BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair and are germ-line cancer pre-disposition genes that result in the hereditary breast and ovarian cancer (HBOC) syndrome. Whether germ-line or somatic alterations in these genes or other members of the HR pathway and if mono- or bi-allelic alterations of HR-related genes have a phenotypic impact in breast and other cancers remains to be fully elucidated. Here we took a combined genomic and functional approach to identify the role of mutations in HR-related genes and their impact on HR DNA repair. Methods: Whole-exome sequencing and Affymetrix SNP6 array data from 8,178 tumors, comprising 24 different cancer types including breast cancer, were retrieved from The Cancer Genome Atlas (TCGA). We identified the prevalence of missense and pathogenic (frame-shift, nonsense, start/stop codon and splice site variants) somatic and germline mutations in 102 HR-related genes curated from the literature. For each mutation, we determined if the alterations were bi-allelic. We evaluated genomic signatures of HR-deficiency in each tumor using large-scale state transitions (LSTs) and a mutational signature of HR-deficiency (signature 3). An independent set of 24 fresh sporadic breast cancer tissue specimens from our institution was subjected to i) an ex-vivo assay that assesses the ability of cancer cells to form RAD51 foci in response to ex-vivo irradiation (IR), and ii) whole exome-sequencing to define whether RAD51 deficient tumors would display LSTs, signature 3 and bi-allelic inactivation of HR-related genes. Results: 13% and 5% of all TCGA cases displayed pathogenic mono- and bi-allelic alterations of HR-related genes, respectively. Of the biallelic alterations, only 45% occurred in traditional BRCA1/2 associated hereditary cancers (HBOCs, namely breast, ovarian and prostate cancer). Bi-allelic, but not mono-allelic, pathogenic genetic alterations in HR-related genes were significantly associated with genomic evidence of HR deficiency across cancer types, in HBOCs and within breast cancer. In HBOCs, bi-allelic alterations in HR-related genes were mutually exclusive (p=0.02). In breast cancer, bi-allelic inactivation of HR DNA repair-related genes was observed in 9.8%, of which 7.8% involved a germline pathogenic mutation and 2.0% were solely somatic. In breast cancer, in addition to BRCA1 and BRCA2, bi-allelic inactivation of PALB2 (0.2%), ATM (1.1%) and POLQ (0.3%) were found to be associated with genomic features of HR deficiency. In the 24 additional breast cancers, 9 were classified by the functional ex-vivo RAD51 assay as HR-deficient, 8 of which displayed bi-allelic inactivation of one HR-related gene, whereas only 1 of the 15 HR-proficient breast cancers harbored bi-allelic inactivation of HR-related genes (p Conclusion: Bi-allelic germline and somatic alterations of HR-related genes in addition to BRCA1 and BRCA2 are present in breast and other cancer types. Irrespective of the gene, these bi-allelic alterations are associated with HR deficiency as defined by genomic methods and functional assays, expanding the potential opportunities for therapies targeting HR DNA repair defects. Citation Format: Riaz N, Blecua P, Lim RS, Shen R, Higginson DS, Weinhold N, Norton L, Weigelt B, Powell SN, Reis-Filho JS. Bi-allelic alterations in homologous recombination (HR) DNA repair-related genes as the basis for HR defects in human cancers: A pan-cancer genomics and functional analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-09.

Published
2018

33. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA

Author

Kelinda Tucker, Raju Kucherlapati, Ng Sam, John N. Weinstein, Lori Boice, Satish K. Tickoo, Saianand Balu, John C. Cheville, B. Arman Aksoy, Chip Stewart, Preethi H. Gunaratne, Martin L. Ferguson, Bogdan Czerniak, Christie Kovar, Theodore C. Goldstein, Mark E. Sherman, Juan M. Mosquera, Chris Sander, Yaron S.N. Butterfield, Leigh Anne Zach, Yiling Lu, Chandra Lebovitz, Gary Witkin, David Pot, Gordon Robertson, Richard A. Gibbs, James J. Hsieh, Benjamin P. Berman, Doug Voet, Kyle Chang, W. Marston Linehan, Margaret Morgan, Joan Pontius, Jodi Harr, Lihua Zhou, Joel S. Parker, David Van Den Berg, Michael B. Atkins, Sheila Reynolds, Petar Stojanov, Joel B. Nelson, Gordon B. Mills, Toni K. Choueiri, Weimin Xiao, Hye Jung E. Chun, Ronglai Shen, Rebecca Carlsen, Jennifer Brown, Tod D. Casasent, Sabina Signoretti, Jo Ellen Weaver, Phillip H. Lai, Dominique L. Berton, Patrick Plettner, Irina Ostrovnaya, Lisle E. Mose, Leslie Cope, Nils Gehlenborg, Heidi J. Sofia, Peter J. Park, Scott Morris, Hsin-Ta Wu, Fabio Vandin, Ranabir Guin, Daniel E. Carlin, Jacqueline E. Schein, Xi Liu, Nils Weinhold, Wandaliz Torres-Garcia, Cureline Olga Potapova, Daniel DiCara, Juok Cho, Steve Schumacher, Chris Wakefield, A. Rose Brannon, Susan M. Benton, Tom Bodenheimer, J. Todd Auman, Brenda Rabeno, Sharon M. Gorski, Eric E. Snyder, Divya Kalra, Brenda Ayala, Jiashan Zhang, Zhang Wei, Kyle Ellrott, Zhining Wang, Stacey Gabriel, Dominik Stoll, Daniel L. Rubin, W. Kimryn Rathmell, Eric Chuah, David Mallery, Tanja Davidsen, David Cogdell, Anders Jacobsen, John A. Demchok, Robert C. Onofrio, Anna Chu, Piotr A. Mieczkowski, Zhiyong Ding, Erin Curley, Johanna Gardner, Robert Worrell, Hailei Zhang, Jennifer C. Fisher, Donna M. Muzny, Rajiv Dhir, Walker Hale, Ari B. Kahn, Sheila Fisher, Giovanni Ciriello, Ken Burnett, Marco A. Marra, Wiam Bshara, Anil V. Parwani, Joshua M. Stuart, Richard Varhol, Kristin G. Ardlie, Han Yi, Lisa R. Trevino, Roy Tarnuzzer, Michael S. Noble, Erin Pleasance, Jesse Walsh, Leigh B. Thorne, Andy Chu, Peter W. Laird, Andrew J. Mungall, Rashmi N. Sanbhadti, Mark Backus, David A. Wheeler, Bradley A. Ozenberger, Jodi K. Maranchie, William Mallard, Jared R. Slobodan, Christine Czerwinski, Jireh Santibanez, Andrew J. Stout, Donghui Tan, Laura S. Schmidt, Junyuan Wu, Jianjiong Gao, Daniel J. Weisenberger, D. Neil Hayes, Scott Frazer, Alan P. Hoyle, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Rahul Vegesna, Lynda Chin, Shelley Alonso, Jeffrey G. Reid, Donna Morton, Cathy D. Vocke, R. Houston Thompson, Christopher C. Benz, Kenna R. Mills Shaw, Liming Yang, Carmelo Gaudioso, Nianxiang Zhang, Caleb F. Davis, Carrie Hirst, Shi Yan, Michael L. Blute, Barry S. Taylor, Mathew G. Soloway, Nina Thiessen, Paul T. Spellman, Deepak Srinivasan, Yongjun Zhao, Boris Reva, Wang Min, Stuart R. Jefferys, Benjamin J. Raphael, Nicholas J. Petrelli, Arash Shafiei, Lora Lewis, Eric Jonasch, David I. Heiman, Scot Waring, Richard A. Moore, Eric S. Lander, Evan O. Paull, Hoon Kim, Janae V. Simons, Stephen B. Baylin, Gad Getz, Stanley Girshik, Victor E. Reuter, Benjamin Gross, Ethan Cerami, Andrew D. Cherniack, Christine I. Smith, Christina Yau, Michael D. Topal, Peter Waltman, Jeff Boyd, Rameen Beroukhim, Angela Tam, Yingchun Liu, Peter A. Kigonya, Miruna Balasundaram, Maria J. Merino, David Haussler, Dinh Huyen, Elizabeth Buda, Michael S. Lawrence, Lin Pei, Charles M. Perou, Timothy J. Triche, Jessica Walton, Greg Eley, Tiffany Ting Liu, Joseph Paulauskis, Matthew Meyerson, Marc Ladanyi, Jaegil Kim, Katherine A. Hoadley, Huang Mei, Ilya Shmulevich, Robin J.N. Coope, Mary Iacocca, Natasja Wye, Adrian Ally, Mark A. Rubin, A. Ari Hakimi, Lori Huelsenbeck-Dill, Steven J.M. Jones, James Peterson, Mark A. Jensen, Barbara Tabak, Andrey Sivachenko, Julie Bergsten, John Eckman, Inanc Birol, Rohini Raman, Nipun Kakkar, Christina Liquori, Rileen Sinha, Dennis T. Maglinte, Lichtenstein Lee, Haiyan I. Li, William G. Kaelin, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Roel G.W. Verhaak, Christopher J. Ricketts, Carrie Sougnez, Harsha Doddapaneni, Mark S. Guyer, Robert Penny, Michael F. Berger, Margi Sheth, Darlene Lee, Dimitra Tsavachidou, Chad J. Creighton, Prachi Kothiyal, Scott L. Carter, Michael Mayo, Zhu Jing, Kenneth Aldape, Corbin D. Jones, Moiz S. Bootwalla, Payal Sipahimalani, Martin Hirst, Sean P. Barletta, Kristian Cibulskis, Jerome Myers, Matthew C. Nicholls, Yidi J. Turman, Julien Baboud, Jeff Gentry, Carl Morrison, Gordon Saksena, Troy Shelton, Swapna Mahurkar, Robert A. Holt, Robert Sfeir, Shen Hui, Suzanne S. Fei, Christopher G. Wood, Candace Carter, S. Onur Sumer, Pheroze Tamboli, Yiming Zhu, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Getz, Gad Asher, Voet, Douglas, Lin, Pei, Chin, Lynda, and Lander, Eric Steven

Subjects
DNA Mutational Analysis, GRB10 Adaptor Protein, AMP-Activated Protein Kinases, Epigenesis, Genetic, PBRM1, Pentose Phosphate Pathway, Phosphatidylinositol 3-Kinases, RNA, Neoplasm, BAP1, Genome, Multidisciplinary, Genomics, Chromatin, Gene Expression Regulation, Neoplastic, DNA methylation, Signal transduction, Acetyl-CoA Carboxylase, Carcinoma, Renal Cell, Chromatin Assembly and Disassembly, Citric Acid Cycle, DNA Methylation, Gene Expression Profiling, Genome, Human, Histone-Lysine N-Methyltransferase, Humans, Metabolic Networks and Pathways, MicroRNAs, Mutation, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, Signal Transduction, Survival Analysis, Human, Biology, Article, Genetic, SETD2, microRNA, medicine, Neoplastic, Carcinoma, Renal Cell, medicine.disease, Clear cell renal cell carcinoma, Gene Expression Regulation, Cancer research, RNA, Neoplasm, Epigenesis
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.

Published
2013

34. Integrated genomic characterization of endometrial carcinoma

Author

Ding Li, Esther Elishaev, Linda Dao, Juok Cho, Alexei Protopopov, Heather Schmidt, Tod D. Casasent, Bobbie S. Gostout, P.J. DiSaia, Jacqueline E. Schein, J. Todd Auman, Jay Bowen, S. Onur Sumer, Beth Y. Karlan, Gordon Saksena, Prachi Kothiyal, Robert E. Pyatt, Theodore C. Goldstein, Lisle E. Mose, Paul J. Goodfellow, Brenda Ayala, Nilsa C. Ramirez, Thomas Barr, Payal Sipahimalani, Gordon B. Mills, Rebecca Carlsen, Linda Van Le, Andy Chu, Peter W. Laird, Russell Broaddus, Helga B. Salvesen, Sam Ng, Cyriac Kandoth, Christopher Adams, Yiling Lu, Donghui Tan, Peter White, Lori Boice, Saianand Balu, Daniel DiCara, Robert A. Holt, Christopher C. Benz, Shi Yan, Joel S. Parker, Jessica Frick, Adrian Ally, Boris Winterhoff, Pamela M. Pollock, Patrick Plettner, Ethan Cerami, Angela Tam, Katherine A. Hoadley, Melissa Hart-Kothari, Robert C. Onofrio, John N. Weinstein, Sheila Reynolds, David Haussler, Kristian Cibulskis, Charles M. Perou, Timothy J. Triche, Rehan Akbani, Jeff Roach, Michael Mayo, Ranabir Guin, W. Kimryn Rathmell, Carmen Helsel, Junyuan Wu, Will Mallard, Nandita Barnabas, Todd Pihl, Ruibin Xi, Nianxiang Zhang, David Mallery, Douglas A. Levine, Aaron D. Black, David I. Heiman, Sugy Kodeeswaran, Lynda Chin, Guoyan Liu, Mark E. Borowsky, Daniel J. Weisenberger, Yuexin Liu, Hailei Zhang, Kenna R. Mills Shaw, Anna K. Unruh, Andrew Berchuck, Michael Button, Noreen Dhalla, Bryan Hernandez, Rayna K. Matsuno, David G. Mutch, Chen Wang, Teresa R. Tabler, Yaron S.N. Butterfield, Jeff Gentry, Stuart R. Jefferys, Thomas Grossman, Kelley Kneile, Fanny Dao, Scot Waring, Barbara Tabak, Eric E. Snyder, Eric S. Lander, Richard A. Moore, David J. Dooling, David Van Den Berg, Jiabin Tang, Piotr A. Mieczkowski, Victoria Blanc, Wei Zhang, Inanc Birol, Harkness Kuck, Mathew G. Soloway, Johanna Gardner, Gary Witkin, Sahil Seth, Heidi J. Sofia, B. Arman Aksoy, Nikolaus Schultz, Marco A. Marra, Andrew D. Cherniack, D L Rotin, Anders Jacobsen, Erik Zmuda, Candace Carter, Christina Yau, Stephen C. Benz, Alexander A. Green, Michael D. Topal, Jean MacKenzie, Elena Nemirovich-Danchenko, Nicholas J. Petrelli, Dana Nicholson, Eve Shinbrot, Han Liang, Rameen Beroukhim, Charlenia Berry-Green, Kristin G. Ardlie, Joan Pontius, David Pot, Ari B. Kahn, Marc T. Goodman, Yevgeniy Antipin, Christopher Szeto, Jianhua Zhang, Ilya Shmulevich, Lori Huelsenbeck-Dill, Steven J.M. Jones, Carrie Sougnez, Kristen M. Leraas, Pei Lin, Robert A. Soslow, Erin Curley, Leigh B. Thorne, Hye Jung E. Chun, Michael S. Lawrence, Michelle O'Laughlin, Moiz S. Bootwalla, Lixing Yang, Mark A. Jensen, Rajiv Dhir, David A. Wheeler, C. Blake Gilks, Jianjiong Gao, Lisa Wise, Giovanni Ciriello, Joelle Kalicki-Veizer, Shaowu Meng, Mei Huang, Elaine R. Mardis, Faina Bogomolniy, Kai Ye, Jenny Lester, Lihua Zou, Hollie A. Harper, Robert Edwards, Ronglai Shen, Xiaojia Ren, Nils Weinhold, Harshad S. Mahadeshwar, Sandra Orsulic, Tom Bodenheimer, Zhenlin Ju, Chris Wakefield, Scott Frazer, John M. S. Bartlett, Gideon Dresdner, Hui Shen, Deepak Srinivasan, Aaron Hobensack, Cynthia McAllister, Marc Ladanyi, Tanja Davidsen, Lucinda Fulton, Michael D. McLellan, Richard K. Wilson, Zeng Dong, Olga Potapova, Sean C. Dowdy, Rui Jing, Kristin K. Zorn, Robert S. Fulton, Matti Annala, Chris Sander, Michael S. Noble, Benjamin Gross, Janae V. Simons, Phillip H. Lai, Laura Monovich, Andrew J. Mungall, Peter J. Park, Fedor Moiseenko, Liming Yang, Gad Getz, John Deardurff, Matthew Meyerson, Jeremy Parfitt, A. Gordon Robertson, Bradley M. Broom, Blaise A. Clarke, Greg Eley, Jennifer O. Fisher, Andrey Sivachenko, Narciso Olvera, Carrie Hirst, Adam M. Farkas, Karuna Garg, Wendy Winckler, Eric Chuah, Stacey Gabriel, Michael E. Carney, Stephen B. Baylin, Doug Voet, Miruna Balasundaram, Christine Czerwinski, Daphne W. Bell, Richard Varhol, Alexandra Meuter, Alan P. Hoyle, Darlene Lee, Elizabeth Buda, Li Ding, Xingzhi Song, Steven E. Schumacher, Anna L. Chu, Attila Teoman, Mary Iacocca, Semin Lee, Rileen Sinha, Itai Pashtan, Haiyan I. Li, Mikhail Abramov, Mark S. Guyer, Robert Penny, Margi Sheth, Scott L. Carter, Corbin D. Jones, Michael J. Birrer, Julie M. Gastier-Foster, D. Neil Hayes, Nathan Vanhoose, Brenda Rabeno, Raju Kucherlapati, Martin L. Ferguson, Joshua M. Stuart, Steve E. Kalloger, Mark G. Cadungog, Petar Stojanov, Tara M. Lichtenberg, Bradley A. Ozenberger, Angela Hadjipanayis, Barry S. Taylor, Boris Reva, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
DNA Copy Number Variations, endocrine system diseases, ARID1A, DNA Mutational Analysis, Breast Neoplasms, Biology, medicine.disease_cause, Article, Uterine serous carcinoma, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, PTEN, Exome, Poly-ADP-Ribose Binding Proteins, neoplasms, 030304 developmental biology, Chromosome Aberrations, Ovarian Neoplasms, 0303 health sciences, Endometrial intraepithelial neoplasia, Multidisciplinary, Genome, Human, Microsatellite instability, DNA Polymerase II, Genomics, medicine.disease, Molecular biology, female genital diseases and pregnancy complications, Endometrial Neoplasms, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, biology.protein, Female, KRAS, Signal Transduction, Transcription Factors
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., National Institutes of Health (U.S.) (Grant 5U24CA143799-04), National Institutes of Health (U.S.) (Grant 5U24CA143835-04), National Institutes of Health (U.S.) (Grant 5U24CA143840-04), National Institutes of Health (U.S.) (Grant 5U24CA143843-04), National Institutes of Health (U.S.) (Grant 5U24CA143845-04), National Institutes of Health (U.S.) (Grant 5U24CA143848-04), National Institutes of Health (U.S.) (Grant 5U24CA143858-04), National Institutes of Health (U.S.) (Grant 5U24CA143866-04), National Institutes of Health (U.S.) (Grant 5U24CA143867-04), National Institutes of Health (U.S.) (Grant 5U24CA143882-04), National Institutes of Health (U.S.) (Grant 5U24CA143883-04), National Institutes of Health (U.S.) (Grant 5U24CA144025-04), National Institutes of Health (U.S.) (Grant U54HG003067-11), National Institutes of Health (U.S.) (Grant U54HG003079-10), National Institutes of Health (U.S.) (Grant U54HG003273-10)

Published
2013

35. DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation

Author

Lucy A. Godley, Karin Luttrop, Mark Reimers, Matthias Kormaksson, Aparna Vasanthakumar, Rita Shaknovich, Tomas J. Ekström, Franziska Michor, Ari Melnick, Lucas Tsikitas, Jared Frank, Leandro Cerchietti, Maria E. Figueroa, Shao Ning Yang, Gianna Ballon, Thomas Clozel, Nils Weinhold, Subhajyoti De, and Olivier Elemento

Subjects
DNA (Cytosine-5-)-Methyltransferase 1, Methyltransferase, DNA damage, Immunology, DNA Methyltransferase Inhibitor, Mice, Transgenic, Validation Studies as Topic, Biochemistry, DNA methyltransferase, Epigenesis, Genetic, Mice, Activation-induced (cytidine) deaminase, Animals, Cluster Analysis, Humans, DNA (Cytosine-5-)-Methyltransferases, Epigenetics, Immunobiology, B-Lymphocytes, Sheep, biology, Gene Expression Profiling, Cell Differentiation, Cell Biology, Hematology, Methylation, DNA Methylation, Germinal Center, Microarray Analysis, Molecular biology, Mice, Inbred C57BL, DNA methylation, biology.protein
Abstract

The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair.

Published
2011

36. ChemProt: a disease chemical biology database

Author

Thomas Skøt Jensen, Alina Bora, Søren Brunak, Ramona Curpan, Sonny Kim Nielsen, Irene Kouskoumvekaki, Tudor I. Oprea, Karine Audouze, Olivier Taboureau, Nils Weinhold, Daniel Edsgärd, and Francisco S. Roque

Subjects
Database, Databases, Factual, Drug discovery, In silico, Chemical biology, Proteins, Disease, Drug action, Articles, Biology, Bioinformatics, computer.software_genre, SDG 3 - Good Health and Well-being, Genes, Pharmaceutical Preparations, Drug Discovery, Protein Interaction Mapping, Genetics, Humans, computer, Organism, Biological network, Systems pharmacology
Abstract

Systems pharmacology is an emergent area that studies drug action across multiple scales of complexity, from molecular and cellular to tissue and organism levels. There is a critical need to develop network-based approaches to integrate the growing body of chemical biology knowledge with network biology. Here, we report ChemProt, a disease chemical biology database, which is based on a compilation of multiple chemical-protein annotation resources, as well as disease-associated protein-protein interactions (PPIs). We assembled more than 700,000 unique chemicals with biological annotation for 30,578 proteins. We gathered over 2-million chemical-protein interactions, which were integrated in a quality scored human PPI network of 428,429 interactions. The PPI network layer allows for studying disease and tissue specificity through each protein complex. ChemProt can assist in the in silico evaluation of environmental chemicals, natural products and approved drugs, as well as the selection of new compounds based on their activity profile against most known biological targets, including those related to adverse drug events. Results from the disease chemical biology database associate citalopram, an antidepressant, with osteogenesis imperfect and leukemia and bisphenol A, an endocrine disruptor, with certain types of cancer, respectively. The server can be accessed at http://www.cbs.dtu.dk/services/ChemProt/.

Published
2010

37. Abstract PR16: Multiplatform analysis of paired primary and recurrent well- and dedifferentiated liposarcoma samples defines copy number alterations as dominant drivers of initiation and progression

Author

Fatima Wilder, Cyriac Kandoth, Willem van Houdt, Cristina R. Antonescu, Samuel Singer, Rachael O'Connor, Amanda Craig, Li-Xuan Qin, Nils Weinhold, Aimee M. Crago, Nicholas D. Socci, and Agnes Viale

Subjects
Cancer Research, Cancer, Liposarcoma, Biology, medicine.disease, medicine.disease_cause, Molecular biology, Small hairpin RNA, Oncology, Gene expression, medicine, DNA microarray, Carcinogenesis, Gene, Comparative genomic hybridization
Abstract

Objective: Initiation of well-differentiated (WD) and dedifferentiated (DD) liposarcoma is driven by 12q13-15 amplification and consequent MDM2 and CDK4 overexpression, but mechanisms that regulate the variable biologic behavior of WD/DD tumors remain poorly understood. We used a multiplatform analysis of paired WD and DD samples to identify genomic events with potential to contribute to liposarcomagenesis. Methods: From serial tumor resections performed on the same patient, we collected paired WD/DD (n=7) or WD/WD (n=2) test samples and normal tissue. Samples were analyzed using whole-exome sequencing, array comparative genomic hybridization (aCGH), Solexa small RNA sequencing, and, in a subset, RNA-seq. Findings were validated in WD/DD cohorts analyzed by custom capture array (n=201), aCGH (n=210), Affymetrix U133A microarrays (n=146), and Solexa (n=118). Lentivirus was used to deliver shRNA to WD cells in vitro; proliferation was assayed by CyQuant, differentiation by immunoblot/oil red O staining, and gene expression by Illumina microarrays. Results: 12q13-15 amplification was observed in all WD/DD test and validation samples. Among WD samples, 1q21-24 and 6q23-25 amplifications were found in test samples and in 28% and 18% of the validation set, respectively. Of genes upregulated in WD vs. normal fat test samples, 465 were validated in the larger cohort [≥2-fold change (FC), FDR90%. Comparison of matched WD/DD samples showed retained amplification of 12q13-15 and 6q23-25 after progression. In contrast to WD, DD showed strong association of the 6q23-25 CNA with increased expression of 6q genes TCF21 and HBS1L (16- and 4-FC, FDRs Conclusions: Genes upregulated during WD initiation are commonly located in regions of CNA or regulated by 12q23-25 oncogenes MDM2 and CDK4 (e.g., AURKA, a potential therapeutic target). 6q23-26 amplification, observed in subsets of both WD and DD, associates with LR of WD, but expression of 6q23-26 genes with potential to modulate oncogenesis (e.g., TAB2 vs TCF21) differs in WD and DD tumors, suggesting that the CNA may differentially modulate early and late disease. Losses affecting broad chromosome regions such as 13q likely mediate progression by affecting multiple regulators of adipogenesis pathways (e.g., insulin signaling), while mutations have little effect on dedifferentiation. Citation Format: Aimee M. Crago, Nicholas D. Socci, Li-Xuan Qin, Fatima Wilder, Rachael O'Connor, Amanda Craig, Willem van Houdt, Nils Weinhold, Cyriac Kandoth, Agnes Viale, Cristina Antonescu, Sam Singer. Multiplatform analysis of paired primary and recurrent well- and dedifferentiated liposarcoma samples defines copy number alterations as dominant drivers of initiation and progression [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR16.

Published
2018

38. The molecular taxonomy of primary prostate cancer

Author

Piotr A. Mieczkowski, Jianhua Zhang, Saianand Balu, Marc Ladanyi, Victor E. Reuter, Johanna Gardner, Junyuan Wu, Troy Shelton, Simone Chevalier, Marco A. Marra, Anuradha Gopalan, Roy Tarnuzzer, Pei Lin, Joel S. Parker, Umadevi Veluvolu, Lisle E. Mose, Rebecca Carlsen, Michel Carmel, Shalini S. Yadav, Joseph Paulauskis, Fadi Brimo, Sheila Reynolds, Scott Frazer, Natalya Dyakova, Christopher A. Bristow, Brian D. Robinson, Lucie Hamel, Yaron S.N. Butterfield, Yao Fu, Syed Haider, Christopher J. Logothetis, Michael Parfenov, Jeff Boyd, Katherine Tarvin, Kjong-Van Lehmann, Stuart R. Jefferys, Alan P. Hoyle, Arshi Arora, A. Gordon Robertson, Matti Annala, Thomas L. Bauer, Jianhua Luo, Rodolfo Borges Dos Reis, Louis Lacombe, Andrew Salner, Matti Nykter, Alexandre Doueik, Mei Huang, Alireza Moinzadeh, Joshua Armenia, Andre Kahles, Rehan Akbani, Todd Pihl, Gordon Saksena, Robert A. Holt, Felipe Amstalden Trevisan, Mario Berrios, Nina Thiessen, Ronglai Shen, Carrie Sougnez, Xiaojia Ren, Matthew G. Soloway, Lixing Yang, W. Marston Linehan, Chip Stewart, Angeliki Pantazi, Alain Bergeron, Andrea Sboner, Angela Hadjipanayis, Xingzhi Song, Carlos Gilberto Carlotti, Manaswi Gupta, Rashi Naresh, Yiling Lu, Hartmut Juhl, Mark Gerstein, Robert Leung, Sahil Seth, Teri A. Longacre, Ignaty Leshchiner, Chris Sander, Andrew Wei Xu, Anne Marie Mes-Masson, Patrick Teebagy, Julian M. Hess, Matthew Meyerson, Adrian Ally, Jiabin Tang, Ye Wu, Janae V. Simons, David Van Den Berg, Kenna R. Mills Shaw, Patricia Troncoso, Thomas Gribbin, Shannon J. McCall, Andrew K. Godwin, Daniel J. Weisenberger, Kimberly Rieger-Christ, Nilsa C. Ramirez, Peter J. Park, Margi Sheth, Mark E. Sherman, Eric S. Lander, Yunhu Wan, Lisa Iype, Robert Penny, J. Todd Auman, Ekta Khurana, Stephen J. Freedland, Jeffry Simko, Nils Weinhold, Bradley M. Broom, Angela Tam, Nikolaus Schultz, Erik Zmuda, Wei Zhang, Wenyi Wang, Jeffrey Roach, Christopher E. Barbieri, Alan H. Bryce, Qingguo Wang, Lawrence D. True, Christopher C. Benz, Mathieu Latour, Richard A. Moore, Michael Mayo, Yi Zhong, Tara M. Lichtenberg, Jacqueline E. Schein, Svitlana Tyekucheva, Ranabir Guin, Scott L. Carter, Michael Kerger, David Canes, Scott M. Lippman, Alexei Protopopov, Katayoon Kasaian, Peter A. Pinto, Peter S. Nelson, W. Kimryn Rathmell, David Mallery, Brett S. Carver, David I. Heiman, Juok Cho, Doug Voet, Thorsten Schlomm, Janet E. Cowan, Heidi J. Sofia, Peggy Yena, Matthew D. Wilkerson, Glenn Bubley, Tucker W. LeBien, Yan Shi, Lucas Lochovsky, Gordon B. Mills, Hailei Zhang, Andrea Holbrook, Christopher M. Hovens, Christina Yau, Jonathan G. Seidman, Samirkumar B. Amin, Corbin D. Jones, Andrew D. Cherniack, Lori Boice, Laxmi Lolla, Kristen M. Leraas, Denise Brooks, Francesca Demichelis, Maria Christina Tsourlakis, Katherine A. Hoadley, Charles Saller, Leigh B. Thorne, Julie M. Gastier-Foster, Jaegil Kim, Rameen Beroukhim, Peter R. Carroll, John A. Demchok, Christopher J. Kane, Jay Bowen, Massimo Loda, Richard Cartun, Ina Felau, Carl Morrison, Kerstin David, Eliezer M. Van Allen, Laura S. Schmidt, D. Neil Hayes, Adrian Bivol, Michael S. Lawrence, Raju Kucherlapati, Kelsey Zhu, Wen-Bin Liu, Matthew R. Cooperberg, Houtan Noushmehr, Daniel Crain, Luciano Neder, Lynda Chin, Barry S. Taylor, Jiashan Zhang, Bradley A. Murray, Ginette McKercher, Miruna Balasundaram, Chia Chin Wu, Peter T. Scardino, Suhn K. Rhie, Mark A. Rubin, Jean C. Zenklusen, Ronald Simon, Jaeil Ahn, Markus Graefen, Phillip H. Lai, Michael Ittmann, June M. Chan, Maria J. Merino, Andy Chu, Liming Yang, Charles M. Perou, Steven J.M. Jones, Gad Getz, Stacey Gabriel, Martin L. Ferguson, Jianjiong Gao, Payal Sipahimalani, Lisa Wise, Serghei Stepa, Arvind Rao, Bettina F. Drake, Antonia H. Holway, Armaz Mariamidze, Kiley Graim, Juliann Shih, Guido Sauter, Sarah Minner, Amanda Clarke, Harshad S. Mahadeshwar, Andrew J. Mungall, Alain Piché, Cathy D. Vocke, Sudha Chudamani, Yulia Newton, Davide Prandi, Roeland Verhaak, Ilya Shmulevich, Matthew T. Chang, Sara Sadeghi, Michael Button, Joshua M. Stuart, Anne Breggia, Kristian Cibulskis, Giovanni Ciriello, Paul C. Boutros, Yu Chen, Zhining Wang, Jerome Myers, Heidi Dvinge, Ashutosh Tewari, Scott Morris, Andrea Sorcini, Tara Skelly, Niall M. Corcoran, Michael S. Noble, Anthony J. Costello, Timothy C. Thompson, Eric Chuah, Carolyn M. Hutter, Robert K. Bradley, Fred Saad, John A. Libertino, Reanne Bowlby, John A. Stewart, Shiyun Ling, Gunnar Rätsch, George E. Sandusky, Alexis Sharp, Eric J. Burks, Thomas Zeng, Erin Curley, Charlie Sun, Rajiv Dhir, Yussanne Ma, Huihui Ye, Hui Shen, Nils Gehlenborg, Imelda Tenggara, Travis Sullivan, Tom Bodenheimer, Jia Liu, Christopher D. Andry, Adam Abeshouse, Daniela P. Tirapelli, John N. Weinstein, Kevin Lau, Francisco Sanchez-Vega, Armen Aprikian, Peter W. Laird, Noreen Dhalla, Candace Shelton, Joel Nelson, Bernard Têtu, Darlene Lee, Eleonora Scarlata, Mark Nelson, Steven E. Schumacher, Robert J. Klein, Mark Gerken, Donghui Tan, Semin Lee, John S. Witte, Shaowu Meng, Huandong Sun, Moiz S. Bootwalla, Scott A. Tomlins, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, and Voet, Douglas

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, DNA Repair, DNA repair, Urology, MEDLINE, Biology, SPOP, Bioinformatics, Molecular taxonomy, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Fusion gene, 03 medical and health sciences, Prostate cancer, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, Neoplasm Metastasis, Gene, 030304 developmental biology, Gynecology, 0303 health sciences, Primary (chemistry), business.industry, Prostatic Neoplasms, medicine.disease, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, GENÉTICA, 030104 developmental biology, medicine.anatomical_structure, Receptors, Androgen, 030220 oncology & carcinogenesis, DNA methylation, Mutation, Cancer research, ras Proteins, Gene Fusion, business, Signal Transduction
Abstract

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)

Published
2015

39. Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis

Author

Ketu Mishra-Gorur, S. Bulent Omay, Kaya Bilguvar, Alexander O. Vortmeyer, Akdes Serin Harmanci, Süleyman Coşkun, Jia Sun, Tanyeri Barak, Mehmet Bakırcıoğlu, Ahmet Okay Caglayan, Victoria E. Clark, Koray Özduman, Jie Li, M. Necmettin Pamir, Nikolaus Schultz, Anita Huttner, Nils Weinhold, Jennifer Moliterno Günel, Murat Gunel, Doğan Köse, Chris Sander, Katsuhito Yasuno, Yavuz Köksal, Burçin Baran, Jacob F Baranoski, E. Zeynep Erson-Omay, Caner Çağlar, Geneive Carrión-Grant, Acibadem University Dspace, ÇAĞLAR, CANER, and Selçuk Üniversitesi

Subjects
Adult, Cancer Research, DNA Copy Number Variations, Somatic cell, DNA Mutational Analysis, Biology, polymerase epsilon, Disease-Free Survival, Young Adult, Germline mutation, Glioma, medicine, Humans, Child, Poly-ADP-Ribose Binding Proteins, Gene, Exome, ultramutated tumor, Brain Neoplasms, glioblastoma, DNA Polymerase II, germline MSH6 mutation, medicine.disease, Prognosis, Phenotype, MSH6, Oncology, better prognosis, Giant cell, Child, Preschool, Mutation, Basic and Translational Investigations, Cancer research, Neurology (clinical)
Abstract

WOS: 000364783100007, PubMed: 25740784, Background. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments., Gregory M. Kiez and Mehmet Kutman Foundation, This study was supported by the Gregory M. Kiez and Mehmet Kutman Foundation.

Published
2015

40. The landscape of T cell infiltration in human cancer and its association with antigen presenting gene expression

Author

David A. Scheinberg, Chris Sander, Martin H. Voss, Irina Ostrovnaya, William Lee, A. Ari Hakimi, Augustin Luna, Emily H. Cheng, Yasin Senbabaoglu, James J. Hsieh, Ming O. Li, Jonathan A. Coleman, Paul Russo, Samuel D. Kaffenberger, Ying-Bei Chen, Victor E. Reuter, Nils Weinhold, Andrew G. Winer, Ron S. Gejman, Timothy A. Chan, and Ming Liu

Subjects
Clear cell renal cell carcinoma, Cell type, Tumor microenvironment, Immune system, medicine.anatomical_structure, Antigen, T cell, Immunology, medicine, Biology, medicine.disease, Infiltration (medical), CD8
Abstract

Infiltrating T cells in the tumor microenvironment have crucial roles in the competing processes of pro-tumor and anti-tumor immune response. However, the infiltration level of distinct T cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery (APM) genes, remain poorly characterized across human cancers. Here, we define a novel mRNA-based T cell infiltration score (TIS) and profile infiltration levels in 19 tumor types. We find that clear cell renal cell carcinoma (ccRCC) is the highest for TIS and among the highest for the correlation between TIS and APM expression, despite a modest mutation burden. This finding is contrary to the expectation that immune infiltration and mutation burden are linked. To further characterize the immune infiltration in ccRCC, we use RNA-seq data to computationally infer the infiltration levels of 24 immune cell types in a discovery cohort of 415 ccRCC patients and validate our findings in an independent cohort of 101 ccRCC patients. We find three clusters of tumors that are primarily separated by levels of T cell infiltration and APM gene expression. In ccRCC, the levels of Th17 cells and the ratio of CD8+ T/Treg levels are associated with improved survival whereas the levels of Th2 cells and Tregs are associated with negative clinical outcome. Our analysis illustrates the utility of computational immune cell decomposition for solid tumors, and the potential of this method to guide clinical decision-making.

Published
2015
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41. Genomic Classification of Cutaneous Melanoma

Author

W. Kimryn Rathmell, Lauren E. Haydu, Nils Gehlenborg, David Mallery, Lynn M. Herbert, Hailei Zhang, Darlene Lee, Payal Sipahimalani, Richard A. Scolyer, Jonathan R. Stretch, Amanda Clarke, Sudha Chudamani, Dirk Schadendorf, Jeffrey Roach, Troy Shelton, Kerwin F. Shannon, Kadir C. Akdemir, Alexander J. Lazar, Lixing Yang, D. Murawa, Jingchun Zhu, Michael Mayo, Steven E. Schumacher, Marc Ladanyi, Yiling Lu, Levi A. Garraway, Andrew J. Spillane, Giandomenico Russo, Ian R. Watson, Matthew D. Wilkerson, Mei Huang, Chang Jiun Wu, Pedamallu Chandra Sekhar, Laura Brockway-Lunardi, Wiktoria Maria Suchorska, Michael A. Davies, John M. S. Bartlett, Benjamin Gross, Mark Gerken, Georgy Manikhas, William R. Jeck, Michael Dinikin, Sam Ng, Antje Sucker, Sharon K. Huang, Donghui Tan, Semin Lee, Da Yang, Yardena Samuels, Boris C. Bastian, Katherine A. Hoadley, Kenna R. Mills Shaw, Shaowu Meng, Kunal Rai, Sheila Fisher, Tom Bodenheimer, Robyn P. M. Saw, Joel S. Parker, Victoria Fulidou, Scot Waring, Vesteinn Thorsson, Jacqueline E. Schein, Heidi J. Sofia, Jia Liu, Eric S. Lander, Martin L. Miller, Scott E. Woodman, Yunhu Wan, Olga Voronina, Brenda Ayala, Moiz S. Bootwalla, Rileen Sinha, Yonathan Lissanu Deribe, Yussanne Ma, Gabriel Sica, Matthew Ibbs, Pam Bartlett, Arkadiusz Spychała, Sheila Reynolds, Nikolaus Schultz, Jianhua Zhang, Stephen B. Baylin, Saianand Balu, Jay Bowen, Eran Hodis, Olga Potapova, Lori Boice, Julie M. Gastier-Foster, Singer Ma, Victor G. Prieto, Steven J.M. Jones, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Ruibin Xi, Stergios J. Moschos, Lisa Iype, Robert Penny, Vonn Walter, Peter Hersey, Umadevi Veluvolu, Jiabin Tang, Mark A. Jensen, Aaron Chevalier, Nils Weinhold, Yaron S.N. Butterfield, S. Onur Sumer, Lisle E. Mose, Leslie Cope, Angela Tam, Carmelo Gaudioso, Giovanni Ciriello, Jaegil Kim, Noreen Dhalla, Candace Shelton, Andrzej Mackiewicz, Travis I. Zack, James G. Herman, Lisa Zimmer, Chia Chin Wu, Elena Pagani, Franklin W. Huang, Tanja Davidsen, Stuart R. Jefferys, Andy Chu, Harmanjatinder S. Sekhon, Richard A. Moore, Scott L. Carter, Ludmila Danilova, Peter W. Laird, Nicholas K. Hayward, Julien Baboud, A. Gordon Robertson, Scott Morris, Honorata Tatka, Gordon Saksena, Robert A. Holt, Angela Hadjipanayis, Jakub Brzezinski, Lihua Zou, Nilsa C. Ramirez, Witold Kycler, Yasin Senbabaoglu, Xingzhi Song, Barbara Tabak, Christopher C. Benz, Michael Dubina, Wei Zhang, Sophie Egea, Fedor Moiseenko, Marcus Bosenberg, Piotr A. Mieczkowski, Michael J. Quinn, Harindra Arachchi, Andrew J. Mungall, Lynn Cherney, Suresh Ramalingam, Christopher A. Bristow, Hojabr Kakavand, Chris Sander, Peiling Tsou, Anil Korkut, Alan P. Hoyle, Arshi Arora, Kenneth K. Lee, Netty Santoso, Raymond J. Cho, Ricardo Ramirez, Melissa Saul, Haiyan I. Li, Jeremy Parfitt, Valerie Jakrot, Tiffany L. Calderone, Jessica Frick, John N. Weinstein, Brady Bernard, John M. Kirkwood, Dave S.B. Hoon, Carolyn J. Shiau, Carmen Gomez-Fernandez, Michael Krauthammer, Carrie Sougnez, George E. Sandusky, Xiaojia Ren, Charles Schwallier, Carolyn M. Hutter, Radoslaw Łaźniak, Dmitry Belyaev, Richard F. Kefford, Jeffrey M. Trent, Ouida Liu, J. Stephen Ebrom, Yoon La Choi, Maciej Wiznerowicz, Ranabir Guin, Yan Shi, Ewa Leporowska, Zhenlin Ju, Charles Saller, Hyojin Kang, Jean C. Zenklusen, Tony Gutschner, Peter White, Luigi Nezi, Oxana Paklina, Harshad S. Mahadeshwar, Wiam Bshara, Roeland Verhaak, Kenneth Y. Tsai, Ilya Shmulevich, Kristian Cibulskis, Jonathan G. Seidman, Corbin D. Jones, Ayush T. Raman, D. Neil Hayes, Nandita Barnabas, Uma Rao, Jennifer Eschbacher, Timothy R. Fennell, Jeffrey E. Lee, Matthew Meyerson, Jeffrey E. Gershenwald, Elizabeth Buda, Xiaobei Zhao, Jason Roszik, M. Teresiak, Daniel DiCara, Pei Lin, Eliezer M. Van Allen, Scott Frazer, Genevieve M. Boland, Zhining Wang, Susan Hoppough, Konstanty Korski, Michael S. Noble, B. Arman Aksoy, Reanne Bowlby, Adeboye Osunkoya, Taofeek K. Owonikoko, Madhusmita Behera, Shiyun Ling, Erin Curley, Rajiv Dhir, Andrew Wei Xu, David I. Heiman, Samirkumar B. Amin, Andrew D. Cherniack, Brenna Matejka, Rameen Beroukhim, Michael S. Lawrence, Kelsey Zhu, Wen-Bin Liu, Stacey Gabriel, Martin L. Ferguson, Samantha Sharpe, Giannicola Genovese, Jay Engel, Johanna Gardner, Junyuan Wu, Marco A. Marra, Roy Tarnuzzer, John F. Thompson, Denise Brooks, Lawrence N. Kwong, Woong-Yang Park, Daniel J. Weisenberger, J. Todd Auman, Kristen M. Leraas, Margi Sheth, Riccardo Bono, John A. Demchok, Stefania D'Atri, Candace D. Carter, Miruna Balasundaram, Natalie Bir, Matthew G. Soloway, Angeliki Pantazi, Sahil Seth, Qixia A. Deng, Junehawk Lee, Dana Nicholson, Ye Wu, Keith T. Flaherty, Peter J. Park, Amie Radenbaugh, Benjamin Hanf, Katherine Tarvin, James S. Wilmott, Giancarlo Antonini Cappellini, Pawel Murawa, Maria Synott, Jonna Grimsby, Stephen Coons, Joachim Klode, Michael Button, Alyssa Janning, Alexei Protopopov, Florian L. Muller, Donald L. Morton, Joshua M. Stuart, Ina Felau, Cindy Sander, Ruth Halaban, John P. Miller, David Haussler, Monique Albert, Charles M. Perou, Timothy J. Triche, Yichao Sun, Aaron D. Black, Adrian Ally, Sousan Mehrabi, David Van Den Berg, Graham J. Mann, Erik Zmuda, Carl Morrison, Daniel Crain, Douglas Voet, Janae V. Simons, Norman E. Sharpless, Fadlo R. Khuri, Phillip H. Lai, Liming Yang, Anders Jacobsen, Keith A. Delman, Teresa R. Tabler, Gad Getz, Tara M. Lichtenberg, William Lee, Georgina V. Long, Nina Thiessen, Ronglai Shen, Francesca Passarelli, Bradley A. Ozenberger, Gordon B. Mills, Jessica Walton, Greg Eley, Leigh B. Thorne, Merrick I. Ross, Jared Malke, Barry S. Taylor, Juok Cho, William R. Burns, Michael Parfenov, Thomas Gribbin, Yuling Wang, Raju Kucherlapati, Lynda Chin, Bradley A. Murray, Lee Lichtenstein, Jianjiong Gao, and Lisa Wise

Subjects
Skin Neoplasms, Mutant, Medizin, Biology, General Biochemistry, Genetics and Molecular Biology, Subclass, Article, Transcriptome, chemistry.chemical_compound, Databases, Genetic, medicine, Humans, Gene, Melanoma, Genetics, Biochemistry, Genetics and Molecular Biology(all), Cancer, Binimetinib, medicine.disease, National Cancer Institute (U.S.), United States, 3. Good health, chemistry, Cutaneous melanoma, Mutation, Cancer research
Abstract

Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

Published
2015

42. Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Author

Luc G. T. Morris, Timothy A. Chan, Sviatoslav M. Kendall, Walter J. Urba, John-William Sidhom, Nadeem Riaz, Shailender Bhatia, Jonathan J. Havel, Diego Chowell, Rachna Shah, William H. Sharfman, Rajarsi Mandal, Vladimir Makarov, Wen-Jen Hwu, Craig L. Slingluff, Thomas F. Gajewski, Nils Weinhold, Salvador Martín-Algarra, F. Stephen Hodi, Han Chang, Alexis Desrichard, Christine Horak, Jennifer S. Sims, Jonathan P. Schneck, and Fengshen Kuo

Subjects
0301 basic medicine, T-Lymphocytes, medicine.medical_treatment, T cell, Programmed Cell Death 1 Receptor, Antineoplastic Agents, Ipilimumab, Biology, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, Tumor Microenvironment, medicine, Humans, Melanoma, Tumor microenvironment, Antibodies, Monoclonal, Immunotherapy, medicine.disease, Immune checkpoint, Nivolumab, 030104 developmental biology, medicine.anatomical_structure, Immunology, Genome-Wide Association Study, medicine.drug
Abstract

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

Published
2017

43. Abstract 2988: Immunogenomic analyses of tumor cells and microenvironment in patients with advanced melanoma before and after treatment with nivolumab

Author

Walter J. Urba, Sviatoslav M. Kendall, Alexis Desrichard, Christine Horak, Timothy A. Chan, William H. Sharfman, Thomas F. Gajewski, Craig L. Slingluff, Nadeem Riaz, Jonathan J. Havel, Vladimir Makarov, John-William Sidhom, F. Stephen Hodi, Han Chang, Nils Weinhold, Salvador Martín-Algarra, Wen-Jen Hwu, Jonathan P. Schneck, Jennifer S. Sims, and Shailender Bhatia

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Tumor microenvironment, LAG3, business.industry, Cancer, Ipilimumab, medicine.disease, Immune checkpoint, hemic and lymphatic diseases, Internal medicine, medicine, Nivolumab, business, CD8, Progressive disease, medicine.drug
Abstract

Background: Response to checkpoint blockade may be dependent on tumor mutational load and the presence of antigen-specific effector T cells in the tumor microenvironment; however, how blockade modulates these features during therapy is unclear. We assessed genomic changes in tumors from patients (pts) with advanced melanoma receiving nivolumab (nivo) who progressed on ipilimumab (ipi-P) or were ipi-naive (ipi-N). Methods: Tumor biopsies were collected pretreatment and 4 weeks post first nivo dose from ipi-N or ipi-P pts treated with nivo 3 mg/kg Q2W in the phase 1 open-label CA209-038 study (NCT01621490). Biopsies from 68 pts were analyzed by whole exome, transcriptome, and/or TCR sequencing (paired biopsies from 41, 42, and 34 pts, respectively). Results: Objective response rate (ORR) in the overall cohort (n=85) was 27% with similar ORR in ipi-N and ipi-P cohorts. In the genomic cohort (n=68), ORR was 23% with a similar number of complete or partial responses (CR/PR) in ipi-N and ipi-P pts (n=7 and n=8, respectively). Prior to treatment, mutational and neoantigen load were comparable, regardless of previous treatment. Following nivo treatment, both mutational and neoantigen load were reduced 5-fold in pts who responded (CR/PR; n=9) and 1.2-fold in pts with stable disease (SD, n=13) compared with a 1.1-fold increase in pts with progressive disease (PD, n=19). Intratumoral heterogeneity analysis before and after nivo demonstrated that CR/PR pts generally lost tumor mutation clones/subclones. Novel tumor mutation clones were observed in on-treatment samples from 2 CR/PR pts and all pts who progressed on nivo. Transcriptome analyses revealed significant increases in distinct tumor immune cell subsets (CD8+ T cells and NK cells) and immune checkpoint gene expression (LAG3, CTLA4, PCDC1, and CD274 [PD-L1]) following nivo, which were more pronounced in pts with CR/PR vs PD (log2 fold-changes of 1.24, 1.07, 1.71, and 0.74, respectively). Consistent with the transcriptome analyses, tumor-infiltrating lymphocytes, as assessed by immunohistochemistry, generally increased following nivo in pts who responded: 2.8 vs 1.9-fold change in CR/PR/SD vs PD in the ipi-P cohort; 4.8 vs 1.8-fold change in CR/PR/SD vs PD in the ipi-N cohort. Differences in treatment-related TCR repertoire diversity changes were apparent between pts who responded within the ipi-N and ipi-P cohorts: a decrease in the evenness of T-cell clonotype distribution was observed among pts with CR/PR/SD relative to pts with PD in the ipi-N cohort (P=0.036), but not in the ipi-P cohort. Conclusion: Nivo and ipi modulate T-cell repertoire and tumor mutational heterogeneity in pts with advanced melanoma, presenting potential mechanisms of action underlying successful nivo therapy. These data also show that prior ipi treatment may influence biological response to nivo, but further investigation is warranted. Citation Format: Timothy A. Chan, Nadeem Riaz, Jonathan J. Havel, Vladimir Makarov, Alexis Desrichard, Jennifer S. Sims, F. Stephen Hodi, Salvador Martín-Algarra, William H. Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F. Gajewski, Craig L. Slingluff, Sviatoslav M. Kendall, Han Chang, John-William Sidhom, Jonathan P. Schneck, Nils Weinhold, Christine E. Horak, Walter J. Urba. Immunogenomic analyses of tumor cells and microenvironment in patients with advanced melanoma before and after treatment with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2988. doi:10.1158/1538-7445.AM2017-2988

Published
2017

44. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication

Author

A. Yasemin Göksenin, Hsu Chao, Eve Shinbrot, Erin E. Henninger, Zachary F. Pursell, David A. Wheeler, Kyle R. Covington, Chris Sander, Harshavardhan Doddapaneni, Donna M. Muzny, Nikolaus Schultz, Nils Weinhold, and Richard A. Gibbs

Subjects
DNA Replication, Exonucleases, Models, Molecular, Mutation rate, DNA polymerase II, Nonsense mutation, DNA Mutational Analysis, DNA polymerase epsilon, Mutation, Missense, Replication Origin, Ataxia Telangiectasia Mutated Proteins, medicine.disease_cause, Phosphatidylinositol 3-Kinases, Neoplasms, Databases, Genetic, Genetics, medicine, Humans, Mutation frequency, Genetics (clinical), DNA Polymerase III, Mutation, biology, Point mutation, Research, DNA Polymerase II, Molecular biology, Protein Structure, Tertiary, Class Ia Phosphatidylinositol 3-Kinase, Codon, Nonsense, biology.protein, Dynamic mutation, Microsatellite Instability, Tumor Suppressor Protein p53, Genome-Wide Association Study
Abstract

Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication.

Published
2014

45. Characterization of HPV and host genome interactions in primary head and neck cancers

Author

J. Jack Lee, Carter Van Waes, Michael B. Prystowsky, Akinyemi I. Ojesina, Joshua M. Stuart, Mitchell J. Frederick, Angela By Hui, Saianand Balu, Scot Waring, Inanc Birol, Bayardo Perez-Ordonez, Aaron D. Black, Payal Sipahimalani, Wiktoria Maria Suchorska, Michele C. Hayward, Jeffrey Roach, Adrian Ally, Ranabir Guin, Samuel S. Freeman, J. Todd Auman, Hollie A. Harper, Mark E. Prince, David Van Den Berg, Nipun Kakkar, James G. Herman, Adam M. Zanation, Nilsa C. Ramirez, Daniel DiCara, Carol R. Bradford, Paul C. Boutros, Peter W. Laird, Evan G. Taylor, Yan Shi, Jonathan M. Irish, Kristian Cibulskis, Junyuan Wu, Darlene Lee, Katherine A. Hoadley, Jeff Bruce, Yingchun Liu, Heather M. Walline, Carol G. Shores, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Steven E. Schumacher, Wendell G. Yarbrough, Tanguy Y. Seiwert, Sophie C. Egea, Elena Ivanova, Troy Shelton, Jiexin Zhang, Patrick K. Kimes, Nikolaus Schultz, Noreen Dhalla, Maciej Wiznerowicz, Daniel J. Weisenberger, Martin L. Ferguson, Tamara R. Jones, Haiyan I. Li, Nishant Agrawal, Yiling Lu, Lixing Yang, Brandee T. Brown, Julie M. Gastier-Foster, Nils Weinhold, Harshad S. Mahadeshwar, Angela Tam, Lihua Zou, Tom Bodenheimer, Gordon B. Mills, W. Kimryn Rathmell, David Mallery, Semin Lee, Scott J. Morris, Lynn M. Herbert, Hailei Zhang, Thomas C. Motter, Walker Hale, Tina Wong, Yichao Sun, Heidi J. Sofia, Rileen Sinha, Dennis T. Maglinte, Robert I. Haddad, Matthew D. Wilkerson, Jinze Liu, Julien Baboud, Brenda Diergaarde, Michelle Q. Pham, Tanja M. Davidsen, Maureen A. Sartor, Robert A. Holt, Angela Hadjipanayis, Pei Lin, Anders Jacobsen, Stephen C. Benz, Dean Cheng, Matthew Meyerson, Andy Chu, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Scott Frazer, Leigh B. Thorne, Andrew J. Mungall, David A. Wheeler, Nina Thiessen, Jay Bowen, Hui Cheng, D. Neil Hayes, Jennifer Drummond, Patrick Kwok Shing Ng, Harshavardhan Doddapaneni, S. Onur Sumer, Katherine Tarvin, John W.F. Waldron, Nils Gehlenborg, Douglas B. Chepeha, Janae V. Simons, Robert L. Ferris, Paweł Golusiński, Christina Beard, Donna Morton, Boris Reva, Psalm Haseley, Andrew Wei Xu, Giovanni Ciriello, Gregory T. Wolf, Ken Burnett, Lisa A. Peterson, Sylvia Wrenn, Mark A. Jensen, Travis I. Zack, Deepak Srinivasan, Thomas E. Carey, Lisle E. Mose, Mark E. Sherman, Leslie Cope, Adel K. El-Naggar, Marjorie Romkes, D Wheeler, Christopher A. Bristow, Andrea Haddad, Mayya Malakh, Ludmila Danilova, Jean C. Zenklusen, Jiabin Tang, Laura S. Rozek, Jon G. Seidman, Steven J.M. Jones, Hsu Chao, Candance Shelton, Carmen Gomez-Fernandez, Carrie Sougnez, Piotr A. Mieczkowski, Lee Lichtenstein, Erik Zmuda, Johanna Gardner, Jianjiong Gao, Marco A. Marra, Juok Cho, Alexei Protopopov, Roy Tarnuzzer, Tod D. Casasent, Timothy M. Chan, Michael Parfenov, Jing Wang, Christine M. Komarck, Lauren Averett Byers, Rehan Akbani, Todd Pihl, Curtis R. Pickering, Aaron D. Tward, Chandra Sekhar Pedamallu, Han Si, Jan F. Prins, Vonn Walter, Simion I. Chiosea, Jacqueline E. Schein, James Stephen Marron, Ariane Nguyen, William W. Shockley, Jennifer R. Grandis, Zhining Wang, Jeffrey N. Myers, Konstanty Korski, Bradley A. Ozenberger, Margaret L. Gulley, Barry S. Taylor, B. Arman Aksoy, Ni Zhao, Ashley H. Salazar, Petar Stojanov, Tara M. Lichtenberg, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Andrzej Mackiewicz, A. Gordon Robertson, Ronglai Shen, Lisa Wise, Charles M. Perou, Michael Mayo, Charles Saller, Timothy J. Triche, Dong Zeng, Yan Guo, Lixia Diao, Jonathan B. McHugh, Zhixiang Zuo, Gad Getz, John A. Demchok, Raja R. Seethala, Gordon Saksena, Liu Xi, Liming Yang, Justin A. Bishop, Jessica Walton, Greg Eley, Jessica Frick, John N. Weinstein, Kevin Lau, Jianhua Zhang, Kenna R. Mills Shaw, Miruna Balasundaram, Zubair Khan, Umadevi Veluvolu, Stuart R. Jefferys, Christie Kovar, Moiz S. Bootwalla, Rebecca Carlsen, Daniel Crain, Fei-Fei Liu, Matthiew Ibbs, Michael S. Noble, William K. Funkhouser, Shaowu Meng, Mei Huang, Ann Marie Egloff, George E. Sandusky, Yi Han, Eric S. Lander, Sam Ng, William Lee, Christina Yau, Reanne Bowlby, Erin Curley, Donna M. Muzny, Lynda Chin, Joel S. Parker, Stephen B. Baylin, Peter S. Hammerman, Julie Ahn, Christopher C. Benz, Benjamin Gross, Paul M. Weinberger, Gideon Dresdner, Luc G. T. Morris, Zhong Chen, You Hong Fan, Angeliki Pantazi, David I. Heiman, Bartosz Szybiak, Sahil Seth, Richard A. Gibbs, Trevor Hackman, Peggy Yena, Richard A. Moore, Darshan Singh, Yaron S.N. Butterfield, Andrew D. Cherniack, Jeffrey S. Moyer, Robert A. Burton, Peter J. Park, Rameen Beroukhim, Ricardo Ramirez, Natalia Issaeva, Michael S. Lawrence, Wen-Bin Liu, Xiaojia Ren, Chris Sander, Yunhu Wan, Daryl Waggott, Joseph A. Califano, David A. Pot, Mathew G. Soloway, Roni J. Bollag, Stacey Gabriel, Jeffrey S. Reid, Netty Santoso, Elizabeth Buda, Doug Voet, Xingzhi Song, Kyle Chang, Joseph Paulauskis, Thomas M. Harris, Jaegil Kim, Alan P. Hoyle, Marc Ladanyi, Anthony Saleh, Mark C. Weissler, Scott L. Carter, Kai Wang, Jonathan G. Seidman, Corbin D. Jones, Wojciech Golusiński, Robert Penny, Margi Sheth, and Lori Boice

Subjects
Cervical Cancer, Genome, head and neck, Cancer Genome Atlas Network, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Papillomaviridae, Aetiology, Genetics, Multidisciplinary, biology, HPV infection, virus diseases, Biological Sciences, integration sites, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Infectious Diseases, Head and Neck Neoplasms, DNA methylation, Host-Pathogen Interactions, HIV/AIDS, Infection, Human, Virus Integration, Molecular Sequence Data, DNA sequencing, Rare Diseases, medicine, Humans, cancer, Dental/Oral and Craniofacial Disease, Gene, genome rearrangement, Neoplastic, Base Sequence, Genome, Human, Human Genome, DNA Methylation, biology.organism_classification, medicine.disease, Human genetics, Gene Expression Regulation, Genes, Neoplasm, Sexually Transmitted Infections, Human genome, Genes, Neoplasm, papilloma virus
Abstract

Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.

Published
2014

46. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

Author

Hoadley, Katherine A., Yau, Christina, Wolf, Denise M., Cherniack, Andrew D., Tamborero, David, Sam, Ng, Leiserson, Max D. M., Niu, Beifang, Mclellan, Michael D., Uzunangelov, Vladislav, Zhang, Jiashan, Kandoth, Cyriac, Akbani, Rehan, Shen, Hui, Omberg, Larsson, Chu, Andy, Margolin, Adam A., Van'T Veer, Laura J., Lopez Bigas, Nuria, Laird, Peter W., Raphael, Benjamin J., Ding, Li, Robertson, A. Gordon, Byers, Lauren A., Mills, Gordon B., Weinstein, John N., Van Waes, Carter, Chen, Zhong, Collisson, Eric A., Benz, Christopher C, Perou, Charles M., Stuart, Joshua M., Rachel, Abbott, Scott, Abbott, Arman Aksoy, B., Kenneth, Aldape, Adrian, Ally, Samirku mar Amin, Dimitris, Anastassiou, Todd Auman, J., Baggerly, Keith A., Miruna, Balasundaram, Saianand, Balu, Baylin, Stephen B., Benz, Stephen C., Berman, Benjamin P., Brady, Bernard, Bhatt, Ami S., Inanc, Birol, Black, Aaron D., Tom, Bodenheimer, Bootwalla, Moiz S., Jay, Bowen, Ryan, Bressler, Bristow, Christopher A., Brooks, Angela N., Bradley, Broom, Elizabeth, Buda, Robert, Burton, Butterfield, Yaron S. N., Daniel, Carlin, Carter, Scott L., Casasent, Tod D., Kyle, Chang, Stephen, Chanock, Lynda, Chin, Dong Yeon Cho, Juok, Cho, Eric, Chuah, Chun, Hye Jung E., Kristian, Cibulskis, Giovanni, Ciriello, James Cle land, Melisssa, Cline, Brian, Craft, Creighton, Chad J., Ludmila, Danilova, Tanja, Davidsen, Caleb, Davis, Dees, Nathan D., Kim, Delehaunty, Demchok, John A., Noreen, Dhalla, Daniel, Dicara, Huyen, Dinh, Dobson, Jason R., Deepti, Dodda, Harshavardhan, Doddapaneni, Lawrence, Donehower, Dooling, David J., Gideon, Dresdner, Jennifer, Drummond, Andrea, Eakin, Mary, Edgerton, Eldred, Jim M., Greg, Eley, Kyle, Ellrott, Cheng, Fan, Suzanne, Fei, Ina, Felau, Scott, Frazer, Freeman, Samuel S., Jessica, Frick, Fronick, Catrina C., Ful ton, Lucinda L., Robert, Fulton, Gabriel, Stacey B., Jianjiong, Gao, Gastier Foster, Julie M., Nils, Gehlenborg, Myra, George, Gad, Getz, Richard, Gibbs, Mary, Goldman, Abel Gonzalez Perez, Benjamin, Gross, Ranabir, Guin, Preethi, Gunaratne, Angela, Hadjipanayis, Hamilton, Mark P., Hamilton, Stanley R., Leng, Han, Han, Yi, Harper, Hollie A., Psalm, Haseley, David, Haussler, Neil Hayes, D., Heiman, David I., Elena, Helman, Carmen, Helsel, Herbrich, Shelley M., Her man, James G., Toshinori, Hinoue, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Hoyle, Alan P., Lisa, Iype, Anders, Jacobsen, Jeffreys, Stuart R., Jensen, Mark A., Jones, Corbin D., Jones, Steven J. M., Zhenlin, Ju, Joonil, Jung, Andre, Kahles, Ari, Kahn, Joelle Kalicki Veizer, Divya, Kalra, Krishna Latha Kanchi, Kane, David W., Hoon, Kim, Jaegil, Kim, Theo, Knijnenburg, Koboldt, Daniel C., Christie, Kovar, Roger, Kramer, Richard, Kreisberg, Raju, Kucherlapati, Marc, Ladanyi, Lander, Eric S., Larson, David E., Lawrence, Michael S., Darlene, Lee, Eunjung, Lee, Semin, Lee, William, Lee, Kjong Van Lehmann, Kalle, Leinonen, Ler aas, Kristen M., Seth, Lerner, Levine, Douglas A., Lora, Lewis, Ley, Timothy J., Haiyan I., Li, Jun, Li, Wei, Li, Han, Liang, Lichtenberg, Tara M., Jake, Lin, Ling, Lin, Pei, Lin, Wen bin Liu, Yingchun, Liu, Yuexin, Liu, Lorenzi, Philip L., Charles, Lu, Yiling, Lu, Luquette, Love lace J., Singer, Ma, Magrini, Vincent J., Mahadeshwar, Harshad S., Mardis, Elaine R., Adam, Margolin, Marra, Marco A., Michael, Mayo, Cynthia, Mcallister, Mcguire, Sean E., Mcmichael, Joshua F., James, Melott, Shaowu, Meng, Matthew, Meyerson, Mieczkowski, Piotr A., Miller, Christopher A., Miller, Martin L., Michael, Miller, Moore, Richard A., Margaret, Morgan, Donna, Morton, Mose, Lisle E., Mungall, Andrew J., Donna, Muzny, Lam, Nguyen, Noble, Michael S., Houtan, Noushmehr, Michelle, O’Laughlin, Ojesina, Akinyemi I., Tai Hsien Ou Yang, Brad, Ozenberger, Angeliki, Pantazi, Michael, Parfenov, Park, Peter J., Parker, Joel S., Evan, Paull, Chandra Sekhar Pedamallu, Todd, Pihl, Craig, Pohl, David, Pot, Alexei, Protopopov, Teresa, Przytycka, Amie Raden baugh, Ramirez, Nilsa C., Ricardo, Ramirez, Gunnar Ra, ̈ tsch, Jeffrey, Reid, Xiao jia Ren, Boris, Reva, Reynolds, Sheila M., Rhie, Suhn K., Jeffrey, Roach, Hector, Rovira, Michael, Ryan, Gordon, Saksena, Sofie, Salama, Chris, Sander, Netty, Santoso, Schein, Jacqueline E., Heather, Schmidt, Nikolaus, Schultz, Schumacher, Steven E., Jonathan, Seidman, Yasin, Senbabaoglu, Sahil, Seth, Saman tha Sharpe, Ronglai, Shen, Margi, Sheth, Yan, Shi, Ilya, Shmulevich, Silva, Grace O., Simons, Janae V., Rileen, Sinha, Payal, Sipahimalani, Smith, Scott M., Sofia, Heidi J., Artem, Sokolov, Soloway, Mathew G., Xingzhi, Song, Carrie Soug nez, Paul, Spellman, Louis, Staudt, Chip, Stewart, Petar, Stojanov, Xiaoping, Su, Onur Sumer, S., Yichao, Sun, Teresa, Swatloski, Barbara, Tabak, Angela, Tam, Donghui, Tan, Jiabin, Tang, Roy, Tarnuzzer, Taylor, Barry S., Nina, Thiessen, Ves teinn Thorsson, Timothy Triche, J. r., Van Den Berg, David J., Vandin, Fabio, Varhol, Richard J., Vaske, Charles J., Umadevi, Veluvolu, Roeland, Verhaak, Doug, Voet, Jason, Walker, Wallis, John W., Peter, Waltman, Yunhu, Wan, Min, Wang, Wenyi, Wang, Zhining, Wang, Scot, Waring, Nils, Weinhold, Weisenberger, Daniel J., Wendl, Michael C., David, Wheeler, Wilkerson, Matthew D., Wilson, Richard K., Lisa, Wise, Andrew, Wong, Chang Jiun Wu, Chia Chin Wu, Hsin Ta Wu, Junyuan, Wu, Todd, Wylie, Liu, Xi, Ruibin, Xi, Zheng, Xia, Andrew W., Xu, Yang, Da, Liming, Yang, Lixing, Yang, Yang, Yang, Jun, Yao, Rong, Yao, Kai, Ye, Ko suke Yoshihara, Yuan, Yuan, Yung, Alfred K., Travis, Zack, Dong, Zeng, Jean Claude Zenklusen, Hailei, Zhang, Jianhua, Zhang, Nianxiang, Zhang, Qunyuan, Zhang, Wei, Zhang, Wei, Zhao, Siyuan, Zheng, Jing, Zhu, Erik, Zmuda, and Lihua, Zou

Subjects
Genetics and Molecular Biology (all), Cluster Analysis, Humans, Neoplasms, Transcriptome, Biochemistry, Genetics and Molecular Biology (all), Extramural, Biochemistry, Genetics and Molecular Biology(all), Cancer, Computational biology, Disease, Biology, medicine.disease, Bioinformatics, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, 3. Good health, Molecular classification, TP63, CLUSTERS (ANÁLISE), medicine, Head and neck, Gene
Abstract

Summary Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014

47. The Cancer Genome Atlas Pan-Cancer analysis project

Author

Qunyuan Zhang, B. Arman Aksoy, Fabio Vandin, Eric A. Collisson, Larsson Omberg, S. Onur Sumer, John A. Demchok, Sven Nelander, Vladislav Uzunangelov, Michael C. Wendl, Roger Kramer, John W. Wallis, Brian Craft, Angeliki Pantazi, Leng Han, W. K. Alfred Yung, Brad Ozenberger, Philip L. Lorenzi, James G. Herman, Andy Chu, Sahil Seth, Richard A. Gibbs, Angela Hadjipanayis, Hector Rovira, Peter W. Laird, Inanc Birol, Richard K. Wilson, James Cleland, Peter J. Park, Jiashan Zhang, Payal Sipahimalani, Stanley R. Hamilton, Liming Yang, Seth Lerner, Amie Radenbaugh, Barry S. Taylor, Carrie Hirst, David Tamborero, Stephen B. Baylin, Gad Getz, Tanja Davidsen, Miruna Balasundaram, Cheng Fan, Yuan Yuan, Kristian Cibulskis, Yan Shi, Angela Tam, Divya Kalra, Chris Sander, Scott Abbott, Catrina Fronick, Margi Sheth, Chip Stewart, Angela N. Brooks, Noreen Dhalla, Lam Nguyen, Hui Shen, Travis I. Zack, Andrew J. Mungall, Artem Sokolov, Douglas A. Levine, Carrie Sougnez, Paul T. Spellman, Greg Eley, Deepti Dodda, Wenbin Liu, Michael B. Ryan, Liu Xi, Aaron D. Black, Rong Yao, Saianand Balu, Benjamin P. Berman, Raju Kucherlapati, James M. Melott, Xingzhi Song, Boris Reva, Huyen Dinh, David A. Pot, Michael D. McLellan, Kjong-Van Lehmann, Wenyi Wang, Petar Stojanov, Bradley McIntosh Broom, Timothy J. Ley, Da Yang, Mary Elizabeth Edgerton, Houtan Noushmehr, Mathew G. Soloway, Nina Thiessen, Zhenlin Ju, Mark D.M. Leiserson, Michael Parfenov, Laura van 't Veer, Scott L. Carter, Ludmila Danilova, Adrian Ally, Hailei Zhang, Ina Felau, Carmen Helsel, Kenneth Aldape, Teresia Kling, Charles Lu, Psalm Haseley, A. Gordon Robertson, Andrew Wei Xu, Jessica Frick, Benjamin Gross, Louis M. Staudt, Craig Pohl, Dimitris Anastassiou, Netty Santoso, Donna Muzny, Chad J. Creighton, Donghui Tan, Ryan Bressler, Andrew J. Wong, Barbara Tabak, Yasin Senbabaoglu, Daniel C. Koboldt, Darlene Lee, Doug Voet, Joonil Jung, Hollie A. Harper, Jianhua Zhang, Kyle Chang, Wei Zhao, Marc Ladanyi, Lisa Iype, Ricardo Ramirez, Ami S. Bhatt, Lisle E. Mose, Singer Ma, Abel Gonzalez-Perez, Jonathan G. Seidman, Kosuke Yoshihara, Denise M. Wolf, Corbin D. Jones, Patrik Johansson, Siyuan Zheng, André Kahles, Stacey Gabriel, John N. Weinstein, Han Liang, Samantha Sharpe, Steven E. Schumacher, Matthew Meyerson, D. Neil Hayes, David Haussler, Krishna L. Kanchi, Julie M. Gastier-Foster, Umadevi Veluvolu, Ari B. Kahn, Brady Bernard, Tod D. Casasent, Christopher A. Bristow, Akinyemi I. Ojesina, Sam Ng, Charles M. Perou, Moiz S. Bootwalla, Cyriac Kandoth, Lixing Yang, Joel S. Parker, Alan P. Hoyle, Timothy J. Triche, Dong Zeng, Sean E. McGuire, Christie Kovar, Kim D. Delehaunty, Juok Cho, Alexei Protopopov, Shaowu Meng, Ling Lin, Heather Schmidt, Nils Gehlenborg, Yuexin Liu, Elaine R. Mardis, Martin L. Miller, Jake Lin, Jason Walker, Lisa Wise, Suzanne S. Fei, Jacqueline E. Schein, Semin Lee, Christina Yau, Melisssa Cline, Tara M. Lichtenberg, David I. Heiman, Scot Waring, Richard A. Moore, Margaret B. Morgan, Robert S. Fulton, David E. Larson, Xiaoping Su, Kalle Leinonen, Samirkumar B. Amin, Joshua M. Stuart, J. Todd Auman, Rebecka Jörnsten, Rileen Sinha, Andrew D. Cherniack, Caleb F. Davis, Stephen J. Chanock, Nathan D. Dees, Adam Margolin, Haiyan I. Li, Yaron S.N. Butterfield, Daniel E. Carlin, Tai Hsien Ou Yang, Rameen Beroukhim, Vincent Magrini, Mark P. Hamilton, Grace O. Silva, Nils Weinhold, Harshad S. Mahadeshwar, Michael S. Lawrence, Eric Chuah, Jun Li, Wei Li, Robert A. Burton, Teresa M. Przytycka, Katherine A. Hoadley, Keith A. Baggerly, Sheila M. Reynolds, Daniel DiCara, Tom Bodenheimer, Charles J. Vaske, James M. Eldred, Richard Varhol, Mark A. Jensen, David W. Kane, Xiaojia Ren, Christopher A. Miller, Elizabeth Buda, Li Ding, Michael Mayo, Hsin-Ta Wu, Joelle Kalicki-Veizer, Shelley M. Herbrich, Eunjung Lee, Yingchun Liu, Joshua F. McMichael, Jennifer Drummond, Teresa Swatloski, Harshavardhan Doddapaneni, William Lee, Daniel J. Weisenberger, David A. Wheeler, Chia Chin Wu, Richard Kreisberg, Roeland Verhaak, Elena Helman, Piotr A. Mieczkowski, Mary Goldman, Ilya Shmulevich, Nikolaus Schultz, Min Wang, Lovelace J. Luquette, Marco A. Marra, Todd Pihl, Roy Tarnuzzer, Ronglai Shen, Donna Morton, Yichao Sun, Lawrence A. Donehower, Jun Yao, Theo A. Knijnenburg, Benjamin J. Raphael, Lora Lewis, Peter Waltman, Andrea Eakin, Martin Hirst, Jaegil Kim, Lihua Zou, Ranabir Guin, Yi Han, Scott M. Smith, Hoon Kim, Kristen M. Leraas, Heidi J. Sofia, Erik Zmuda, Matthew D. Wilkerson, Michelle O'Laughlin, Jianjiong Gao, Jeffrey G. Reid, Jing Zhu, Toshinori Hinoue, Gunnar Rätsch, Hye Jung E. Chun, Anders Jacobsen, Stephen C. Benz, Kenna R. Mills Shaw, Gordon B. Mills, Zhining Wang, Cynthia McAllister, Michael S. Noble, Christopher C. Benz, Rehan Akbani, Ruibin Xi, Nianxiang Zhang, Jay Bowen, Wei Zhang, Chandra Sekhar Pedamallu, Eric S. Lander, Yunhu Wan, David J. Dooling, Dong Yeon Cho, Preethi Gunaratne, Todd Wylie, Pei Lin, Chang-Jiun Wu, Jeffrey Roach, Scott Frazer, Samuel S. Freeman, Rachel Abbott, Zheng Xia, Lucinda Fulton, Kyle Ellrott, Nuria Lopez-Bigas, Yang Yang, Michael Miller, Nilsa C. Ramirez, Evan O. Paull, Janae V. Simons, Junyuan Wu, Lynda Chin, Gordon Saksena, Jiabin Tang, Vesteinn Thorsson, Robert A. Holt, Suhn K. Rhie, Steven J.M. Jones, Stuart R. Jeffreys, Giovanni Ciriello, Sofie R. Salama, Gideon Dresdner, Yiling Lu, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
Genetics, medicine.medical_specialty, Genome, Gene Expression Profiling, Genomics, Computational biology, Biology, Humans, Neoplasms, Article, Analysis Project, Gene expression profiling, GENÉTICA MOLECULAR, Cancer genome, Genomic Profile, medicine, Medical genetics, Epigenetics
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., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.)

Published
2013

48. Comprehensive molecular characterization of urothelial bladder carcinoma

Author

Elizabeth Buda, Nikolaus Schultz, Donghui Tan, Pat Swanson, Xingzhi Song, Jennifer Owens, Carmelo Gaudioso, Liming Yang, Kenna R. Mills Shaw, Sophie C. Egea, John N. Weinstein, Lihua Zou, Dmitry A. Gordenin, Gad Getz, Stuart R. Jefferys, Wiam Bshara, David Haussler, Ari B. Kahn, Mary Iacocca, Brady Bernard, Charles M. Perou, Leigh B. Thorne, Kimberly R. Christ, Eric S. Lander, Yunhu Wan, Timothy J. Triche, Dong Zeng, Bogdan Czerniak, Wenbin Liu, Jianhua Zhang, David Mallery, B. Arman Aksoy, Lynn M. Herbert, Hailei Zhang, Jennifer DiPiero, Tod D. Casasent, Sugy Kodeeswaran, Daniel DiCara, Jacqueline E. Schein, Scott L. Carter, Umadevi Veluvolu, John M. S. Bartlett, Theresa M. Koppie, Ji Yeon Yang, Ronglai Shen, Yingchun Liu, Daniel J. Weisenberger, Ranabir Guin, Myra M. George, Marc Ladanyi, J. Todd Auman, Moiz S. Bootwalla, Shaowu Meng, Mark S. Soloway, Tatjana Antic, Greg Eley, Hikmat Al-Ahmadie, Carolyn M. Hutter, Jonathan G. Seidman, Corbin D. Jones, Lori Boice, Xiaoping Su, Jay Bowen, Raju Kucherlapati, Hui Shen, Benjamin Gross, Reanne Bowlby, Lawrence A. Donehower, Phan Thi Hanh, David J. McConkey, Saianand Balu, Jiexin Zhang, Tina Wong, Juok Cho, Alexei Protopopov, Carolyn L. Smith, Yuexin Liu, Angeliki Pantazi, Jason R. Gee, Xuan Van Le, Ricardo Ramirez, Ami S. Bhatt, Samuel S. Freeman, Jaegil Kim, Bui Duc Phu, Michael Ittman, Charles C. Guo, Carmen Gomez-Fernandez, Norm D. Smith, S. Onur Sumer, Bradley A. Ozenberger, Paul M. Weinberger, George E. Sandusky, Troy Shelton, Seth P. Lerner, Charles Saller, Nicholas J. Petrelli, Nguyen Van Bang, Sahil Seth, Richard A. Gibbs, Lisle E. Mose, Aaron D. Black, Yair Lotan, Carrie Sougnez, Jessie Au, Martin L. Ferguson, Ashley Marie Regazzi, Matthew Meyerson, Joel B. Nelson, Natasja Wye, Daniel E. Carlin, Nils Weinhold, Tom Bodenheimer, Nilsa C. Ramirez, Michael Ryan, Anders Jacobsen, Eric J. Burks, Lee Lichtenstein, Erin Curley, Angela Hadjipanayis, Nils Gehlenborg, Hector Rovira, Bernard Kohl, Jean C. Zenklusen, Travis Sullivan, Margaret Morgan, Rajiv Dhir, Julie M. Gastier-Foster, Gary D. Steinberg, Mathew G. Soloway, Nina Thiessen, Jianjiong Gao, Lisa Wise, Barry S. Taylor, Gordon Saksena, Hui Yao, David Van Den Berg, Jiabin Tang, Robert Penny, Nguyen Viet Tien, Jeffrey R. Gingrich, Jing Zhu, Ronald L. Hrebinko, Dick Kreisberg, Pei Lin, Christopher A. Bristow, Andrey Sivachenko, Andy Chu, Peter W. Laird, Thomas Barr, Junyuan Wu, Robert A. Holt, Harshad S. Mahadeshwar, Piotr A. Mieczkowski, Steven A. Roberts, Victor E. Reuter, Jeffrey S. Damrauer, Roni J. Bollag, Chad J. Creighton, Johanna Gardner, Michael Parfenov, Qiang Li, Phillip H. Lai, Thomas C. Motter, Alireza Moinzadeh, Jodi K. Maranchie, Christopher C. Benz, Lynda Chin, Angela Tam, Margi Sheth, David B. Solit, Erik Zmuda, Lixing Yang, Peter J. Park, Marco A. Marra, Katherine A. Hoadley, Eila C. Skinner, Scott Frazer, Roy Tarnuzzer, Heidi J. Sofia, Bradley M. Broom, Zhining Wang, David I. Heiman, Sebrina A Tello, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Ilana Rebecca Garcia-Grossman, Merce Jorda, Roeland Verhaak, Ilya Shmulevich, W.K. Rathmell, Bernard H. Bochner, Scot Waring, Kenneth Aldape, Richard A. Moore, Toshinori Hinoue, Carrie Hirst, Mark A. Jensen, Payal Kapur, Andrew D. Cherniack, Dean F. Bajorin, Evano Paull, Cheryl M. Lewis, William Y. Kim, Giovanni Ciriello, David C. Fargo, Gordon B. Mills, Michael S. Noble, Stephanie Weaver, Whitney D. McClenden, Benjamin Davies, Payal Sipahimalani, Vina Alexopoulou, Bo Peng, Stephen B. Baylin, Michael Mayo, Rameen Beroukhim, Boris Reva, Anil V. Parwani, Joshua M. Stuart, David J. Kwiatkowski, Stacey B. Gabrie, Janae V. Simons, Rehan Akbani, Todd Pihl, Nianxiang Zhang, Suzie Carter, Michael S. Lawrence, Carmen Helsel, Carl Morrison, Xiaojia Ren, Jeffrey Roach, Peter H. O'Donnell, Miruna Balasundaram, Yevgeniy Antipin, Gideon Dresdner, Cynthia McAllister, Tanja Davidsen, Brenda Rabeno, Jolanta Bondaruk, Kristian Cibulskis, Chip Stewart, Matthew D. Wilkerson, Jonathan E. Rosenberg, Brian D. Robinson, Patricia Castro, Wei Zhang, Chandra Sekhar Pedamallu, Allison Beaver, Andrew Wei Xu, Adrian Ally, Andrea Sorcini, Andrew J. Mungall, Katherine Tarvin, Christine Czerwinski, Petar Stojanov, Philip L. Lorenzi, Alan P. Hoyle, Jay Engel, Tara M. Lichtenberg, D. Neil Hayes, John A. Demchok, Eric Chuah, Benjamin Hanf, Deepak Srinivasan, Donna E. Hansel, Noreen Dhalla, Zhenlin Ju, Leszek J. Klimczak, Trevor J. Pugh, Richard Thorp, A. Gordon Robertson, Darlene Lee, Steven E. Schumacher, Semin Lee, Sheldon I. Bastacky, Rileen Sinha, Haiyan I. Li, William Lee, Sam Ng, Joel S. Parker, Sheila Reynolds, Teresa R. Tabler, Yaron S.N. Butterfield, David Pot, Chris Sander, Wenyi Wang, Weiguo Jian, Le Quang Vinh, Netty Santoso, Doug Voet, and Joonil Jung

Subjects
Metastatic Urothelial Carcinoma, Invasive urothelial carcinoma, Virus Integration, Down-Regulation, Disease, Bioinformatics, Malignancy, Article, Phosphatidylinositol 3-Kinases, Cancer genome, medicine, Carcinoma, Humans, Molecular Targeted Therapy, RNA, Messenger, Urothelial carcinoma, Multidisciplinary, business.industry, TOR Serine-Threonine Kinases, Cell Cycle, Creative commons, medicine.disease, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, Oxidative Stress, Urinary Bladder Neoplasms, business, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Published
2013

49. Comprehensive molecular profiling of lung adenocarcinoma

Author

Amie Radenbaugh, Noreen Dhalla, Christina Williamson, Charles Saller, James Suh, Ramaswamy Govindan, Travis I. Zack, Paul T. Spellman, Daniel DiCara, Harvey I. Pass, Deepak Srinivasan, William G. Richards, Robert J. Cerfolio, Igor Letovanec, A. Gordon Robertson, Gabriel Sica, Chad J. Creighton, Hendrik Dienemann, Jeffrey A. Borgia, Boris Reva, Bryan F. Meyers, Yiling Lu, Nikolaus Schultz, Christopher I. Amos, Dante Trusty, Carmelo Gaudioso, Michael Meister, James T. Robinson, Lihua Zou, James Shin, Jeremy Parfitt, Darlene Lee, Junyuan Wu, Carl Morrison, Scott L. Carter, Giovanni Ciriello, Nils Weinhold, Elena Nemirovich-Danchenko, Andrew Wei Xu, Christopher G. Maher, Lori Boice, Irina Zaytseva, Dennis A. Wigle, Kenna R. Mills Shaw, Matthew G. Soloway, Matthew Meyerson, Peng Chieh Chen, Frank Schneider, Troy Shelton, Douglas Voet, Steven E. Schumacher, D L Rotin, Saianand Balu, Stuart R. Jefferys, Tom Bodenheimer, Bradley A. Ozenberger, Eric S. Lander, Edward Gabrielson, Konstantin V. Fedosenko, Rehan Akbani, William D. Travis, Ari B. Kahn, Marcin Imielinski, Jacqueline E. Schein, Thomas L. Bauer, Kai Ye, Samuel A. Yousem, Robert C. Onofrio, Thomas Muley, Ayesha S. Bryant, Michael K. Asiedu, Monique Albert, Pei Lin, Corbin D. Jones, Edwina Duhig, Jean C. Zenklusen, Lucinda Fulton, Christina Yau, J. Todd Auman, Leigh B. Thorne, Elena Helman, Richard T. Cheney, William Lee, Patrick K. Kimes, Juok Cho, Alexei Protopopov, Wenbin Liu, Lee Lichtenstein, Jing Wang, Lixing Yang, W. Kimryn Rathmell, Jo Ellen Weaver, David A. Wheeler, Leslie Cope, Mark A. Watson, Heidi J. Sofia, Angeliki Pantazi, Ronglai Shen, Jeffrey Roach, Eric A. Collisson, Patrick Kwok Shing Ng, Angela Hadjipanayis, Peter S. Hammerman, David Van Den Berg, Kwun M. Fong, Nils Gehlenborg, Natasha Rekhtman, William K. Funkhouser, D. Neil Hayes, Harshad S. Mahadeshwar, Semin Lee, Martin Peifer, David Mallery, Piotr A. Mieczkowski, Ranabir Guin, Madhusmita Behera, Philipp A. Schnabel, Jill M. Siegfried, Carmen Gomez-Fernandez, Johanna Gardner, Lynn M. Herbert, Hailei Zhang, Robert S. Fulton, Travis Sullivan, Sahil Seth, Sam Ng, Chandra Sekhar Pedamallu, Barry S. Taylor, Venkatraman E. Seshan, Valerie W. Rusch, Jinze Liu, Daniel P. Raymond, Jianjiong Gao, Nathan A. Pennell, Marco A. Marra, Jan F. Prins, Payal Sipahimalani, Janae V. Simons, Joel S. Parker, Rileen Sinha, Lindy Hunter, Raju Kucherlapati, Dennis T. Maglinte, Fedor Moiseenko, Eric E. Snyder, Roy Tarnuzzer, Beverly Lee, James Stephen Marron, Kristian Cibulskis, Jerome Myers, Haiyan I. Li, Robert Penny, Hartmut Juhl, Richard K. Wilson, Zhining Wang, Eran Hodis, Carrie Sougnez, Jiabin Tang, William Mallard, Bryan Hernandez, Liming Yang, Jennifer Brown, Gad Getz, Farhad Kosari, Catrina Fronick, Juliann Chmielecki, Jianhua Zhang, Suresh S. Ramalingam, Michael Parfenov, Peter J. Park, Tanja Davidsen, Philip H. Lai, Jeff Boyd, Dang Huy Quoc Thinh, Harmanjatinder S. Sekhon, Malcolm V. Brock, Mark Pool, Margi Sheth, Kimberly M. Rieger-Christ, Michael J. Liptay, E. Getz, S. Onur Sumer, Ian A. Yang, B. Arman Aksoy, Douglas B. Flieder, Bradley M. Broom, Carrie Hirst, Solange Peters, Joshua M. Stuart, Khurram Z. Khan, Scott Morris, Donghui Tan, Andrew J. Mungall, Ming-Sound Tsao, Gordon B. Mills, Stephen B. Baylin, Rebecca Carlsen, Sanja Dacic, Julien Baboud, Brenda Rabeno, Richard A. Hajek, Lauren Averett Byers, Yaron S.N. Butterfield, Miruna Balasundaram, Chip Stewart, Katherine Tarvin, Peter B. Illei, James G. Herman, David J. Kwiatkowski, Andy Chu, David Haussler, Natasja Wye, Charles M. Perou, Peter W. Laird, Timothy J. Triche, Yan Shi, Jill P. Mesirov, Angela N. Brooks, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Lixia Diao, Anthony A. Gal, David G. Beer, Angela Tam, Ashley H. Salazar, Mark A. Jensen, Robert A. Holt, Katherine A. Hoadley, John A. Demchok, Sandra McDonald, Chandra Goparaju, David Pot, Belinda E. Clarke, Gordon Robertson, Michael C. Wendl, Helga Thorvaldsdottir, Kristen Rogers, Joshua D. Campbell, Chris Sander, Rayleen V. Bowman, Marc Danie Nazaire, Michael Mayo, Olga Voronina, Ludmila Danilova, Paul Zippile, Netty Santoso, John V. Heymach, Matthew D. Wilkerson, John Eckman, Morgan Windsor, Cureline Oleg Dolzhanskiy, Nina Thiessen, Mara Rosenberg, Gideon Dresdner, Levi A. Garraway, Eric Chuah, Richard Varhol, Elizabeth Buda, Li Ding, Alice H. Berger, Xingzhi Song, John M. S. Bartlett, Michael D. McLellan, Olga Potapova, Joseph Paulauskis, Igor Jurisica, Benjamin Gross, Jaegil Kim, John N. Weinstein, Kevin Lau, Christopher R. Cabanski, Philip Bonomi, Michael S. Noble, Maureen F. Zakowski, George E. Sandusky, Mary Iacocca, Eric J. Burks, Erin Curley, Lynda Chin, Rajiv Dhir, Singer Ma, Sophie C. Egea, Umadevi Veluvolu, Sugy Kodeeswaran, Christopher A. Miller, Moiz S. Bootwalla, Daniel J. Weisenberger, Shaowu Meng, Mei Huang, Elaine R. Mardis, Gordon Saksena, Nicholas J. Petrelli, Yvonne Owusu-Sarpong, Christopher C. Benz, Bernard Kohl, Jingchun Zhu, David I. Heiman, Carol Farver, Scot Waring, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Stacey Gabriel, Christine Czerwinski, Alan P. Hoyle, Cancer Genome Atlas Research Network, Collisson, E. A., Campbell, J.D., Brooks, A.N., Berger, A.H., Lee, W., Chmielecki, J., Beer, D.G., Cope, L., Creighton, C.J., Danilova, L., Ding, L., Getz, G., Hammerman, P.S., Hayes, D.N., Hernandez, B., Herman, J.G., Heymach, J.V., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M.S., Travis, W.D., Weinstein, J.N., Wigle, D.A., Wilkerson, M.D., Chu, A., Cherniack, A.D., Hadjipanayis, A., Rosenberg, M., Weisenberger, D.J., Laird, P.W., Radenbaugh, A., Ma, S., Stuart, J.M., Averett Byers, L., Baylin, S.B., Govindan, R., Meyerson, M., Gabriel, S.B., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E.S., Lawrence, M.S., Kandoth, C., Fulton, R., Fulton, L.L., McLellan, M.D., Wilson, R.K., Ye, K., Fronick, C.C., Maher, C.A., Miller, C.A., Wendl, M.C., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y.S., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H.I., Mayo, M., Moore, R.A., Mungall, A.J., Schein, J.E., Sipahimalani, P., Tam, A., Varhol, R., Robertson, A., Wye, N., Thiessen, N., Holt, R.A., Jones, S.J., Marra, M.A., Imielinski, M., Onofrio, R.C., Hodis, E., Zack, T., Helman, E., Sekhar Pedamallu, C., Mesirov, J., Saksena, G., Schumacher, S.E., Carter, S.L., Garraway, L., Beroukhim, R., Lee, S., Mahadeshwar, H.S., Pantazi, A., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Yang, L., Zhang, J., Chen, P.C., Parfenov, M., Wei Xu, A., Santoso, N., Chin, L., Park, P.J., Hoadley, K.A., Auman, J.T., Meng, S., Shi, Y., Buda, E., Waring, S., Veluvolu, U., Tan, D., Mieczkowski, P.A., Jones, C.D., Simons, J.V., Soloway, M.G., Bodenheimer, T., Jefferys, S.R., Roach, J., Hoyle, A.P., Wu, J., Balu, S., Singh, D., Prins, J.F., Marron, J.S., Parker, J.S., Perou, C.M., Liu, J., Maglinte, D.T., Lai, P.H., Bootwalla, M.S., Van Den Berg, D.J., Triche, T., Cho, J., DiCara, D., Heiman, D., Lin, P., Mallard, W., Voet, D., Zhang, H., Zou, L., Noble, M.S., Gehlenborg, N., Thorvaldsdottir, H., Nazaire, M.D., Robinson, J., Aksoy, B.A., Ciriello, G., Taylor, B.S., Dresdner, G., Gao, J., Gross, B., Seshan, V.E., Reva, B., Sumer, S.O., Weinhold, N., Sander, C., Ng, S., Zhu, J., Benz, C.C., Yau, C., Haussler, D., Spellman, P.T., Kimes, P.K., Broom, B.M., Wang, J., Lu, Y., Kwok Shing Ng, P., Diao, L., Liu, W., Amos, C.I., Akbani, R., Mills, G.B., Curley, E., Paulauskis, J., Lau, K., Morris, S., Shelton, T., Mallery, D., Gardner, J., Penny, R., Saller, C., Tarvin, K., Richards, W.G., Cerfolio, R., Bryant, A., Raymond, D.P., Pennell, N.A., Farver, C., Czerwinski, C., Huelsenbeck-Dill, L., Iacocca, M., Petrelli, N., Rabeno, B., Brown, J., Bauer, T., Dolzhanskiy, O., Potapova, O., Rotin, D., Voronina, O., Nemirovich-Danchenko, E., Fedosenko, K.V., Gal, A., Behera, M., Ramalingam, S.S., Sica, G., Flieder, D., Boyd, J., Weaver, J., Kohl, B., Huy Quoc Thinh, D., Sandusky, G., Juhl, H., Duhig, E., Illei, P., Gabrielson, E., Shin, J., Lee, B., Rodgers, K., Trusty, D., Brock, M.V., Williamson, C., Burks, E., Rieger-Christ, K., Holway, A., Sullivan, T., Asiedu, M.K., Kosari, F., Rekhtman, N., Zakowski, M., Rusch, V.W., Zippile, P., Suh, J., Pass, H., Goparaju, C., Owusu-Sarpong, Y., Bartlett, J.M., Kodeeswaran, S., Parfitt, J., Sekhon, H., Albert, M., Eckman, J., Myers, J.B., Cheney, R., Morrison, C., Gaudioso, C., Borgia, J.A., Bonomi, P., Pool, M., Liptay, M.J., Moiseenko, F., Zaytseva, I., Dienemann, H., Meister, M., Schnabel, P.A., Muley, T.R., Peifer, M., Gomez-Fernandez, C., Herbert, L., Egea, S., Huang, M., Thorne, L.B., Boice, L., Hill Salazar, A., Funkhouser, W.K., Rathmell, W.K., Dhir, R., Yousem, S.A., Dacic, S., Schneider, F., Siegfried, J.M., Hajek, R., Watson, M.A., McDonald, S., Meyers, B., Clarke, B., Yang, I.A., Fong, K.M., Hunter, L., Windsor, M., Bowman, R.V., Peters, S., Letovanec, I., Khan, K.Z., Jensen, M.A., Snyder, E.E., Srinivasan, D., Kahn, A.B., Baboud, J., Pot, D.A., Mills Shaw, K.R., Sheth, M., Davidsen, T., Demchok, J.A., Wang, Z., Tarnuzzer, R., Zenklusen, J.C., Ozenberger, B.A., Sofia, H.J., Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
Male, Lung Neoplasms, Adenocarcinoma/genetics, Adenocarcinoma/pathology, Cell Cycle Proteins/genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms/genetics, Lung Neoplasms/pathology, Molecular Typing, Mutation/genetics, Oncogenes/genetics, Sex Factors, Transcriptome/genetics, Adenocarcinoma of Lung, Cell Cycle Proteins, Biology, Adenocarcinoma, Exon, Germline mutation, microRNA, Adenocarcinoma of the lung, medicine, Gene, Multidisciplinary, Oncogene, Oncogenes, medicine.disease, MET Exon 14 Skipping Mutation, Molecular biology, 3. Good health, Mutation, Transcriptome
Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2013

50. Genome-Wide Assessment of the Association of Rare and Common Copy Number Variations to Testicular Germ Cell Cancer

Author

Henrik Leffers, Nils Weinhold, Ewa Rajpert-De Meyts, Marlene Danner Dalgaard, Ramneek Gupta, Thomas Skøt Jensen, Agata Wesolowska-Andersen, Daniel Edsgärd, Anne Marie Ottesen, Anders Juul, Niels E. Skakkebæk, and Søren Brunak

Subjects
Genetics, lcsh:RC648-665, Endocrinology, Diabetes and Metabolism, copy number variation, rare variants, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, medicine.disease, Genome, lcsh:Diseases of the endocrine glands. Clinical endocrinology, testicular cancer, Endocrinology, SDG 3 - Good Health and Well-being, testicular germ cell cancers, medicine, Copy-number variation, Gene, Testicular cancer, Original Research, Genetic association, Genome-Wide Association Study
Abstract

Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms, largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of CNV on a cohort of 212 cases and 437 controls from Denmark, which was genotyped at ∼1.8 million markers, half of which were non-polymorphic copy number markers. No association of common variants were found, whereas analysis of rare variants (present in less than 1% of the samples) initially indicated a single gene with significantly higher accumulation of rare CNVs in cases as compared to controls, at the gene PTPN1 (P = 3.8 × 10(-2), 0.9% of cases and 0% of controls). However, the CNV could not be verified by qPCR in the affected samples. Further, the CNV calling of the array-data was validated by sequencing of the GSTM1 gene, which showed that the CNV frequency was in complete agreement between the two platforms. This study therefore disconfirms the hypothesis that there exists a single CNV locus with a major effect size that predisposes to TGCC. Genome-wide pathway association analysis indicated a weak association of rare CNVs related to cell migration (false-discovery rate = 0.021, 1.8% of cases and 1.1% of controls). Dysregulation during migration of primordial germ cells has previously been suspected to be a part of TGCC development and this set of multiple rare variants may thereby have a minor contribution to an increased susceptibility of TGCCs.

Published
2013
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