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1.  Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour 
Open Biology  2016;6(11):160275.
The activities of pathways that regulate malignant transformation can be influenced by microRNAs (miRs). Recently, we showed that increased expression of five tumour-suppressor miRs, miR-508-3p, miR-508-5p, miR-509-3p, miR-509-5p and miR-130b-3p, correlate with improved clinical outcomes in human ovarian cancer patients, and that miR-509-3p attenuates invasion of ovarian cancer cell lines. Here, we investigate the mechanism underlying this reduced invasive potential by assessing the impact of these five miRs on the physical properties of cells. Human ovarian cancer cells (HEYA8, OVCAR8) that are transfected with miR mimics representing these five miRs exhibit decreased invasion through collagen matrices, increased cell size and reduced deformability as measured by microfiltration and microfluidic assays. To understand the molecular basis of altered invasion and deformability induced by these miRs, we use predicted and validated mRNA targets that encode structural and signalling proteins that regulate cell mechanical properties. Combined with analysis of gene transcripts by real-time PCR and image analysis of F-actin in single cells, our results suggest that these tumour-suppressor miRs may alter cell physical properties by regulating the actin cytoskeleton. Our findings provide biophysical insights into how tumour-suppressor miRs can regulate the invasive behaviour of ovarian cancer cells, and identify potential therapeutic targets that may be implicated in ovarian cancer progression.
PMCID: PMC5133448  PMID: 27906134
cell deformability; actin cytoskeleton; microfluidics; microfiltration; tumour cell invasion
2.  Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia 
Nature Communications  2016;7:13331.
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
PMCID: PMC5105166  PMID: 27824051
5.  Cross-cancer profiling of molecular alterations within the human autophagy interaction network 
Autophagy  2015;11(9):1668-1687.
Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumor-related alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival.
PMCID: PMC4590660  PMID: 26208877
AML; autophagy; cancer; gene expression; LAPTM4B; mutation; SNV; SQSTM1; TCGA; tumor
6.  Comprehensive Molecular Characterization of Papillary Renal Cell Carcinoma 
Linehan, W. Marston | Spellman, Paul T. | Ricketts, Christopher J. | Creighton, Chad J. | Fei, Suzanne S. | Davis, Caleb | Wheeler, David A. | Murray, Bradley A. | Schmidt, Laura | Vocke, Cathy D. | Peto, Myron | Al Mamun, Abu Amar M. | Shinbrot, Eve | Sethi, Anurag | Brooks, Samira | Rathmell, W. Kimryn | Brooks, Angela N. | Hoadley, Katherine A. | Robertson, A. Gordon | Brooks, Denise | Bowlby, Reanne | Sadeghi, Sara | Shen, Hui | Weisenberger, Daniel J. | Bootwalla, Moiz | Baylin, Stephen B. | Laird, Peter W. | Cherniack, Andrew D. | Saksena, Gordon | Haake, Scott | Li, Jun | Liang, Han | Lu, Yiling | Mills, Gordon B. | Akbani, Rehan | Leiserson, Mark D.M. | Raphael, Benjamin J. | Anur, Pavana | Bottaro, Donald | Albiges, Laurence | Barnabas, Nandita | Choueiri, Toni K. | Czerniak, Bogdan | Godwin, Andrew K. | Hakimi, A. Ari | Ho, Thai | Hsieh, James | Ittmann, Michael | Kim, William Y. | Krishnan, Bhavani | Merino, Maria J. | Mills Shaw, Kenna R. | Reuter, Victor E. | Reznik, Ed | Shelley, Carl Simon | Shuch, Brian | Signoretti, Sabina | Srinivasan, Ramaprasad | Tamboli, Pheroze | Thomas, George | Tickoo, Satish | Burnett, Kenneth | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Mallery, David | Morris, Scott | Paulauskis, Joseph D. | Penny, Robert J. | Shelton, Candace | Shelton, W. Troy | Sherman, Mark | Thompson, Eric | Yena, Peggy | Avedon, Melissa T. | Bowen, Jay | Gastier-Foster, Julie M. | Gerken, Mark | Leraas, Kristen M. | Lichtenberg, Tara M. | Ramirez, Nilsa C. | Santos, Tracie | Wise, Lisa | Zmuda, Erik | Demchok, John A. | Felau, Ina | Hutter, Carolyn M. | Sheth, Margi | Sofia, Heidi J. | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean C. | Zhang, Jiashan (Julia) | Ayala, Brenda | Baboud, Julien | Chudamani, Sudha | Liu, Jia | Lolla, Laxmi | Naresh, Rashi | Pihl, Todd | Sun, Qiang | Wan, Yunhu | Wu, Ye | Ally, Adrian | Balasundaram, Miruna | Balu, Saianand | Beroukhim, Rameen | Bodenheimer, Tom | Buhay, Christian | Butterfield, Yaron S.N. | Carlsen, Rebecca | Carter, Scott L. | Chao, Hsu | Chuah, Eric | Clarke, Amanda | Covington, Kyle R. | Dahdouli, Mahmoud | Dewal, Ninad | Dhalla, Noreen | Doddapaneni, HarshaVardhan | Drummond, Jennifer | Gabriel, Stacey B. | Gibbs, Richard A. | Guin, Ranabir | Hale, Walker | Hawes, Alicia | Hayes, D. Neil | Holt, Robert A. | Hoyle, Alan P. | Jefferys, Stuart R. | Jones, Steven J.M. | Jones, Corbin D. | Kalra, Divya | Kovar, Christie | Lewis, Lora | Li, Jie | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Meng, Shaowu | Meyerson, Matthew | Mieczkowski, Piotr A. | Moore, Richard A. | Morton, Donna | Mose, Lisle E. | Mungall, Andrew J. | Muzny, Donna | Parker, Joel S. | Perou, Charles M. | Roach, Jeffrey | Schein, Jacqueline E. | Schumacher, Steven E. | Shi, Yan | Simons, Janae V. | Sipahimalani, Payal | Skelly, Tara | Soloway, Matthew G. | Sougnez, Carrie | Tam, Angela | Tan, Donghui | Thiessen, Nina | Veluvolu, Umadevi | Wang, Min | Wilkerson, Matthew D. | Wong, Tina | Wu, Junyuan | Xi, Liu | Zhou, Jane | Bedford, Jason | Chen, Fengju | Fu, Yao | Gerstein, Mark | Haussler, David | Kasaian, Katayoon | Lai, Phillip | Ling, Shiyun | Radenbaugh, Amie | Van Den Berg, David | Weinstein, John N. | Zhu, Jingchun | Albert, Monique | Alexopoulou, Iakovina | Andersen, Jeremiah J | Auman, J. Todd | Bartlett, John | Bastacky, Sheldon | Bergsten, Julie | Blute, Michael L. | Boice, Lori | Bollag, Roni J. | Boyd, Jeff | Castle, Erik | Chen, Ying-Bei | Cheville, John C. | Curley, Erin | Davies, Benjamin | DeVolk, April | Dhir, Rajiv | Dike, Laura | Eckman, John | Engel, Jay | Harr, Jodi | Hrebinko, Ronald | Huang, Mei | Huelsenbeck-Dill, Lori | Iacocca, Mary | Jacobs, Bruce | Lobis, Michael | Maranchie, Jodi K. | McMeekin, Scott | Myers, Jerome | Nelson, Joel | Parfitt, Jeremy | Parwani, Anil | Petrelli, Nicholas | Rabeno, Brenda | Roy, Somak | Salner, Andrew L. | Slaton, Joel | Stanton, Melissa | Thompson, R. Houston | Thorne, Leigh | Tucker, Kelinda | Weinberger, Paul M. | Winemiller, Cythnia | Zach, Leigh Anne | Zuna, Rosemary
The New England journal of medicine  2015;374(2):135-145.
Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist.
We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas.
Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene.
Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.
PMCID: PMC4775252  PMID: 26536169
7.  Divergent clonal selection dominates medulloblastoma at recurrence 
Morrissy, A. Sorana | Garzia, Livia | Shih, David J. H. | Zuyderduyn, Scott | Huang, Xi | Skowron, Patryk | Remke, Marc | Cavalli, Florence M. G. | Ramaswamy, Vijay | Lindsay, Patricia E. | Jelveh, Salomeh | Donovan, Laura K. | Wang, Xin | Luu, Betty | Zayne, Kory | Li, Yisu | Mayoh, Chelsea | Thiessen, Nina | Mercier, Eloi | Mungall, Karen L. | Ma, Yusanne | Tse, Kane | Zeng, Thomas | Shumansky, Karey | Roth, Andrew J. L. | Shah, Sohrab | Farooq, Hamza | Kijima, Noriyuki | Holgado, Borja L. | Lee, John J. Y. | Matan-Lithwick, Stuart | Liu, Jessica | Mack, Stephen C. | Manno, Alex | Michealraj, K. A. | Nor, Carolina | Peacock, John | Qin, Lei | Reimand, Juri | Rolider, Adi | Thompson, Yuan Y. | Wu, Xiaochong | Pugh, Trevor | Ally, Adrian | Bilenky, Mikhail | Butterfield, Yaron S. N. | Carlsen, Rebecca | Cheng, Young | Chuah, Eric | Corbett, Richard D. | Dhalla, Noreen | He, An | Lee, Darlene | Li, Haiyan I. | Long, William | Mayo, Michael | Plettner, Patrick | Qian, Jenny Q. | Schein, Jacqueline E. | Tam, Angela | Wong, Tina | Birol, Inanc | Zhao, Yongjun | Faria, Claudia C. | Pimentel, José | Nunes, Sofia | Shalaby, Tarek | Grotzer, Michael | Pollack, Ian F. | Hamilton, Ronald L. | Li, Xiao-Nan | Bendel, Anne E. | Fults, Daniel W. | Walter, Andrew W. | Kumabe, Toshihiro | Tominaga, Teiji | Collins, V. Peter | Cho, Yoon-Jae | Hoffman, Caitlin | Lyden, David | Wisoff, Jeffrey H. | Garvin, James H. | Stearns, Duncan S. | Massimi, Luca | Schüller, Ulrich | Sterba, Jaroslav | Zitterbart, Karel | Puget, Stephanie | Ayrault, Olivier | Dunn, Sandra E. | Tirapelli, Daniela P. C. | Carlotti, Carlos G. | Wheeler, Helen | Hallahan, Andrew R. | Ingram, Wendy | MacDonald, Tobey J. | Olson, Jeffrey J. | Van Meir, Erwin G. | Lee, Ji-Yeoun | Wang, Kyu-Chang | Kim, Seung-Ki | Cho, Byung-Kyu | Pietsch, Torsten | Fleischhack, Gudrun | Tippelt, Stephan | Ra, Young Shin | Bailey, Simon | Lindsey, Janet C. | Clifford, Steven C. | Eberhart, Charles G. | Cooper, Michael K. | Packer, Roger J. | Massimino, Maura | Garre, Maria Luisa | Bartels, Ute | Tabori, Uri | Hawkins, Cynthia E. | Dirks, Peter | Bouffet, Eric | Rutka, James T. | Wechsler-Reya, Robert J. | Weiss, William A. | Collier, Lara S. | Dupuy, Adam J. | Korshunov, Andrey | Jones, David T. W. | Kool, Marcel | Northcott, Paul A. | Pfister, Stefan M. | Largaespada, David A. | Mungall, Andrew J. | Moore, Richard A. | Jabado, Nada | Bader, Gary D. | Jones, Steven J. M. | Malkin, David | Marra, Marco A. | Taylor, Michael D.
Nature  2016;529(7586):351-357.
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
PMCID: PMC4936195  PMID: 26760213
9.  Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution 
Nature  2014;518(7539):422-426.
Human cancers, including breast cancers, are comprised of clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution1,2, underpinning important emergent features such as drug resistance and metastasis3–7. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours8–10. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment.
PMCID: PMC4864027  PMID: 25470049 CAMSID: cams5567
10.  Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress 
Oncotarget  2016;7(19):28169-28182.
DDX3X encodes a DEAD-box family RNA helicase (DDX3) commonly mutated in medulloblastoma, a highly aggressive cerebellar tumor affecting both children and adults. Despite being implicated in several facets of RNA metabolism, the nature and scope of DDX3′s interactions with RNA remain unclear. Here, we show DDX3 collaborates extensively with the translation initiation machinery through direct binding to 5′UTRs of nearly all coding RNAs, specific sites on the 18S rRNA, and multiple components of the translation initiation complex. Impairment of translation initiation is also evident in primary medulloblastomas harboring mutations in DDX3X, further highlighting DDX3′s role in this process. Arsenite-induced stress shifts DDX3 binding from the 5′UTR into the coding region of mRNAs concomitant with a general reduction of translation, and both the shift of DDX3 on mRNA and decreased translation are blunted by expression of a catalytically-impaired, medulloblastoma-associated DDX3R534H variant. Furthermore, despite the global repression of translation induced by arsenite, translation is preserved on select genes involved in chromatin organization in DDX3R534H-expressing cells. Thus, DDX3 interacts extensively with RNA and ribosomal machinery to help remodel the translation landscape in response to stress, while cancer-related DDX3 variants adapt this response to selectively preserve translation.
PMCID: PMC5053718  PMID: 27058758
medulloblastoma; DDX3X; DDX3; RNA helicase; CLIP-seq
11.  A somatic reference standard for cancer genome sequencing 
Scientific Reports  2016;6:24607.
Large-scale multiplexed identification of somatic alterations in cancer has become feasible with next generation sequencing (NGS). However, calibration of NGS somatic analysis tools has been hampered by a lack of tumor/normal reference standards. We thus performed paired PCR-free whole genome sequencing of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. We generated mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Results were combined with previously generated data allowing for comparison to a fourth lineage on earlier NGS technology. Aggregate variant detection led to the identification of consensus variants, including key events that represent hallmark mutation types including amplified BRAF V600E, a CDK2NA small deletion, a 12 kb PTEN deletion, and a dinucleotide TERT promoter substitution. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions.
PMCID: PMC4837349  PMID: 27094764
12.  Tracking of Normal and Malignant Progenitor Cell Cycle Transit in a Defined Niche 
Scientific Reports  2016;6:23885.
While implicated in therapeutic resistance, malignant progenitor cell cycle kinetics have been difficult to quantify in real-time. We developed an efficient lentiviral bicistronic fluorescent, ubiquitination-based cell cycle indicator reporter (Fucci2BL) to image live single progenitors on a defined niche coupled with cell cycle gene expression analysis. We have identified key differences in cell cycle regulatory gene expression and transit times between normal and chronic myeloid leukemia progenitors that may inform cancer stem cell eradication strategies.
PMCID: PMC4819192  PMID: 27041210
13.  Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors 
Cancer cell  2015;27(2):286-297.
We report the most common single nucleotide substitution/deletion mutations in Favorable Histology Wilms Tumors (FHWT) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPG) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG-mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.
PMCID: PMC4800737  PMID: 25670082
14.  Molecular etiology of an indolent lymphoproliferative disorder determined by whole-genome sequencing 
In an attempt to assess potential treatment options, whole-genome and transcriptome sequencing were performed on a patient with an unclassifiable small lymphoproliferative disorder. Variants from genome sequencing were prioritized using a combination of comparative variant distributions in a spectrum of lymphomas, and meta-analyses of gene expression profiling. In this patient, the molecular variants that we believe to be most relevant to the disease presentation most strongly resemble a diffuse large B-cell lymphoma (DLBCL), whereas the gene expression data are most consistent with a low-grade chronic lymphocytic leukemia (CLL). The variant of greatest interest was a predicted NOTCH2-truncating mutation, which has been recently reported in various lymphomas.
PMCID: PMC4849852  PMID: 27148583
increase in B cell number; lymphocytosis
15.  Putative BRAF activating fusion in a medullary thyroid cancer 
Medullary thyroid cancer (MTC) is a malignancy of the calcitonin-producing parafollicular cells of the thyroid gland. Surgery is the only curative treatment for this cancer. External beam radiation therapy is reserved for adjuvant treatment of MTC with aggressive features. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large subpopulation of MTCs. However, not all patients carry oncogenic alterations of this kinase. Hence, there is still a need for comprehensive molecular characterization of MTC utilizing whole-genome and transcriptome-sequencing methodologies with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations, previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no treatment options.
PMCID: PMC4849853  PMID: 27148585
medullary thyroid carcinoma; neoplasm of the endocrine system
16.  MEF2 transcription factors: developmental regulators and emerging cancer genes 
Oncotarget  2015;7(3):2297-2312.
The MEF2 transcription factors have roles in muscle, cardiac, skeletal, vascular, neural, blood and immune system cell development through their effects on cell differentiation, proliferation, apoptosis, migration, shape and metabolism. Altered MEF2 activity plays a role in human diseases and has recently been implicated in the development of several cancer types. In particular, MEF2B, the most divergent and least studied protein of the MEF2 family, has a role unique from its paralogs in non-Hodgkin lymphomas. The use of genome-scale technologies has enabled comprehensive MEF2 target gene sets to be identified, contributing to our understanding of MEF2 proteins as nodes in complex regulatory networks. This review surveys the molecular interactions of MEF2 proteins and their effects on cellular and organismal phenotypes. We include a discussion of the emerging roles of MEF2 proteins as oncogenes and tumor suppressors of cancer. Throughout this article we highlight similarities and differences between the MEF2 family proteins, including a focus on functions of MEF2B.
PMCID: PMC4823036  PMID: 26506234
MEF2; transcription factor; cancer; gene regulation; developmental biology
17.  MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours 
Nature Communications  2015;6:10013.
Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.
Wilms tumour is a rare renal neoplasm that primarily affects children but the genomic changes responsible for its development are currently largely unknown. In this study, the authors identify somatic mutations of the MLLT1 gene that are potentially involved in the aetiology of a subset of Wilms tumours.
PMCID: PMC4686660  PMID: 26635203
18.  The genomic and transcriptomic landscape of anaplastic thyroid cancer: implications for therapy 
BMC Cancer  2015;15:984.
Anaplastic thyroid carcinoma is the most undifferentiated form of thyroid cancer and one of the deadliest of all adult solid malignancies. Here we report the first genomic and transcriptomic profile of anaplastic thyroid cancer including those of several unique cell lines and outline novel potential drivers of malignancy and targets of therapy.
We describe whole genomic and transcriptomic profiles of 1 primary anaplastic thyroid tumor and 3 authenticated cell lines. Those profiles augmented by the transcriptomes of 4 additional and unique cell lines were compared to 58 pairs of papillary thyroid carcinoma and matched normal tissue transcriptomes from The Cancer Genome Atlas study.
The most prevalent mutations were those of TP53 and BRAF; repeated alterations of the epigenetic machinery such as frame-shift deletions of HDAC10 and EP300, loss of SMARCA2 and fusions of MECP2, BCL11A and SS18 were observed. Sequence data displayed aneuploidy and large regions of copy loss and gain in all genomes. Common regions of gain were however evident encompassing chromosomes 5p and 20q. We found novel anaplastic gene fusions including MKRN1-BRAF, FGFR2-OGDH and SS18-SLC5A11, all expressed in-frame fusions involving a known proto-oncogene. Comparison of the anaplastic thyroid cancer expression datasets with the papillary thyroid cancer and normal thyroid tissue transcriptomes suggested several known drug targets such as FGFRs, VEGFRs, KIT and RET to have lower expression levels in anaplastic specimens compared with both papillary thyroid cancers and normal tissues, confirming the observed lack of response to therapies targeting these pathways. Further integrative data analysis identified the mTOR signaling pathway as a potential therapeutic target in this disease.
Anaplastic thyroid carcinoma possessed heterogeneous and unique profiles revealing the significance of detailed molecular profiling of individual tumors and the treatment of each as a unique entity; the cell line sequence data promises to facilitate the more accurate and intentional drug screening studies for anaplastic thyroid cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1955-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4683857  PMID: 26680454
Anaplastic thyroid carcinoma; cell line; whole genome and transcriptome sequencing; FGFR2-OGDH fusion; SS18-SLC5A11 fusion; MKRN1-BRAF fusion; epigenetic alterations; mTOR signaling pathway; therapy targets
Neuro-Oncology  2014;16(Suppl 5):v100-v101.
Recurrence of the childhood brain cancer medulloblastoma is almost universally fatal. The current strategy for clinical trials is to test novel therapies at the time of recurrence, using targets discovered at diagnosis. To define the relationship between naïve and post-treatment medulloblastoma, we developed a functional genomic transposon-driven mouse-model. Deep sequencing of the commonly inserted genes in diagnostic and recurrent tumors revealed dramatic divergence post-therapy, with recurrences demonstrating a convergence on the TP53 pathway. Loss of function insertions in Tp53 are clonal in the recurrence, result in loss of expression of the Tp53 target gene P21, and arise through selection of minor subclones present before therapy. The majority of insertions identified at diagnosis are no longer present at recurrence, and therefore represent futile targets for therapy. To validate these findings, we studied 36 pairs of human primary/recurrent tumors by whole genome sequencing. When comparing SNVs, indels or structural aberrations, we found minimal genetic overlap between the dominant clones at diagnosis versus recurrence. Recurrent tumors have more genomic aberrations than their paired diagnostic sample, and commonly display alterations in the TP53 (SHH), or the TP53 and TGF-β pathways (Group 3/4 tumors). Clonal dynamics between primary and recurrent tumors was measured using ultra-deep sequencing (1,500X). Overall, recurrent tumors share little genetic identity with their diagnostic tumor, arise through clonal selection, target specific signaling pathways to avoid cell death, and assume clinical dominance after therapy. Our findings undermine the key assumption that diagnostic medulloblastoma samples provide rational targets for therapy in recurrent disease, and provide a simple reason for the failure of prior trials of targeted therapy. Repeated genetic convergence on specific signaling pathways at the time of recurrence suggests that it may be possible to develop ‘anticipatory therapy’ delivered up front to prevent the later emergence of minor resistant clones driving recurrence.
PMCID: PMC4218185
Neuro-Oncology  2014;16(Suppl 5):v102.
INTRODUCTION: Comprehensive, genome-wide profiling and next-generation sequencing based studies have dramatically improved our understanding of pediatric brain tumor biology in recent years. However, the vast majority of these studies rely on the assumption that single biopsies are representative of all areas within a tumor. Intratumor heterogeneity comprises a common phenomenon previously described in glioblastoma multiforme and other tumors. Highly disparate genetic profiles of spatially separated areas within the same tumor may preclude development of personalized, molecularly targeted therapies based on single tumor biopsies. MATERIAL AND METHODS: To assess the degree of intratumor heterogeneity, we conducted multiregion whole exome sequencing, high-resolution DNA copy number analysis (Cytoscan HD) and DNA methylation profiling (Infinium HumanMethylation450 BeadChip) on over 25 distinct pediatric and adult brain tumors with a median of six biopsies per tumor (range 4-9). Histological entities comprised ATRT (n = 2), DIPG (n = 2), ependymoma (n = 1), glioblastoma (n = 10), medulloblastoma (n = 10), and medulloepithelioma (n = 1). We elucidated the degree of intratumor heterogeneity and subgroup affiliation using integrated genomics and unsupervised hierarchical clustering algorithms. RESULTS: Epigenetic signatures were highly similar in multiregion biopsies from a single tumor. However, we identified up to 250,000 CpG dinucleotides that were differentially methylated when determining the intertumor heterogeneity of DNA methylation patterns even within disease subgroups. In addition, pediatric brain tumors displayed highly similar focal and broad DNA copy number alterations compared to their adult counterparts. Multiregion sequencing further reinforced the relatively higher degree of intratumor homogeneity in pediatric brain tumors. Lastly, we showed that subgroup affiliation was stable in all multiregion biopsies in medulloblastomas and glioblastomas. CONCLUSIONS: Our results reveal that single biopsies are representative of the tumor genomics landscape in pediatric brain tumors and that DNA methylation based subgrouping is geographically stable.
PMCID: PMC4218192
21.  Integrated Genomic Characterization of Papillary Thyroid Carcinoma 
Agrawal, Nishant | Akbani, Rehan | Aksoy, B. Arman | Ally, Adrian | Arachchi, Harindra | Asa, Sylvia L. | Auman, J. Todd | Balasundaram, Miruna | Balu, Saianand | Baylin, Stephen B. | Behera, Madhusmita | Bernard, Brady | Beroukhim, Rameen | Bishop, Justin A. | Black, Aaron D. | Bodenheimer, Tom | Boice, Lori | Bootwalla, Moiz S. | Bowen, Jay | Bowlby, Reanne | Bristow, Christopher A. | Brookens, Robin | Brooks, Denise | Bryant, Robert | Buda, Elizabeth | Butterfield, Yaron S.N. | Carling, Tobias | Carlsen, Rebecca | Carter, Scott L. | Carty, Sally E. | Chan, Timothy A. | Chen, Amy Y. | Cherniack, Andrew D. | Cheung, Dorothy | Chin, Lynda | Cho, Juok | Chu, Andy | Chuah, Eric | Cibulskis, Kristian | Ciriello, Giovanni | Clarke, Amanda | Clayman, Gary L. | Cope, Leslie | Copland, John | Covington, Kyle | Danilova, Ludmila | Davidsen, Tanja | Demchok, John A. | DiCara, Daniel | Dhalla, Noreen | Dhir, Rajiv | Dookran, Sheliann S. | Dresdner, Gideon | Eldridge, Jonathan | Eley, Greg | El-Naggar, Adel K. | Eng, Stephanie | Fagin, James A. | Fennell, Timothy | Ferris, Robert L. | Fisher, Sheila | Frazer, Scott | Frick, Jessica | Gabriel, Stacey B. | Ganly, Ian | Gao, Jianjiong | Garraway, Levi A. | Gastier-Foster, Julie M. | Getz, Gad | Gehlenborg, Nils | Ghossein, Ronald | Gibbs, Richard A. | Giordano, Thomas J. | Gomez-Hernandez, Karen | Grimsby, Jonna | Gross, Benjamin | Guin, Ranabir | Hadjipanayis, Angela | Harper, Hollie A. | Hayes, D. Neil | Heiman, David I. | Herman, James G. | Hoadley, Katherine A. | Hofree, Matan | Holt, Robert A. | Hoyle, Alan P. | Huang, Franklin W. | Huang, Mei | Hutter, Carolyn M. | Ideker, Trey | Iype, Lisa | Jacobsen, Anders | Jefferys, Stuart R. | Jones, Corbin D. | Jones, Steven J.M. | Kasaian, Katayoon | Kebebew, Electron | Khuri, Fadlo R. | Kim, Jaegil | Kramer, Roger | Kreisberg, Richard | Kucherlapati, Raju | Kwiatkowski, David J. | Ladanyi, Marc | Lai, Phillip H. | Laird, Peter W. | Lander, Eric | Lawrence, Michael S. | Lee, Darlene | Lee, Eunjung | Lee, Semin | Lee, William | Leraas, Kristen M. | Lichtenberg, Tara M. | Lichtenstein, Lee | Lin, Pei | Ling, Shiyun | Liu, Jinze | Liu, Wenbin | Liu, Yingchun | LiVolsi, Virginia A. | Lu, Yiling | Ma, Yussanne | Mahadeshwar, Harshad S. | Marra, Marco A. | Mayo, Michael | McFadden, David G. | Meng, Shaowu | Meyerson, Matthew | Mieczkowski, Piotr A. | Miller, Michael | Mills, Gordon | Moore, Richard A. | Mose, Lisle E. | Mungall, Andrew J. | Murray, Bradley A. | Nikiforov, Yuri E. | Noble, Michael S. | Ojesina, Akinyemi I. | Owonikoko, Taofeek K. | Ozenberger, Bradley A. | Pantazi, Angeliki | Parfenov, Michael | Park, Peter J. | Parker, Joel S. | Paull, Evan O. | Pedamallu, Chandra Sekhar | Perou, Charles M. | Prins, Jan F. | Protopopov, Alexei | Ramalingam, Suresh S. | Ramirez, Nilsa C. | Ramirez, Ricardo | Raphael, Benjamin J. | Rathmell, W. Kimryn | Ren, Xiaojia | Reynolds, Sheila M. | Rheinbay, Esther | Ringel, Matthew D. | Rivera, Michael | Roach, Jeffrey | Robertson, A. Gordon | Rosenberg, Mara W. | Rosenthall, Matthew | Sadeghi, Sara | Saksena, Gordon | Sander, Chris | Santoso, Netty | Schein, Jacqueline E. | Schultz, Nikolaus | Schumacher, Steven E. | Seethala, Raja R. | Seidman, Jonathan | Senbabaoglu, Yasin | Seth, Sahil | Sharpe, Samantha | Mills Shaw, Kenna R. | Shen, John P. | Shen, Ronglai | Sherman, Steven | Sheth, Margi | Shi, Yan | Shmulevich, Ilya | Sica, Gabriel L. | Simons, Janae V. | Sipahimalani, Payal | Smallridge, Robert C. | Sofia, Heidi J. | Soloway, Matthew G. | Song, Xingzhi | Sougnez, Carrie | Stewart, Chip | Stojanov, Petar | Stuart, Joshua M. | Tabak, Barbara | Tam, Angela | Tan, Donghui | Tang, Jiabin | Tarnuzzer, Roy | Taylor, Barry S. | Thiessen, Nina | Thorne, Leigh | Thorsson, Vésteinn | Tuttle, R. Michael | Umbricht, Christopher B. | Van Den Berg, David J. | Vandin, Fabio | Veluvolu, Umadevi | Verhaak, Roel G.W. | Vinco, Michelle | Voet, Doug | Walter, Vonn | Wang, Zhining | Waring, Scot | Weinberger, Paul M. | Weinstein, John N. | Weisenberger, Daniel J. | Wheeler, David | Wilkerson, Matthew D. | Wilson, Jocelyn | Williams, Michelle | Winer, Daniel A. | Wise, Lisa | Wu, Junyuan | Xi, Liu | Xu, Andrew W. | Yang, Liming | Yang, Lixing | Zack, Travis I. | Zeiger, Martha A. | Zeng, Dong | Zenklusen, Jean Claude | Zhao, Ni | Zhang, Hailei | Zhang, Jianhua | Zhang, Jiashan (Julia) | Zhang, Wei | Zmuda, Erik | Zou., Lihua
Cell  2014;159(3):676-690.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
PMCID: PMC4243044  PMID: 25417114
22.  Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation 
Cell reports  2014;9(1):261-271.
Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines.
Graphical abstract
PMCID: PMC4612615  PMID: 25263553
23.  Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers 
Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted “panel” sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.
PMCID: PMC4850882  PMID: 27148575
24.  Next-Generation Sequencing Approaches in Cancer: Where Have They Brought Us and Where Will They Take Us? 
Cancers  2015;7(3):1925-1958.
Next-generation sequencing (NGS) technologies and data have revolutionized cancer research and are increasingly being deployed to guide clinicians in treatment decision-making. NGS technologies have allowed us to take an “omics” approach to cancer in order to reveal genomic, transcriptomic, and epigenomic landscapes of individual malignancies. Integrative multi-platform analyses are increasingly used in large-scale projects that aim to fully characterize individual tumours as well as general cancer types and subtypes. In this review, we examine how NGS technologies in particular have contributed to “omics” approaches in cancer research, allowing for large-scale integrative analyses that consider hundreds of tumour samples. These types of studies have provided us with an unprecedented wealth of information, providing the background knowledge needed to make small-scale (including “N of 1”) studies informative and relevant. We also take a look at emerging opportunities provided by NGS and state-of-the-art third-generation sequencing technologies, particularly in the context of translational research. Cancer research and care are currently poised to experience significant progress catalyzed by accessible sequencing technologies that will benefit both clinical- and research-based efforts.
PMCID: PMC4586802  PMID: 26404381
cancer; next-generation sequencing; translational research; precision oncology medicine
25.  Integrative analysis of 111 reference human epigenomes 
Kundaje, Anshul | Meuleman, Wouter | Ernst, Jason | Bilenky, Misha | Yen, Angela | Kheradpour, Pouya | Zhang, Zhizhuo | Heravi-Moussavi, Alireza | Liu, Yaping | Amin, Viren | Ziller, Michael J | Whitaker, John W | Schultz, Matthew D | Sandstrom, Richard S | Eaton, Matthew L | Wu, Yi-Chieh | Wang, Jianrong | Ward, Lucas D | Sarkar, Abhishek | Quon, Gerald | Pfenning, Andreas | Wang, Xinchen | Claussnitzer, Melina | Coarfa, Cristian | Harris, R Alan | Shoresh, Noam | Epstein, Charles B | Gjoneska, Elizabeta | Leung, Danny | Xie, Wei | Hawkins, R David | Lister, Ryan | Hong, Chibo | Gascard, Philippe | Mungall, Andrew J | Moore, Richard | Chuah, Eric | Tam, Angela | Canfield, Theresa K | Hansen, R Scott | Kaul, Rajinder | Sabo, Peter J | Bansal, Mukul S | Carles, Annaick | Dixon, Jesse R | Farh, Kai-How | Feizi, Soheil | Karlic, Rosa | Kim, Ah-Ram | Kulkarni, Ashwinikumar | Li, Daofeng | Lowdon, Rebecca | Mercer, Tim R | Neph, Shane J | Onuchic, Vitor | Polak, Paz | Rajagopal, Nisha | Ray, Pradipta | Sallari, Richard C | Siebenthall, Kyle T | Sinnott-Armstrong, Nicholas | Stevens, Michael | Thurman, Robert E | Wu, Jie | Zhang, Bo | Zhou, Xin | Beaudet, Arthur E | Boyer, Laurie A | De Jager, Philip | Farnham, Peggy J | Fisher, Susan J | Haussler, David | Jones, Steven | Li, Wei | Marra, Marco | McManus, Michael T | Sunyaev, Shamil | Thomson, James A | Tlsty, Thea D | Tsai, Li-Huei | Wang, Wei | Waterland, Robert A | Zhang, Michael | Chadwick, Lisa H | Bernstein, Bradley E | Costello, Joseph F | Ecker, Joseph R | Hirst, Martin | Meissner, Alexander | Milosavljevic, Aleksandar | Ren, Bing | Stamatoyannopoulos, John A | Wang, Ting | Kellis, Manolis
Nature  2015;518(7539):317-330.
The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.
PMCID: PMC4530010  PMID: 25693563

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