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1. Patient and Clinician Experiences With the Combination of Virtual and In-Person Chronic Kidney Disease Care Since the COVID-19 Pandemic

Author

Micheli Bevilacqua, Yuriy Melnyk, Helen Chiu, Janet Williams, Paul Watson, Brenda Lee, Palvir Dhariwal, Marlee McGuire, Julie Wei, Robin Chohan, Anne Logie, Michele Fryer, Dominik Stoll, and Adeera Levin

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

Background: Following onset of the COVID-19 pandemic, chronic kidney disease (CKD) clinics in BC shifted from established methods of mostly in-person care delivery to virtual care (VC) and thereafter a hybrid of the two. Objectives: To determine strengths, weaknesses, quality-of-care delivery, and key considerations associated with VC usage to inform optimal way(s) of integrating virtual and traditional methods of care delivery in multidisciplinary kidney clinics. Design: Qualitative evaluation. Setting: British Columbia, Canada. Participants: Patients and health care providers associated with multidisciplinary kidney care clinics. Methods: Development and delivery of semi-structured interviews of patients and health care providers. Results: 11 patients and/or caregivers and 12 health care providers participated in the interviews. Participants reported mixed experiences with VC usage. All participants foresaw a future where both VC and in-person care was offered. A reported benefit of VC was convenience for patients. Challenges identified with VC included difficulty establishing new therapeutic relationships, and variable of abilities of both patients and health care providers to engage and communicate in a virtual format. Participants noted a preference for in-person care for more complex situations. Four themes were identified as considerations when selecting between in-person and VC: person’s nonmedical context, support available, clinical parameters and tasks to be completed, and clinic operations. Participants indicated that visit modality selection is an individualized and ongoing process involving the patient and their preferences which may change over time. Health care provider participants noted that new workflow challenges were created when using both VC and in-person care in the same clinic session. Limitations: Limited sample size in the setting of one-on-one interviews and use of convenience sampling which may result in missing perspectives, including those already facing challenges accessing care who could potentially be most disadvantaged by implementation of VC. Conclusions: A list of key considerations, aligned with quality care delivery was identified for health care providers and programs to consider as they continue to utilize VC and refine how best to use different visit modalities in different patient and clinical situations. Further work will be needed to validate these findings and evaluate clinical outcomes with the combination of virtual and traditional modes of care delivery. Trial registration: Not registered.

Published
2023
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2. Protocol for a Multistage Mixed-Methods Evaluation of Multidisciplinary Chronic Kidney Disease Care Quality Following Integration of Virtual and In-Person Care During the COVID-19 Pandemic

Author

Micheli Bevilacqua, Helen Chiu, Yuriy Melnyk, Janet Williams, Robin Chohan, Julie Wei, Dominik Stoll, Michele Fryer, Marlee McGuire, Anne Logie, Paul Watson, and Adeera Levin

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

Background: Multidisciplinary care of patients with chronic kidney disease (CKD) as it previously existed was predicated on an evidence and experience base of improved patient outcomes within an established and well-described service delivery model. The onset of the COVID-19 pandemic brought with it a departure from this established care delivery model toward integration of virtual care and in-person care. Objective: To develop an evaluation framework to determine whether this shift in service delivery models has affected quality of multidisciplinary kidney care and/or patient-clinician interactions and relationships. Design: A sequential multiphase, mixed-methods evaluation. Setting: All 15 British Columbia (BC) multidisciplinary kidney care clinics (KCCs). Participants: All patients and all clinicians in all KCCs across BC will be invited to participate in the planned evaluation. Measurements: Qualitative and quantitative feedback from patients and families living with CKD and KCC clinicians. Methods: The planned multiphase evaluation of virtual care integration in KCCs will be conducted across all 15 KCCs in the province of BC, Canada. The following phases are proposed: (1) review of current virtual care integration and practices, (2) assessment of patient and clinician experiences and perspectives via semi-structured interviews, (3) validation of those patient and clinician perspectives via survey of a larger sample, (4) compilation and analysis of all phases to provide informed recommendations for patient and visit format selection in a mixed in-person and virtual multidisciplinary clinic setting. Limitations: This work will not capture any information about the relationship between differences in virtual usage parameters and clinical outcomes or financial implications. Conclusions: There is no existing framework for either evaluation of multidisciplinary CKD care quality in a virtual setting or evaluation of care quality following a substantial change in service delivery models. The proposed evaluation protocol will enable better understanding of the nuances in kidney care delivery in this new format and inform how best to optimize the integration of virtual and pre-existing formats into kidney clinic care delivery beyond the pandemic. Beyond the current evaluation, this protocol may be of use for other jurisdictions to evaluate their own local instances of virtual care implementation and integration. The model may be adapted to evaluate quality of multidisciplinary kidney care delivery following other changes to clinic service delivery models.

Published
2022
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4. 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

5. Kinetics and stereochemistry of theCellulomonas fimiβ-mannanase studied using1H-NMR

Author

Per Hägglund, Torbjörn Drakenberg, Leila Lo Leggio, Dominik Stoll, Henrik Stålbrand, and Lars Anderson

Subjects
biology, Chemistry, Stereochemistry, Cellulomonadaceae, Mannose, biology.organism_classification, Biochemistry, Catalysis, Mutarotation, chemistry.chemical_compound, Residue (chemistry), Hydrolysis, DNA glycosylase, Glycoside hydrolase, Enzyme kinetics, Biotechnology
Abstract

Endo–1,4-β-mannanases (β-mannanases) randomly hydrolyse the mannosidic bonds within the main chain of various mannans and heteromannans. Some of these polysaccharides are hemicelluloses, a major part of the plant cell-wall. The β-mannanases have been assigned to family 5 and 26 of the glycoside hydrolase clan A. This work presents a detailed kinetic analysis of the family 26 β-mannanase CfMan26A from the soil-bacterium Cellulomonas fimi. The full-length enzyme consists of five modules: a family 26 catalytic module, an immunoglobulin-like module, a mannan-binding module, a surface layer homology-module and a module of unknown function. A truncated variant consisting of the catalytic module and the immunoglobulin-like module was used in these studies. The degradation of mannotriose, mannotetraose and mannopentaose was studied by 1H-NMR. First, the mutarotation of one of the hydrolysis products (mannose) was determined to be 1.7 10−5s−1 at 5°C and pH 5.0. As expected for a family 26 glycoside hydrolase, the ...

Published
2008
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6. Mechanism, Mutagenesis, and Chemical Rescue of a β-Mannosidase from Cellulomonas fimi

Author

Stephen P. Reid, Stephen G. Withers, Dominik Stoll, Oyekanmi Nashiru, and R. Antony J. Warren, and David L. Zechel

Subjects
Fluorine Radioisotopes, Glycosylation, Stereochemistry, Biochemistry, Catalysis, Substrate Specificity, chemistry.chemical_compound, Mannosidases, Amino Acid Sequence, Enzyme kinetics, Nuclear Magnetic Resonance, Biomolecular, Cellulomonas, chemistry.chemical_classification, Binding Sites, Sequence Homology, Amino Acid, biology, Chemistry, Aryl, Mutagenesis, beta-Mannosidase, Active site, Substrate (chemistry), Hydrogen-Ion Concentration, Kinetics, Enzyme, Amino Acid Substitution, Mannosides, biology.protein, Thermodynamics, Ethylene glycol
Abstract

The chemical mechanism of a retaining beta-mannosidase from Cellulomonas fimi has been characterized through steady-state kinetic analyses with a range of substrates, coupled with chemical rescue studies on both the wild-type enzyme and mutants in which active site carboxyl groups have been replaced. Studies with a series of aryl beta-mannosides of vastly different reactivities (pK(a)(lg) = 4-10) allowed kinetic isolation of the glycosylation and deglycosylation steps. Substrate inhibition was observed for all but the least reactive of these substrates. Brønsted analysis of k(cat) revealed a downward breaking plot (beta(lg) = -0.54 +/- 0.05) that is consistent with a change in rate-determining step (glycosylation to deglycosylation), and this was confirmed by partitioning studies with ethylene glycol. The pH dependence of k(cat)/K(m) follows an apparent single ionization of a group of pK(a) = 7.65 that must be protonated for catalysis. The tentative assignment of E429 as the acid-base catalyst of Man2A on the basis of sequence alignments with other family 2 glycosidases was confirmed by the increased turnover rate observed for the mutant E429A in the presence of azide and fluoride, leading to the production of beta-mannosyl azide and beta-mannosyl fluoride, respectively. A pH-dependent chemical rescue of E429A activity is also observed with citrate. Substantial oxocarbenium ion character at the transition state was demonstrated by the alpha-deuterium kinetic isotope effect for Man2A E429A of alpha-D(V) = 1.12 +/- 0.01. Surprisingly, this isotope effect was substantially greater in the presence of azide (alpha-D(V) = 1.166 +/- 0.009). Likely involvement of acid/base catalysis was revealed by the pH dependence of k(cat) for Man2A E429A, which follows a bell-shaped profile described by pK(a) values of 6.1 and 8.4, substantially different from that of the wild-type enzyme. The glycosidic bond cleaving activity of Man2A E519A and E519S nucleophile mutants is restored with azide and fluoride and appears to correlate with the corresponding "glycosynthase" activities. The contribution of the substrate 2-hydroxyl to stabilization of the Man2A glycosylation transition state (DeltaDeltaG() = 5.1 kcal mol(-1)) was probed using a 2-deoxymannose substrate. This value, surprisingly, is comparable to that found from equivalent studies with beta-glucosidases despite the geometric differences at C-2 and the importance of hydrogen bonding at that position. Modes of stabilizing the mannosidase transition state are discussed.

Published
2003
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8. Substrate Distortion by a -Mannanase: Snapshots of the Michaelis and Covalent-Intermediate Complexes Suggest a B2,5 Conformation for the Transition State

Author

Dominik Stoll, Garib N. Murshudov, Lóránd Szabó, Stephen G. Withers, David L. Zechel, Gideon J. Davies, Valérie M.-A. Ducros, and Harry J. Gilbert

Subjects
chemistry.chemical_compound, Glycosylation, chemistry, Transition (genetics), Covalent bond, Stereochemistry, Distortion, Hydrolase, Substrate (chemistry), General Chemistry, β mannanase, Catalysis, Enzyme catalysis
Published
2002
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9. β-Mannosynthase: Synthesis ofβ-Mannosides with a Mutantβ-Mannosidase

Author

Taraneh Mohammadzadeh, R. Antony J. Warren, Stephen G. Withers, Oyekanmi Nashiru, Dominik Stoll, and David L. Zechel

Subjects
Mannosidase, Mannosides, biology, Chemistry, Stereochemistry, Fluorinase, General Chemistry, Glycosynthase, General Medicine, Catalysis, Enzyme catalysis, carbohydrates (lipids), Serine, chemistry.chemical_compound, Residue (chemistry), Nucleophile, biology.protein, Fluoride
Abstract

Engineering enzymes: The glutamic acid nucleophile of a retaining β-mannosidase has been replaced with a serine residue to form a β-mannosynthase. When the new enzyme is provided with an α-mannosyl fluoride donor and an appropriate acceptor, β-mannoside linkages are synthesized. Remarkably, α-mannosyl fluoride can be generated in situ by providing the mannosynthase with excess fluoride ion.

Published
2001
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11. Identification of Glu-519 as the catalytic nucleophile in β-mannosidase 2A from Cellulomonas fimi

Author

Shouming He, R. Antony J. Warren, Dominik Stoll, and Stephen G. Withers

Subjects
chemistry.chemical_classification, Stereochemistry, Electrospray ionization, Peptide, Cell Biology, Tripeptide, Biochemistry, Dissociation constant, chemistry.chemical_compound, chemistry, Covalent bond, Gentiobiose, Peptide bond, Glycoside hydrolase, Molecular Biology
Abstract

Incubation of the beta-mannosidase Man2A from Cellulomonas fimi with 2-deoxy-2-fluoro-beta-D-mannosyl fluoride (2FMan beta F) resulted in time-dependent inactivation of the enzyme (inactivation rate constant k(i)=0.57 min(-1), dissociation constant for the inactivator K(i)=0.41 mM) through the accumulation of a covalent 2-deoxy-2-fluoro-alpha-D-mannosyl-beta-mannosidase 2A (2FMan-Man2A) enzyme intermediate, as observed by electrospray ionization mass spectrometry. The stoichiometry of inactivation was 1:1. Removal of excess inactivator and regeneration of active enzyme by transglycosylation of the covalently attached inhibitor to gentiobiose [Glc beta(1-6)Glc] demonstrated that the covalent intermediate was catalytically competent. Comparison by MS of the peptic digests of 2FMan-Man2A with peptic digests of native Man2A revealed a peptide of m/z 1520 that was unique to 2FMan-Man2A, and one of m/z 1036.5 that was unique to a Man2A peptide. Their sequences, determined by collision-induced fragmentation, were CSEFGFQGPPTW and FGFQGPPTW, corresponding to residues 517-528 and 520-528 of Man2A respectively. The difference in mass of 483.5 between the two peptides equals the sum of the masses of the tripeptide CSE plus that of 2-fluoromannose. It was concluded that in 2FMan-Man2A, the 2-fluoromannose esterified to Glu-519 blocks hydrolysis of the Glu-519-Phe-520 peptide bond, and that Glu-519 is the catalytic nucleophile in this enzyme. This residue is conserved in all members of family 2 of the glycosyl hydrolases. This represents the first ever labelling and identification of an active-site nucleophile in a beta-mannosidase.

Published
2000
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12. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

Author

Ley, Timothy, Miller, Christopher, Ding, Li, Raphael, Benjamin J., Mungall, Andrew J., Robertson, A. Gordon, Hoadley, Katherine, Triche, Timothy J., Laird, Peter W., Baty, Jack D., Fulton, Lucinda L., Fulton, Robert, Heath, Sharon E., Kalicki Veizer, Joelle, Kandoth, Cyriac, Klco, Jeffery M., Koboldt, Daniel C., Kanchi, Krishna Latha, Shashikant, Kulkarni, M. S., P. h. D., F. A. C. M. G., Lamprecht, Tamara L., B. S., Washington, University, Louis, S. t., Larson, David E., P. h. D., Ling, Lin, M. S., Charles, Lu, Mclellan, Michael D., Mcmichael, Joshua F., the Genome Institute at Washington University, Jacqueline, Payton, M. D., P. h. D., Heather, Schmidt, Spencer, David H., Tomasson, Michael H., M. D., Siteman Cancer Center, S. t. Louis, Wallis, John W., Wartman, Lukas D., Watson, Mark A., John, Welch, Wendl, Michael C., Adrian, Ally, B. S. c., Miruna, Balasundaram, B. A. S. c., Inanc, Birol, Yaron, Butterfield, Readman, Chiu, M. S. c., Andy, Chu, Eric, Chuah, Hye Jung Chun, Richard, Corbett, Noreen, Dhalla, Ranabir, Guin, An, He, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Steven, Jones, Aly, Karsan, Darlene, Lee, Haiyan I., Li, Marra, Marco A., Michael, Mayo, Moore, Richard A., Karen, Mungall, Jeremy, Parker, Erin, Pleasance, Patrick, Plettner, Jacquie, Schein, Dominik, Stoll, Lucas, Swanson, Angela, Tam, Nina, Thiessen, Richard, Varhol, Natasja, Wye, Yongjun, Zhao, M. S. c., D. V. M., British Columbia Cancer Agency's Genome Sciences Centre, Vancouver, Canada, Stacey, Gabriel, Gad, Getz, Carrie, Sougnez, Lihua, Zou, Broad Institute of Harvard, Massachusetts Institute of Technology, Cambridge, Ma, Mark D. M. Leiserson, B. A., Vandin, Fabio, Hsin Ta Wu, Brown, University, Center for Computational Molecular Biology, Providence, Ri, Frederick, Applebaum, Fred Hutchinson Cancer Research Center, Division of Medical Oncology, Seattle Cancer Care Alliance, Seattle, Baylin, Stephen B., Johns Hopkins University, Baltimore, Rehan, Akbani, Broom, Bradley M., Ken, Chen, Motter, Thomas C., B. A., Khanh, Nguyen, Weinstein, John N., Nianziang, Zhang, Anderson Cancer Center, University of Texas M. D., Houston, Ferguson, Martin L., Mlf, Consulting, Biotechnology Consultant, Boston, Christopher, Adams, Aaron, Black, Jay, Bowen, Julie Gastier Foster, Thomas, Grossman, Tara, Lichtenberg, Lisa, Wise, the Research Institute at Nationwide Children's Hospital, Columbus, Oh, Tanja, Davidsen, Demchok, John A., Mills Shaw, Kenna R., Margi, Sheth, National Cancer Institute, Bethesda, Md, Sofia, Heidi J., P. h. D., M. P. H., National Human Genome Research Institute, Liming, Yang, Downing, James R., Jude Children's Research Hospital, S. t., Memphis, Greg, Eley, Sciementis, Llc, Statham, Ga, Shelley, Alonso, Brenda, Ayala, Julien, Baboud, Mark, Backus, Barletta, Sean P., Berton, Dominique L., M. S. C. S., Chu, Anna L., Stanley, Girshik, Jensen, Mark A., Ari, Kahn, Prachi, Kothiyal, Nicholls, Matthew C., Pihl, Todd D., Pot, David A., Rohini, Raman, B. E., Sanbhadti, Rashmi N., Snyder, Eric E., Deepak, Srinivasan, Jessica, Walton, Yunhu, Wan, Zhining, Wang, Sra, International, Fairfax, Va, Issa, Jean Pierre J., Temple, University, Philadelphia, Michelle Le Beau, University of Chicago, Chicago, Martin, Carroll, University of Pennsylvania, Hagop Kantarjian, M. D., Steven, Kornblau, Bootwalla, Moiz S., B. S. c., M. S., Lai, Phillip H., Hui, Shen, Van Den Berg, David J., Weisenberger, Daniel J., University of Southern California, Epigenome, Center, Los, Angeles, Daniel C. Link, M. D., Walter, Matthew J., Ozenberger, Bradley A., Mardis, Elaine R., Peter, Westervelt, Graubert, Timothy A., Dipersio, John F., and Wilson, Richard K.

Subjects
Myeloid, Adult, Epigenomics, Male, NPM1, Gene Expression, CpG Islands, DNA Methylation, Female, Gene Fusion, Genome, Human, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Middle Aged, Sequence Analysis, DNA, Mutation, Acute, Enasidenib, Biology, CEBPA, Genetics, Genome, Leukemia, Massive parallel sequencing, MicroRNA sequencing, Myeloid leukemia, DNA, General Medicine, KMT2A, biology.protein, Sequence Analysis, Nucleophosmin, Human, Comparative genomic hybridization
Abstract

BACKGROUND—Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS—We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS—AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcriptionfactor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumorsuppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS—We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.) The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades. Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (i.e., somatic mutations) have an essential role in pathogenesis. 1,2 However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays 3-5 (see Glossary). Targeted sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2. 6-8 Massively parallel sequencing enabled the discovery of recurrent mutations in DNMT3A 9,10 and IDH1. 11 Recent studies have shown that many patients with

Published
2013

13. Expansion of the glycosynthase repertoire to produce defined manno-oligosaccharides

Author

Valérie M.-A. Ducros, Michael Jahn, Stephen G. Withers, Gideon J. Davies, Pritpal Singh, Dominik Stoll, Lóránd Szabó, H.J. Gilbert, and R. A. J. Warren

Subjects
Models, Molecular, Glycosylation, Time Factors, Glycoside Hydrolases, Stereochemistry, Molecular Sequence Data, Mutant, Oligosaccharides, Catalysis, Mannans, Nucleophile, Multienzyme Complexes, Transferases, Mannosidases, Hydrolase, Materials Chemistry, Cellulases, Chemistry, Repertoire, Glycopeptides, Metals and Alloys, General Chemistry, Glycosynthase, Hydrogen-Ion Concentration, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, carbohydrates (lipids), Carbohydrate Sequence, Chemical engineering, Mutagenesis, Site-Directed, Ceramics and Composites, lipids (amino acids, peptides, and proteins), Function (biology)
Abstract

Mutant endo-mannanases, in which the catalytic nucleophile has been replaced, function as glycosynthases in the synthesis of manno-oligosaccharides of defined lengths.

Published
2003
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14. Comprehensive genomic characterization of squamous cell lung cancers

Author

Charles J. Vaske, Ying Du, Theodore C. Goldstein, Ping Yang, Yufeng Liu, Bryan Hernandez, Daniel R. Zerbino, Kenneth H. Buetow, Khurram Z. Khan, Semin Lee, Martin Peifer, Kristin G. Ardlie, James G. Herman, Sanja Dacic, Ashley Hill, Christopher Szeto, Jianjiong Gao, Singer Ma, Peng Chieh Chen, Carl F. Schaefer, David G. Beer, Kerstin David, Brent W. Zanke, Karen Mungall, Beverly Lee, Daniel DiCara, Kristen Rogers, Rui Jing, Christina Liquori, Carrie Sougnez, Ron Bose, Brian O'Connor, Piotr A. Mieczkowski, Scott L. Carter, Andy Chu, Peter W. Laird, David J. Kwiatkowski, R. Craig Cason, Marie Christine Aubry, Rileen Sinha, Dennis T. Maglinte, Chad J. Creighton, Howard H. Sussman, Jill M. Siegfried, Laura A.L. Dillon, Agnes Viale, Marco A. Marra, Stephen E. Schumacher, Dennis A. Wigle, Yongjun Zhao, Robert C. Onofrio, Heidi J. Sofia, Ranabir Guin, Lori Boice, Ling Li, Mark Backus, Pei Lin, Prachi Kothiyal, Jan F. Prins, Lauren Averett Byers, Haiyan I. Li, An He, Ka Ming Nip, Chang-Jiun Wu, Peter Dolina, James A. Robinson, Saianand Balu, Collisson E, Jinze Liu, Nicholas D. Socci, Erin Pleasance, Joan Pontius, Christina Yau, Eric E. Snyder, Shaowu Meng, Mei Huang, Aaron McKenna, Corbin D. Jones, Carl Morrison, Malcolm V. Brock, Chris Wakefield, Jared R. Slobodan, Ethan Cerami, Angela Tam, Jane Peterson, Michael D. Topal, Jacob M. Kaufman, Elena Helman, Richard T. Cheney, Dominik Stoll, Cristiane M. Ida, Dante Trusty, Peter S. Hammerman, Yevgeniy Antipin, D. Neil Hayes, Anders Jacobsen, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Peter Waltman, Chris Sander, Zhining Wang, Derek Y. Chiang, Elizabeth J. Thomson, Vonn Walter, JoEllen Weaver, Elena Nemirovich-Danchenko, Jacqueline E. Schein, Bradley M. Broom, Sandra C. Tomaszek, Peter A. Kigonya, Tod D. Casasent, Ari B. Kahn, Joanne Yi, Kyle Ellrott, John M. S. Bartlett, Payal Sipahimalani, William D. Travis, Douglas Voet, Sean P. Barletta, Elizabeth Chun, J. Todd Auman, Ludmila Danilova, Katherine A. Hoadley, Marcin Imielinski, Ramaswamy Govindan, David P. Carbone, Leigh B. Thorne, David A. Wheeler, Carrie Hirst, Barbara Tabak, Sugy Kodeeswaran, Ijeoma A. Azodo, James Stephen Marron, Michael S. Noble, Jianjua John Zhang, Paul K. Paik, Deepak Srinivasan, Boris Reva, B. Arman Aksoy, Kristian Cibulskis, Douglas B. Flieder, Fei Pan, Daniel J. Weisenberger, Ronglai Shen, Jinhua Zhang, Nils Weinhold, Harman Sekhon, David Van Den Berg, Mark S. Guyer, Robert Penny, Hartmut Juhl, Marc Danie Nazaire, Yiqun Zhang, Eric A. Collisson, Robin J.N. Coope, Tom Bodenheimer, Richard Thorp, Junyuan Wu, Matthew Meyerson, Nguyen Phi Hung, Jerome Myers, Artem Sokolov, Yidi J. Turman, Thomas Muley, Stephen B. Baylin, Anisha Gulabani, A. Gordon Robertson, Lynda Chin, Eric Chuah, Richard Varhol, Margi Sheth, Janae V. Simons, Nils Gehlenborg, Tanja Davidsen, Psalm Haseley, Miruna Balasundaram, Olga Potapova, Spring Yingchun Liu, W. Kimryn Rathmell, Bizhan Bandarchi-Chamkhaleh, Wendy Winckler, David Mallery, Nicholas J. Petrelli, Nicole Todaro, Alex E. Lash, James Shin, Travis Brown, Igor Jurisica, Benjamin Gross, Hailei Zhang, Nikolaus Schultz, Kenna R. Mills Shaw, Nam Pho, William Pao, Darlene Lee, Zhen Fan, Troy Shelton, Yan Shi, Shelley Alonso, Carmelo Gaudioso, Peter B. Illei, Stuart R. Jefferys, Maureen F. Zakowski, Marian Rutledge, Bruce E. Johnson, Andrew J. Mungall, Eric S. Lander, Matthew G. Soloway, Michael Mayo, Christopher G. Maher, John V. Heymach, Lihua Zou, Dominique L. Berton, Nina Thiessen, Gary K. Scott, Anna L. Chu, Richard A. Hajek, Ming-Sound Tsao, Liming Yang, Qianxing Mo, Nguyen Van Bang, Martin Hirst, John Eckman, Erin Curley, Rajiv Dhir, Gad Getz, Stanley Girshik, Xuan Van Le, Jeff Boyd, Roman K. Thomas, Konstantin V. Fedosenko, Juok Cho, Alexei Protopopov, Nguyen Viet Tien, Lixing Yang, Laetitia Borsu, Steven J.M. Jones, Matthew D. Wilkerson, Mark Sherman, Andrew Crenshaw, Doug Voet, Elizabeth Buda, Jennifer Brown, Yaron S.N. Butterfield, Rehan Akbani, Todd Pihl, Ruibin Xi, Nianxiang Zhang, Jessica Walton, Ricardo Ramirez, Lisle E. Mose, Leslie Cope, Greg Eley, Mark A. Jensen, John N. Weinstein, Li Ding, Li-Wei Chang, Matthew C. Nicholls, Peter J. Park, Bui Duc Phu, Christopher R. Cabanski, Bernard Kohl, Julien Baboud, Joseph Paulauskis, David Pot, Gordon Robertson, Jingchun Zhu, John A. Demchok, Eunjung Lee, Giovanni Ciriello, Mary Iacocca, Gordon Saksena, Jesse Walsh, Yupu Liang, William K. Funkhouser, Rashmi N. Sanbhadti, Sam Ng, Venkatraman E. Seshan, Valerie W. Rusch, Robert A. Holt, Robert Sfeir, Jung E. Hye-Chun, Kai Wang, Helga Thorvaldsdottir, Huy V. Nguyen, Christopher Wilks, Brian Craft, Donghui Tan, David Haussler, Charles M. Perou, Timothy J. Triche, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Stacey Gabriel, Martha Hatfield, Christine Czerwinski, Alan P. Hoyle, Marc Ladanyi, Joshua M. Stuart, Andrey Sivachenko, Jacqueline D. Palchik, Thomas Zeng, Inanc Birol, Rohini Raman, Ijeoma Azodo, Jianhua Zhang, Adam B. Olshen, Bradley A. Ozenberger, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Jill P. Mesirov, Petar Stojanov, Raju Kucherlapati, Richard Corbett, Farhad Kosari, Martin L. Ferguson, Natasha Rekhtman, Keith A. Baggerly, Scott Morris, Brenda Rabeno, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
Lung Neoplasms, Squamous Differentiation, DNA Mutational Analysis, Adenocarcinoma of Lung, Biology, Adenocarcinoma, Article, Phosphatidylinositol 3-Kinases, Gefitinib, Mutation Rate, CDKN2A, Carcinoma, medicine, Humans, Molecular Targeted Therapy, Lung cancer, Multidisciplinary, Genome, Human, Gene Expression Profiling, Genes, p16, Genomics, medicine.disease, Genes, p53, Gene expression profiling, Gene Expression Regulation, Neoplastic, Mutation, Cancer research, Carcinoma, Squamous Cell, Gene Deletion, medicine.drug, Necitumumab, Signal Transduction
Abstract

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers., National Institutes of Health (U.S.) (Grant U24 CA126561), National Institutes of Health (U.S.) (Grant U24 CA126551), National Institutes of Health (U.S.) (Grant U24 CA126554), National Institutes of Health (U.S.) (Grant U24 CA126543), National Institutes of Health (U.S.) (Grant U24 CA126546), National Institutes of Health (U.S.) (Grant U24 CA126563), National Institutes of Health (U.S.) (Grant U24 CA126544), National Institutes of Health (U.S.) (Grant U24 CA143845), National Institutes of Health (U.S.) (Grant U24 CA143858), National Institutes of Health (U.S.) (Grant U24 CA144025), National Institutes of Health (U.S.) (Grant U24 CA143882), National Institutes of Health (U.S.) (Grant U24 CA143866), National Institutes of Health (U.S.) (Grant U24 CA143867), National Institutes of Health (U.S.) (Grant U24 CA143848), National Institutes of Health (U.S.) (Grant U24 CA143840), National Institutes of Health (U.S.) (Grant U24 CA143835), National Institutes of Health (U.S.) (Grant U24 CA143799), National Institutes of Health (U.S.) (Grant U24 CA143883), National Institutes of Health (U.S.) (Grant U24 CA143843), National Institutes of Health (U.S.) (Grant U54 HG003067), National Institutes of Health (U.S.) (Grant U54 HG003079), National Institutes of Health (U.S.) (Grant U54 HG003273)

Published
2012

15. Comprehensive molecular characterization of human colon and rectal cancer

Author

Donghui Tan, Nils Gehlenborg, Robert S. Fulton, Pat Swanson, Pei Lin, Chang-Jiun Wu, Piotr A. Mieczkowski, David Haussler, Marco A. Marra, Stephen E. Schumacher, Bernard Kohl, Jingchun Zhu, Lucinda Fulton, Charles M. Perou, Timothy J. Triche, Madhumati Gundapuneni, Mark Backus, Eve Shinbrot, Yonghong Xiao, Xuan Van Le, Liming Yang, Gad Getz, Stanley Girshik, Jessica Walton, Barbara Tabak, Greg Eley, Brian O'Connor, Larissa K. Temple, Saianand Balu, Eric A. Collisson, Tanja Davidsen, Elizabeth Buda, Janae V. Simons, Anisha Gulabani, Joseph Willis, Tod D. Casasent, Scott Morris, Doug Voat, Jireh Santibanez, Jennifer Drummond, Li Ding, Nicholas J. Petrelli, Andrew J. Mungall, Michael Mayo, Aaron D. Black, Gerald C. Chu, Elizabeth N. Medina, Huy V. Nguyen, Aaron E. Cozen, Yongjun Zhao, Hui Shen, Christopher Szeto, Brenda Rabeno, Martin Hirst, Bogumil Kaczkowski, Lisle E. Mose, Lora Lewis, Brian Craft, Joseph Paulauskis, Ari B. Kahn, Andy Chu, Peter W. Laird, Benjamin Gross, Matthew D. Wilkerson, Raju Kucherlapati, Matthew C. Nicholls, David Van Den Berg, Vesteinn Thorsson, Richard W. Park, Ethan Cerami, David A. Wheeler, Laura A.L. Dillon, Angela Tam, Julien Baboud, Kim D. Delehaunty, Katherine A. Hoadley, Ranabir Guin, Donna M. Muzny, Gordon Saksena, Shaowu Meng, Richard Kreisberg, Kenneth H. Buetow, Rajiv Dhir, Inanc Birol, Timo Erkkilä, Martin L. Ferguson, Robert A. Holt, Elaine R. Mardis, Aaron McKenna, Rohini Raman, Robert Sfeir, Mark Sherman, Andrew Crenshaw, J. Zachary Sanborn, Spring Yingchun Liu, Yuan Qing Wu, Jane Peterson, Eric E. Snyder, Lisa Iype, John N. Weinstein, Helga Thorvaldsdottir, Adam J. Bass, Dominik Stoll, Brady Bernard, Steven J.M. Jones, Peter Dolina, Julie M. Gastier-Foster, Jared R. Slobodan, Mark A. Jensen, Jacqueline E. Schein, Christie Kovar, Anders Jacobsen, Stephen C. Benz, J. Todd Auman, Juinhua Zhang, Peter Fielding, Paul T. Spellman, Jacqueline D. Palchik, Jay Bowen, Thomas Zeng, Douglas Voet, Arnulf Dörner, Joshua M. Stuart, Ryan Demeter, Theodore C. Goldstein, Keith A. Baggerly, Jorma J. de Ronde, Deepak Srinivasan, Boris Reva, Robert E. Pyatt, Andrew Kaufman, Timothy A. Chan, Alexei Protopopov, William G. Richards, Daniel R. Zerbino, Brenda Ayala, Martin R. Weiser, Psalm Haseley, Margaret Morgan, Mary Iacocca, Thomas Robinson, Chad J. Creighton, Dominique L. Berton, Da Yang, Peng Chieh Chen, Carl F. Schaefer, Peter White, Fred Denstman, Giovanni Ciriello, Matthew N. Bainbridge, Heidi J. Sofia, Irene Newsham, Jill P. Mesirov, Ling Li, Benjamin P. Berman, Daniel J. Weisenberger, Garrett M. Nash, Jason Walker, Nina Thiessen, Narayanan Sathiamoorthy, James A. Robinson, Petar Stojanov, Todd Wylie, Derek Y. Chiang, Kristin G. Ardlie, Jianjiong Gao, Lisa Wise, Bradley A. Ozenberger, Jeffrey G. Reid, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Eric Chuah, Richard Varhol, Lisa R. Trevino, Charles J. Vaske, Ying Du, Arthur P. Goldberg, Rui Jing, Jon Whitmore, Joan Pontius, Yevgeniy Antipin, Kyle Ellrott, Nilsa C. Ramirez, Tom Bodenheimer, Junyuan Wu, Lynda Chin, Scott L. Carter, Hailei Zhang, Ryan Bressler, Adam Norberg, Stacey Gabriel, Martha Hatfield, Jonathan G. Seidman, Corbin D. Jones, Huyen Dinh, D. Neil Hayes, Christine Czerwinski, Gerald R. Fowler, Mark S. Guyer, Robert Penny, Alan P. Hoyle, Hartmut Juhl, Catrina Fronick, Margi Sheth, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Toshinori Hinoue, Yaron S.N. Butterfield, Andrew D. Cherniack, Maria C. Mariano, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Gary Witkin, Andrey Sivachenko, David Pot, Michael J. Zinner, Richard Thorp, Jan F. Prins, Eunjung Lee, A. Gordon Robertson, Wendy Winckler, Efsevia Vakiani, Chris Wakefield, Alex H. Ramos, Semin Lee, Zhining Wang, Sam Ng, Lihua Zhou, Christina Liquori, Rileen Sinha, Dennis T. Maglinte, Michael S. Noble, Haiyan I. Li, B. Arman Aksoy, Preethi H. Gunaratne, Michael Meyers, Daniel C. Koboldt, Lawrence A. Donehower, Darlene Lee, Jake Lin, Gary K. Scott, Hye Jung E. Chun, Sheila Reynolds, Anna L. Chu, Rehan Akbani, Todd Pihl, Ruibin Xi, Charles S. Fuchs, Nianxiang Zhang, Stanley R. Hamilton, Bradley M. Broom, Wei Zhang, Chris Sander, Marc Danie Nazaire, Carrie Hirst, Stephen B. Baylin, Joel E. Tepper, Kyle Chang, Miruna Balasundaram, Jen Brown, Yan Shi, Matthew G. Soloway, Richard A. Gibbs, Richard K. Wilson, Peter J. Park, Zhaoshi Zeng, John A. Demchok, Jesse Walsh, Rashmi N. Sanbhadti, Troy Shelton, Lixing Yang, Prachi Kothiyal, Monica M. Bertagnolli, Sean P. Barletta, Kristian Cibulskis, Yidi J. Turman, Nikolaus Schultz, Min Wang, Shelley Alonso, Carsten Zornig, P. Paty, Elizabeth J. Thomson, Peter A. Kigonya, Fei Pan, Yuexin Liu, Matthew Meyerson, Kenna R. Mills Shaw, Nam Pho, Stuart R. Jefferys, Daniel DiCara, Robert C. Onofrio, Erin Pleasance, Eric S. Lander, David J. Dooling, Christina Yau, Michael D. Topal, David B. Solit, Christopher Wilks, Ilya Shmulevich, Robin J.N. Coope, Ronglai Shen, Jose G. Guillem, R. Craig Cason, Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
DNA Copy Number Variations, Colorectal cancer, Biology, medicine.disease_cause, MLH1, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mutation Rate, microRNA, medicine, Humans, Exome, 030304 developmental biology, 0303 health sciences, Multidisciplinary, POLD1, Rectal Neoplasms, Gene Expression Profiling, Microsatellite instability, Sequence Analysis, DNA, DNA Methylation, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, DNA methylation, Colonic Neoplasms, Mutation, Cancer research, KRAS
Abstract

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression., National Institutes of Health (U.S.) (Grant U24CA143799), National Institutes of Health (U.S.) (Grant U24CA143835), National Institutes of Health (U.S.) (Grant U24CA143840), National Institutes of Health (U.S.) (Grant U24CA143843), National Institutes of Health (U.S.) (Grant U24CA143845), National Institutes of Health (U.S.) (Grant U24CA143848), National Institutes of Health (U.S.) (Grant U24CA143858), National Institutes of Health (U.S.) (Grant U24CA143866), National Institutes of Health (U.S.) (Grant U24CA143867), National Institutes of Health (U.S.) (Grant U24CA143882), National Institutes of Health (U.S.) (Grant U24CA143883), National Institutes of Health (U.S.) (Grant U24CA144025), National Institutes of Health (U.S.) (Grant U54HG003067), National Institutes of Health (U.S.) (Grant U54HG003079), National Institutes of Health (U.S.) (Grant U54HG003273)

Published
2011

16. Management of laryngopharyngeal reflux: an unmet medical need

Author

Dominik Stoll and Frank Zerbib

Subjects
medicine.medical_specialty, Esophageal pH Monitoring, medicine.diagnostic_test, Laryngoscopy, Endocrine and Autonomic Systems, Physiology, business.industry, Gastroenterology, Reflux, Placebo, medicine.disease, Endoscopy, Laryngopharyngeal reflux, Internal medicine, medicine, Laryngopharyngeal Reflux, Humans, Esophageal pH monitoring, business
Abstract

Laryngopharyngeal reflux (LPR) is defined by the association of laryngeal symptoms with laryngeal inflammation at laryngoscopy. However, these symptoms are difficult to characterize and the laryngoscopic signs lack specificity. Moreover, to date, the diagnosis of LPR can rely neither on esophageal investigations (endoscopy, pH/impedance monitoring) nor on response to high dose proton pump inhibitors because of a high placebo effect. Therefore, there is a need for the development of new tools which may help to better identify the subgroup of patients with laryngeal symptoms related to supra-esophageal reflux.

Published
2010

17. The structure and characterization of a modular endo-beta-1,4-mannanase from Cellulomonas fimi

Author

Leila Lo Leggio, Dominik Stoll, Jérôme Le Nours, Henrik Stålbrand, and Lars Anderson

Subjects
chemistry.chemical_classification, Models, Molecular, Chemistry, Stereochemistry, Molecular Sequence Data, Oligosaccharides, Oligosaccharide, Crystallography, X-Ray, Biochemistry, Cell wall, Hydrolysis, Enzyme, Polysaccharides, Hydrolase, Mannosidases, Molecular replacement, Amino Acid Sequence, Linker, Sequence Alignment, Trisaccharides, Mannan, Cellulomonas
Abstract

The endo-beta-1,4-mannanase from the soil bacterium Cellulomonas fimi is a modular plant cell wall degrading enzyme involved in the hydrolysis of the backbone of mannan, one of the most abundant polysaccharides of the hemicellulosic network in the plant cell wall. The crystal structure of a recombinant truncated endo-beta-1,4-mannanase from C. fimi (CfMan26A-50K) was determined by X-ray crystallography to 2.25 A resolution using the molecular replacement technique. The overall structure of the enzyme consists of a core (beta/alpha)8-barrel catalytic module characteristic of clan GH-A, connected via a linker to an immunoglobulin-like module of unknown function. A complex with the oligosaccharide mannotriose to 2.9 A resolution has also been obtained. Both the native structure and the complex show a cacodylate ion bound at the -1 subsite, while subsites -2, -3, and -4 are occupied by mannotriose in the complex. Enzyme kinetic analysis and the analysis of hydrolysis products from manno-oligosaccharides and mannopentitol suggest five important active-site cleft subsites. CfMan26A-50K has a high affinity -3 subsite with Phe325 as an aromatic platform, which explains the mannose releasing property of the enzyme. Structural differences with the homologous Cellvibrio japonicus beta-1,4-mannanase (CjMan26A) at the -2 and -3 subsites may explain the poor performance of CfMan26A mutants as "glycosynthases".

Published
2005

18. Mapping of genes encoding glycoside hydrolases on the chromosome of Cellulomonas fimi

Author

Dominik Stoll

Subjects
DNA, Bacterial, Cellulomonas fimi, Glycoside Hydrolases, Immunology, HindIII, Applied Microbiology and Biotechnology, Microbiology, Chromosomes, Actinomycetales, Genetics, Pulsed-field gel electrophoresis, Glycoside hydrolase, Molecular Biology, Gene, biology, Models, Genetic, Chromosome, General Medicine, DNA Restriction Enzymes, Physical Chromosome Mapping, Molecular biology, genomic DNA, Blotting, Southern, biology.protein, Plasmids
Abstract

Cellulomonas fimi genomic DNA was digested with HpaI, MunI, HindIII, and NsiI, producing fragments ranging in size from 20 to 1400 kbp that were resolved by pulsed field gel electrophoresis. Genetic and physical linkages were determined by Southern blotting and were used to construct a genome map. Cellulomonas fimi has a single circular chromosome of approx. 4000 kbp. Except for two closely linked genes, cbh6A and cel5A, the genes known to encode glycoside hydrolases are scattered widely on the chromosome.Key words: Cellulomonas fimi, genome map, pulsed field gel electrophoresis, glycoside hydrolases.

Published
2002

19. Analysis of an Urban Grid with High Photovoltaic and e-Mobility Penetration

Author

Florian Maurer, Christian Rieke, Ralf Schemm, and Dominik Stollenwerk

Subjects
e-mobility, smart-charging, distribution grid simulation, Technology
Abstract

This study analyses the expected utilization of an urban distribution grid under high penetration of photovoltaic and e-mobility with charging infrastructure on a residential level. The grid utilization and the corresponding power flow are evaluated, while varying the control strategies and photovoltaic installed capacity in different scenarios. Four scenarios are used to analyze the impact of e-mobility. The individual mobility demand is modelled based on the largest German studies on mobility “Mobilität in Deutschland”, which is carried out every 5 years. To estimate the ramp-up of photovoltaic generation, a potential analysis of the roof surfaces in the supply area is carried out via an evaluation of an open solar potential study. The photovoltaic feed-in time series is derived individually for each installed system in a resolution of 15 min. The residential consumption is estimated using historical smart meter data, which are collected in London between 2012 and 2014. For a realistic charging demand, each residential household decides daily on the state of charge if their vehicle requires to be charged. The resulting charging time series depends on the underlying behavior scenario. Market prices and mobility demand are therefore used as scenario input parameters for a utility function based on the current state of charge to model individual behavior. The aggregated electricity demand is the starting point of the power flow calculation. The evaluation is carried out for an urban region with approximately 3100 residents. The analysis shows that increased penetration of photovoltaics combined with a flexible and adaptive charging strategy can maximize PV usage and reduce the need for congestion-related intervention by the grid operator by reducing the amount of kWh charged from the grid by 30% which reduces the average price of a charged kWh by 35% to 14 ct/kWh from 21.8 ct/kWh without PV optimization. The resulting grid congestions are managed by implementing an intelligent price or control signal. The analysis took place using data from a real German grid with 10 subgrids. The entire software can be adapted for the analysis of different distribution grids and is publicly available as an open-source software library on GitHub.

Published
2023
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20. ChemInform Abstract: β-Mannosynthase: Synthesis of β-Mannosides with a Mutant β-Mannosidase

Author

Stephen G. Withers, Dominik Stoll, David L. Zechel, Oyekanmi Nashiru, Taraneh Mohammadzadeh, and R. Antony J. Warren

Subjects
chemistry.chemical_classification, Mannosides, Stereochemistry, Mutant, General Medicine, Glutamic acid, carbohydrates (lipids), Serine, chemistry.chemical_compound, Residue (chemistry), Enzyme, chemistry, Nucleophile, Fluoride
Abstract

Engineering enzymes: The glutamic acid nucleophile of a retaining β-mannosidase has been replaced with a serine residue to form a β-mannosynthase. When the new enzyme is provided with an α-mannosyl fluoride donor and an appropriate acceptor, β-mannoside linkages are synthesized. Remarkably, α-mannosyl fluoride can be generated in situ by providing the mannosynthase with excess fluoride ion.

Published
2001
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22. β-Mannosynthase: Synthesis of β-Mannosides with a Mutant β-Mannosidase

Author

Oyekanmi, Nashiru, David L, Zechel, Dominik, Stoll, Taraneh, Mohammadzadeh, R Antony J, Warren, and Stephen G, Withers

Abstract

Engineering enzymes: The glutamic acid nucleophile of a retaining β-mannosidase has been replaced with a serine residue to form a β-mannosynthase. When the new enzyme is provided with an α-mannosyl fluoride donor and an appropriate acceptor, β-mannoside linkages are synthesized. Remarkably, α-mannosyl fluoride can be generated in situ by providing the mannosynthase with excess fluoride ion.

Published
2000

23. Mannanase Man26A from Cellulomonas fimi has a mannan-binding module

Author

Alisdair B. Boraston, Douglas G. Kilburn, Bradley W. McLean, R. Anthony J. Warren, Henrik Stålbrand, and Dominik Stoll

Subjects
animal structures, Molecular Sequence Data, chemical and pharmacologic phenomena, Biology, Microbiology, Mannans, chemistry.chemical_compound, Chitin, Mannosidases, Genetics, Amino Acid Sequence, Cellulose, Binding site, Molecular Biology, Mannan, Binding Sites, Base Sequence, Cellulomonadaceae, Mannan binding, beta-Mannosidase, bacterial infections and mycoses, biology.organism_classification, Xylan, carbohydrates (lipids), Bacteria, Aerobic, chemistry, Biochemistry, Locust bean gum
Abstract

A modular mannanase (Man26A) from the bacterium Cellulomonas fimi contains a mannan-binding module (Man26Abm) that binds to soluble but not to insoluble mannans. Man26Abm does not bind to cellulose, chitin or xylan. The K(d) for binding of Man26Abm to locust bean gum (LBG) is approximately 0.2 microM. Man26A is the first mannanase reported to contain a mannan-binding module.

Published
2000

24. Mannan-Degrading Enzymes from Cellulomonas fimi

Author

R. Antony J. Warren, Dominik Stoll, and Henrik Stålbrand

Subjects
DNA, Bacterial, medicine.medical_treatment, Molecular Sequence Data, Biology, Gram-Positive Asporogenous Rods, medicine.disease_cause, Applied Microbiology and Biotechnology, Microbiology, Mannans, Mannosidases, medicine, Escherichia coli, Glycoside hydrolase, Amino Acid Sequence, Enzymology and Protein Engineering, Peptide sequence, Mannan, Gene Library, chemistry.chemical_classification, Protease, Ecology, Beta-mannosidase, Cellulomonadaceae, beta-Mannosidase, Sequence Analysis, DNA, biology.organism_classification, Enzyme, chemistry, Biochemistry, Food Science, Biotechnology
Abstract

The genes man26a and man2A from Cellulomonas fimi encode mannanase 26A (Man26A) and β-mannosidase 2A (Man2A), respectively. Mature Man26A is a secreted, modular protein of 951 amino acids, comprising a catalytic module in family 26 of glycosyl hydrolases, an S-layer homology module, and two modules of unknown function. Exposure of Man26A produced by Escherichia coli to C. fimi protease generates active fragments of the enzyme that correspond to polypeptides with mannanase activity produced by C. fimi during growth on mannans, indicating that it may be the only mannanase produced by the organism. A significant fraction of the Man26A produced by C. fimi remains cell associated. Man2A is an intracellular enzyme comprising a catalytic module in a subfamily of family 2 of the glycosyl hydrolases that at present contains only mammalian β-mannosidases.

Published
1999

25. Enzymatic Synthesis of Carbon−Fluorine Bonds

Author

Stephen P. Reid, Stephen G. Withers, Oyekanmi Nashiru, Christoph Mayer, David L. Jakeman, David L. Zechel, R. A. J. Warren, and Dominik Stoll

Subjects
Azides, Magnetic Resonance Spectroscopy, Kinetics, Fluorinase, Biochemistry, Catalysis, Colloid and Surface Chemistry, Glucosides, Mannosidases, Carbon–fluorine bond, Nitrobenzenes, biology, Chemistry, beta-Glucosidase, Carbon chemistry, beta-Mannosidase, Fluorine, General Chemistry, Nuclear magnetic resonance spectroscopy, Enzymatic synthesis, Combinatorial chemistry, Carbon, Mannosides, Mutation, Mutation (genetic algorithm), biology.protein
Published
2001
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27. Comprehensive molecular portraits of human breast tumours

Author

Julie M. Gastier-Foster, Nguyen Van Bang, Christopher Szeto, Daoud Meerzaman, Nguyen Viet Tien, Richard K. Wilson, Jennifer Brown, Singer Ma, Andrew H. Beck, Sam Ng, Phillip H. Lai, Peter J. Park, Khurram Z. Khan, Gordon B. Mills, Joel S. Parker, Li Ding, Ying Hu, Jill P. Mesirov, Rebecca Carlsen, Kevin P. White, Benjamin P. Berman, Michael C. Adams, Laura A.L. Dillon, Jake Lin, Giovanni Ciriello, Simeen Malik, Moiz S. Bootwalla, Sheila Reynolds, Petar Stojanov, B. Arman Aksoy, Jerry Usary, Mei Huang, Andrzej Mackiewicz, Prachi Kothiyal, Keith A. Baggerly, Hann Hsiang Chao, Timo Erkkilä, Elaine R. Mardis, Nils Gehlenborg, Bradley M. Broom, Tara M. Lichtenberg, Jeff Gentry, Payal Sipahimalani, Chris Wakefield, Zhining Wang, Anna Chu, Konstanty Korski, Michael S. Noble, Lawrence A. Donehower, Pavana Anur, Janita Thusberg, Rohit Bhargava, Chris Sander, Lori Boice, Juok Cho, Charles Saller, Sophie C. Egea, Marc Danie Nazaire, Heather Schmidt, Bui Duc Phu, Hye Jung E. Chun, Bradley A. Ozenberger, Robert S. Fulton, Carrie Hirst, Stephen B. Baylin, Miruna Balasundaram, Peter White, Fergus J. Couch, Saianand Balu, Christina Yau, Yevgeniy Antipin, Jacek J. Brzeziński, Rehan Akbani, Todd Pihl, Ari B. Kahn, Nianxiang Zhang, Sean P. Barletta, Mary Iacocca, Kelly Daily, Wiam Bshara, Marc Ladanyi, Michael D. Topal, Huy Nguyen, Theodore C. Goldstein, Tari A. King, Bernard Kohl, Jingchun Zhu, Wiktoria Maria Suchorska, Xuan Van Le, Wei Zhang, Yan Shi, Marta Bogusz-Czerniewicz, Barry S. Taylor, Li-Wei Chang, Matthew C. Nicholls, Julien Baboud, Honorata Tatka, Doug Voet, Vesteinn Thorsson, Richard W. Park, Aaron D. Black, Pawel Murawa, Leonid Kvecher, Raju Kucherlapati, Colleen Mitchell, Wei Zhao, Leigh B. Thorne, Artem Sokolov, Modesto Patangan, Yidi J. Turman, Teresa R. Tabler, Kyle Ellrott, Yaron S.N. Butterfield, Gordon Saksena, Ronglai Shen, Yaqin Chen, Olga Voronina, Candace Carter, Yiling Lu, Cynthia McAllister, Thomas Stricker, Chunqing Luo, Dominique L. Berton, Thomas Barr, Robert A. Holt, Christopher Wilks, David Van Den Berg, Robert Sfeir, Ilya Shmulevich, Ranabir Guin, Nilsa C. Ramirez, Hollie A. Harper, John A. Demchok, Matthew J. Ellis, David Haussler, Katherine A. Hoadley, Eric Chuah, Richard J. Mural, Charles M. Perou, Timothy J. Triche, Steven J.M. Jones, Mark A. Jensen, Jeffrey R. Marks, Hanna Perz, Rashmi N. Sanbhadti, Robin J.N. Coope, Brian Craft, Andy Chu, Peter W. Laird, Eric E. Snyder, Chunhua Yan, Martin L. Ferguson, Junyuan Wu, Richard Varhol, Daniel J. Weisenberger, Yongjun Zhao, Ewa Leporowska, Ashley Hill, Katie Tarvin, M. Teresiak, David Pot, Nguyen Phi Hung, Helga Thorvaldsdottir, Erik Zmuda, Spring Yingchun Liu, Melissa Hart-Kothari, Joshua M. Stuart, Caroline Larson, Erin Pleasance, Nikolaus Schultz, Matthew Ibbs, Hubert Stoppler, Joelle Kalicki-Veizer, Andrey Sivachenko, Christopher C. Benz, Dawid Murawa, Swapna Mahurkar, Nicholas J. Petrelli, Lynda Chin, Juinhua Zhang, Pei Lin, Michael Mayo, Wilma L. Lingle, Julian Malicki, Robin Brookens, Ethan Cerami, Angela Tam, Shelley Alonso, Carmelo Gaudioso, Dominik Stoll, Anders Jacobsen, Stephen C. Benz, Mark S. Guyer, Wendy Winckler, Roel R.G. Verhaak, Chang-Jiun Wu, Raktim Sinha, Xiaping He, Nina Thiessen, Craig D. Shriver, Kenna R. Mills Shaw, Heidi J. Sofia, Martin Hirst, Stuart R. Jefferys, Robert Penny, Adam Brufsky, Kristen M. Leraas, Joshua F. McMichael, Brenda Rabeno, Inanc Birol, David J. Dooling, Peggy Yena, Richard A. Moore, Andrew D. Cherniack, Lucinda Fulton, Jessica K. Booker, Lihua Zou, Rileen Sinha, Michael D. Iglesia, Dennis T. Maglinte, Rohini Raman, Evan O. Paull, Rameen Beroukhim, Oleg Dolzhansky, Grace O. Silva, Jiashan Zhang, Witold Kycler, Janae V. Simons, Anisha Gulabani, Michael S. Lawrence, Peter Fielding, Huynh Quyet Thang, Peter A. Kigonya, Myra M. George, Jay Bowen, Haiyan I. Li, Robert E. Pyatt, Margi Sheth, Stacey Gabriel, Ana M. Gonzalez-Angulo, Hui Shen, Andrew J. Mungall, Carmen Gomez-Fernandez, Liming Yang, Hai Hu, Radoslaw Łaźniak, Olufunmilayo I. Olopade, Christine Czerwinski, Richard A. Hajek, Michael D. McLellan, Arash Shafiei, Matthew Meyerson, Gad Getz, Stanley Girshik, Cheng Fan, Shuying Liu, Olga Potapova, Alan P. Hoyle, Mia Grifford, Daniel C. Koboldt, Jacqueline D. Palchik, Jessica Walton, Greg Eley, Jamie Leigh Campbell, Thomas Zeng, Mikhail Abramov, Benjamin Gross, Brenda Deyarmin, Maciej Wiznerowicz, Natasja Wye, Ron Bose, Darlene Lee, Carl Morrison, Albert J. Kovatich, Andrew Crenshaw, Jessica Frick, John N. Weinstein, Adrian Ally, Nam H. Pho, Brady Bernard, Scott L. Carter, Gary K. Scott, Steven E. Schumacher, Barbara Tabak, D. Neil Hayes, Robert C. Onofrio, Sean D. Mooney, Mary D. Dyer, Mark Gerken, Erin Curley, Rajiv Dhir, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Kevin R. Coombes, Richard Thorp, George E. Sandusky, A. Gordon Robertson, Marco A. Marra, Roy Tarnuzzer, Mark Backus, Aleix Prat, Kristin G. Ardlie, Daniel Di Cara, Richard Kreisberg, Kenneth H. Buetow, Jacqueline E. Schein, J. Todd Auman, Jianjiong Gao, Lisa Wise, Ling Li, James A. Robinson, Jonathan S. Berg, Tod D. Casasent, James N. Ingle, Brenda Ayala, Xiaolong Meng, Boris Reva, Rui Jing, Mark D. Pegram, Arkadiusz Spychała, Joan Pontius, Jeffrey A. Hooke, Daniel E. Carlin, Nils Weinhold, Jared R. Slobodan, Tom Bodenheimer, Wenbin Liu, Christopher K. Wong, W. Kimryn Rathmell, David Mallery, Paul T. Spellman, Hailei Zhang, Ryan Bressler, Deepak Srinivasan, Lisle E. Mose, Bryan Hernandez, Stella Somiari, Chad J. Creighton, Howard H. Sussman, Frederic Waldman, Matthew G. Soloway, and Universitat de Barcelona

Subjects
Proteomics, Oncologia, DNA Mutational Analysis, Genes, BRCA1, Retinoblastoma Protein, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Breast cancer, Exome, RNA, Neoplasm, Exome sequencing, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Genetics, 0303 health sciences, Multidisciplinary, Triple Negative Breast Neoplasms, Genomics, 3. Good health, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Oncology, 030220 oncology & carcinogenesis, Female, DNA Copy Number Variations, Class I Phosphatidylinositol 3-Kinases, Protein Array Analysis, MAP Kinase Kinase Kinase 1, Breast Neoplasms, GATA3 Transcription Factor, Biology, Article, Càncer de mama, Genetic Heterogeneity, 03 medical and health sciences, medicine, Humans, RNA, Messenger, 030304 developmental biology, MicroRNA sequencing, Genome, Human, Genetic heterogeneity, Gene Expression Profiling, Cancer, DNA Methylation, Genes, erbB-2, Genes, p53, medicine.disease, Claudin-Low, Expressió gènica, MicroRNAs, Genòmica, Mutation, Gene expression, Genes, Neoplasm
Abstract

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

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