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2. Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis

Author

Vaishnavi, Aria, Juan, Joseph, Jacob, Maebh, Stehn, Christopher, Gardner, Eric E, Scherzer, Michael T, Schuman, Sophia, van Veen, J Edward, Murphy, Brandon, Hackett, Christopher S, Dupuy, Adam J, Chmura, Steve A, van der Weyden, Louise, Newberg, Justin Y, Liu, Annie, Mann, Karen, Rust, Alistair G, Weiss, William A, Kinsey, Conan G, Adams, David J, Grossmann, Allie, Mann, Michael B, and McMahon, Martin

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Lung, Rare Diseases, Genetics, Lung Cancer, Cancer, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Animals, Humans, Mice, Adenocarcinoma of Lung, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Lung Neoplasms, Mutagenesis, Proto-Oncogene Proteins B-raf, RNA-Binding Proteins, Trans-Activators, Wnt Signaling Pathway, Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/β-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non-small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression.SignificanceLoss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.

Published
2022

3. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer

Author

Westcott, Peter MK, Halliwill, Kyle D, To, Minh D, Rashid, Mamunur, Rust, Alistair G, Keane, Thomas M, Delrosario, Reyno, Jen, Kuang-Yu, Gurley, Kay E, Kemp, Christopher J, Fredlund, Erik, Quigley, David A, Adams, David J, and Balmain, Allan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Cancer, Genetics, Lung, Lung Cancer, 2.1 Biological and endogenous factors, Aetiology, 2.2 Factors relating to the physical environment, Adenocarcinoma, Animals, Carcinogens, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, DNA Copy Number Variations, Disease Progression, Female, Genes, ras, Genomic Instability, Germ-Line Mutation, Humans, Lung Neoplasms, Male, Methylnitrosourea, Mice, Models, Genetic, Mutation, Oncogene Protein p21(ras), Point Mutation, Proto-Oncogene Proteins p21(ras), Urethane, General Science & Technology
Abstract

Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.

Published
2015

4. Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Published
2019
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7. Supplementary Data from Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis

Author

Vaishnavi, Aria, primary, Juan, Joseph, primary, Jacob, Maebh, primary, Stehn, Christopher, primary, Gardner, Eric E., primary, Scherzer, Michael T., primary, Schuman, Sophia, primary, Van Veen, J. Edward, primary, Murphy, Brandon, primary, Hackett, Christopher S., primary, Dupuy, Adam J., primary, Chmura, Steven A., primary, van der Weyden, Louise, primary, Newberg, Justin Y., primary, Liu, Annie, primary, Mann, Karen, primary, Rust, Alistair G., primary, Weiss, William A., primary, Kinsey, Conan G., primary, Adams, David J., primary, Grossmann, Allie, primary, Mann, Michael B., primary, and McMahon, Martin, primary

Published
2023
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8. Data from Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis

Author

Vaishnavi, Aria, primary, Juan, Joseph, primary, Jacob, Maebh, primary, Stehn, Christopher, primary, Gardner, Eric E., primary, Scherzer, Michael T., primary, Schuman, Sophia, primary, Van Veen, J. Edward, primary, Murphy, Brandon, primary, Hackett, Christopher S., primary, Dupuy, Adam J., primary, Chmura, Steven A., primary, van der Weyden, Louise, primary, Newberg, Justin Y., primary, Liu, Annie, primary, Mann, Karen, primary, Rust, Alistair G., primary, Weiss, William A., primary, Kinsey, Conan G., primary, Adams, David J., primary, Grossmann, Allie, primary, Mann, Michael B., primary, and McMahon, Martin, primary

Published
2023
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12. Supplementary Tables 1-5 from Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach

Author

Mattison, Jenny, primary, Kool, Jaap, primary, Uren, Anthony G., primary, de Ridder, Jeroen, primary, Wessels, Lodewyk, primary, Jonkers, Jos, primary, Bignell, Graham R., primary, Butler, Adam, primary, Rust, Alistair G., primary, Brosch, Markus, primary, Wilson, Catherine H., primary, van der Weyden, Louise, primary, Largaespada, David A., primary, Stratton, Michael R., primary, Futreal, P. Andy, primary, van Lohuizen, Maarten, primary, Berns, Anton, primary, Collier, Lara S., primary, Hubbard, Tim, primary, and Adams, David J., primary

Published
2023
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14. Supplementary Table 7 from Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach

Author

Mattison, Jenny, primary, Kool, Jaap, primary, Uren, Anthony G., primary, de Ridder, Jeroen, primary, Wessels, Lodewyk, primary, Jonkers, Jos, primary, Bignell, Graham R., primary, Butler, Adam, primary, Rust, Alistair G., primary, Brosch, Markus, primary, Wilson, Catherine H., primary, van der Weyden, Louise, primary, Largaespada, David A., primary, Stratton, Michael R., primary, Futreal, P. Andy, primary, van Lohuizen, Maarten, primary, Berns, Anton, primary, Collier, Lara S., primary, Hubbard, Tim, primary, and Adams, David J., primary

Published
2023
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17. Supplementary Methods from Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach

Author

Mattison, Jenny, primary, Kool, Jaap, primary, Uren, Anthony G., primary, de Ridder, Jeroen, primary, Wessels, Lodewyk, primary, Jonkers, Jos, primary, Bignell, Graham R., primary, Butler, Adam, primary, Rust, Alistair G., primary, Brosch, Markus, primary, Wilson, Catherine H., primary, van der Weyden, Louise, primary, Largaespada, David A., primary, Stratton, Michael R., primary, Futreal, P. Andy, primary, van Lohuizen, Maarten, primary, Berns, Anton, primary, Collier, Lara S., primary, Hubbard, Tim, primary, and Adams, David J., primary

Published
2023
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19. Data from Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach

Author

Mattison, Jenny, primary, Kool, Jaap, primary, Uren, Anthony G., primary, de Ridder, Jeroen, primary, Wessels, Lodewyk, primary, Jonkers, Jos, primary, Bignell, Graham R., primary, Butler, Adam, primary, Rust, Alistair G., primary, Brosch, Markus, primary, Wilson, Catherine H., primary, van der Weyden, Louise, primary, Largaespada, David A., primary, Stratton, Michael R., primary, Futreal, P. Andy, primary, van Lohuizen, Maarten, primary, Berns, Anton, primary, Collier, Lara S., primary, Hubbard, Tim, primary, and Adams, David J., primary

Published
2023
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20. Supplementary Table 6 from Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach

Author

Mattison, Jenny, primary, Kool, Jaap, primary, Uren, Anthony G., primary, de Ridder, Jeroen, primary, Wessels, Lodewyk, primary, Jonkers, Jos, primary, Bignell, Graham R., primary, Butler, Adam, primary, Rust, Alistair G., primary, Brosch, Markus, primary, Wilson, Catherine H., primary, van der Weyden, Louise, primary, Largaespada, David A., primary, Stratton, Michael R., primary, Futreal, P. Andy, primary, van Lohuizen, Maarten, primary, Berns, Anton, primary, Collier, Lara S., primary, Hubbard, Tim, primary, and Adams, David J., primary

Published
2023
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22. A Genomic Regulatory Network for Development

Author

Davidson, Eric H., Rast, Jonathan P., Oliveri, Paola, Ransick, Andrew, Calestani, Cristina, Yuh, Chiou-Hwa, Minokawa, Takuya, Amore, Gabriele, Hinman, Veronica, Arenas-Mena, César, Otim, Ochan, Brown, C. Titus, Livi, Carolina B., Lee, Pei Yun, Revilla, Roger, Rust, Alistair G., Pan, Zheng jun, Schilstra, Maria J., Arnone, Maria I., Rowen, Lee, Cameron, R. Andrew, McClay, David R., Hood, Leroy, and Bolouri, Hamid

Published
2002

28. Mutational Genomics for Cancer Pathway Discovery

Author

de Ridder, Jeroen, Kool, Jaap, Uren, Anthony G., Bot, Jan, de Jong, Johann, Rust, Alistair G., Berns, Anton, van Lohuizen, Maarten, Adams, David J., Wessels, Lodewyk, Reinders, Marcel, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Istrail, Sorin, editor, Pevzner, Pavel, editor, Waterman, Michael S., editor, Ngom, Alioune, editor, Formenti, Enrico, editor, Hao, Jin-Kao, editor, Zhao, Xing-Ming, editor, and van Laarhoven, Twan, editor

Published
2013
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30. Improving Transcription Factor Binding Site Predictions by Using Randomised Negative Examples

Author

Rezwan, Faisal, Sun, Yi, Davey, Neil, Adams, Rod, Rust, Alistair G., Robinson, Mark, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Lones, Michael A., editor, Smith, Stephen L., editor, Teichmann, Sarah, editor, Naef, Felix, editor, Walker, James A., editor, and Trefzer, Martin A., editor

Published
2012
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31. Effect of Using Varying Negative Examples in Transcription Factor Binding Site Predictions

Author

Rezwan, Faisal, Sun, Yi, Davey, Neil, Adams, Rod, Rust, Alistair G., Robinson, Mark, Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Nierstrasz, Oscar, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Sudan, Madhu, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Vardi, Moshe Y., Series editor, Weikum, Gerhard, Series editor, Pizzuti, Clara, editor, Ritchie, Marylyn D., editor, and Giacobini, Mario, editor

Published
2011
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33. Using Real-Valued Meta Classifiers to Integrate and Contextualize Binding Site Predictions

Author

Robinson, Mark, Sharabi, Offer, Sun, Yi, Adams, Rod, te Boekhorst, Rene, Rust, Alistair G., Davey, Neil, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Rangan, C. Pandu, editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Beliczynski, Bartlomiej, editor, Dzielinski, Andrzej, editor, Iwanowski, Marcin, editor, and Ribeiro, Bernardete, editor

Published
2007
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34. "Transposon Mutagenesis Reveals RBMS3 as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis."

Author

Vaishnavi, Aria, primary, Juan, Joseph, additional, Scherzer, Michael T, additional, VanVeen, J Edward, additional, Stehn, Christopher, additional, Hackett, Christopher S., additional, Dupuy, Adam, additional, Chmura, Steven A, additional, van der Weyden, Louise, additional, Newberg, Justin Y., additional, Mann, Karen M, additional, Liu, Annie, additional, Rust, Alistair G., additional, Weiss, William A., additional, Adams, David, additional, Grossman, Allie, additional, Mann, Michael B., additional, and McMahon, Martin, additional

Published
2022
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37. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Author

Australian Pancreatic Cancer Genome Initiative, Mann, Karen M., Ward, Jerrold M., Yew, Christopher Chin Kuan, Kovochich, Anne, Dawson, David W., Black, Michael A., Brett, Benjamin T., Sheetz, Todd E., Dupuy, Adam J., Chang, David K., Biankin, Andrew V., Waddell, Nicola, Kassahn, Karin S., Grimmond, Sean M., Rust, Alistair G., Adams, David J., Jenkins, Nancy A., and Copeland, Neal G.

Published
2012

38. Correction: Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Published
2019
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39. Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β

Author

Silk, Jonathan D., primary, Abbott, Rachel J. M., additional, Adams, Katherine J., additional, Bennett, Alan D., additional, Brett, Sara, additional, Cornforth, Terri V., additional, Crossland, Katherine L., additional, Figueroa, David J., additional, Jing, Junping, additional, O’Connor, Caitriona, additional, Pachnio, Annette, additional, Patasic, Lea, additional, Peredo, Carlos E., additional, Quattrini, Adriano, additional, Quinn, Laura L., additional, Rust, Alistair G., additional, Saini, Manoj, additional, Sanderson, Joseph P., additional, Steiner, Dylan, additional, Tavano, Barbara, additional, Viswanathan, Preetha, additional, Wiedermann, Guy E., additional, Wong, Ryan, additional, Jakobsen, Bent K., additional, Britten, Cedrik M., additional, Gerry, Andrew B., additional, and Brewer, Joanna E., additional

Published
2022
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43. Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Subjects
Pyridones, Correction, Drug Synergism, Azepines, Pyrimidinones, Triazoles, Xenograft Model Antitumor Assays, Colorectal cancer, Article, Gene Expression Regulation, Neoplastic, Organoids, Proto-Oncogene Proteins p21(ras), Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, Mutation, Cancer genomics, Animals, Humans, Female, Gene Regulatory Networks, Interferons, Colorectal Neoplasms
Abstract

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.

Published
2018

44. Generation of the Sotos syndrome deletion in mice

Author

Migdalska, Anna M., van der Weyden, Louise, Ismail, Ozama, Rust, Alistair G., Rashid, Mamunur, White, Jacqueline K., Sánchez-Andrade, Gabriela, Lupski, James R., Logan, Darren W., Arends, Mark J., Adams, David J., and The Sanger Mouse Genetics Project

Published
2012
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45. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses

Author

Litvak, Vladimir, Ratushny, Alexander V., Lampano, Aaron E., Schmitz, Frank, Huang, Albert C., Raman, Ayush, Rust, Alistair G., Bergthaler, Andreas, Aitchison, John D., and Aderem, Alan

Subjects
Interferon -- Physiological aspects -- Research, Genes -- Physiological aspects -- Research, Biological response modifiers -- Physiological aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses (1) and their transcription is [...]

Published
2012

46. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Author

Perez-Mancera, Pedro A., Rust, Alistair G., van der Weyden, Louise, Kristiansen, Glen, Li, Allen, Sarver, Aaron L., Silverstein, Kevin A.T., Grutzmann, Robert, Aust, Daniela, Rummele, Petra, Knosel, Thomas, Herd, Colin, Stemple, Derek L., Kettleborough, Ross, Brosnan, Jacqueline A., Li, Ang, Morgan, Richard, Knight, Spencer, Yu, Jun, Stegeman, Shane, Collier, Lara S., ten Hoeve, Jelle J., de Ridder, Jeroen, Klein, Alison P., Goggins, Michael, Hruban, Ralph H., Chang, David K., Biankin, Andrew V., Grimmond, Sean M., Wessels, Lodewyk F.A., Wood, Stephen A., Iacobuzio-Donahue, Christine A., Pilarsky, Christian, Largaespada, David A., Adams, David J., and Tuveson, David A.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations (1-4) in addition to numerous lower frequency genetic events of uncertain significance (5). Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis (6,7) in a mouse model of pancreatic ductal preneoplasia (8) to identify genes that cooperate with oncogenic [Kras.sup.G12D] to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia (9), we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with [Kras.sup.G12D] to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA., The biological sequelae of PDA has been partially attributed to frequent and well characterized mutations in KRAS (>90%), CDKN2A (>90%), TP53 (70%) and SMAD4 (55%) (1-4). Recent genomewide analyses have [...]

Published
2012
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49. Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers

Author

Khalique, Saira, Naidoo, Kalnisha, Attygalle, Ayoma D, Kriplani, Divya, Daley, Frances, Lowe, Anne, Campbell, James, Jones, Thomas, Hubank, Michael, Fenwick, Kerry, Matthews, Nicholas, Rust, Alistair G, Lord, Christopher J, Banerjee, Susana, and Natrajan, Rachael

Subjects
next generation sequencing, clear cell ovarian cancer, Genital Neoplasms, Female, Nuclear Proteins, Biomarker, Original Articles, ARID1A immunohistochemistry, Immunohistochemistry, DNA-Binding Proteins, Next generation sequencing, Mutation, biomarker, Humans, Clear cell ovarian cancer, Original Article, Female, Transcription Factors
Abstract

ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next‐generation sequencing. Three commercially available antibodies – EPR13501 (Abcam), D2A8U (Cell Signaling), and HPA005456 (Sigma) – were optimised for IHC using cell line models and human tissue, and screened across a cohort of 45 gynaecological tumours. IHC was scored independently by three pathologists using an immunoreactive score. ARID1A mutation status was assessed using two independent sequencing platforms and the concordance between ARID1A mutation and protein expression was evaluated using Receiver Operating Characteristic statistics. Overall, 21 ARID1A mutations were identified in 14/43 assessable tumours (33%), the majority of which were predicted to be deleterious. Mutations were identified in 6/17 (35%) ovarian clear cell carcinomas, 5/8 (63%) ovarian endometrioid carcinomas, 2/5 (40%) endometrial carcinomas, and 1/7 (14%) carcinosarcomas. ROC analysis identified greater than 95% concordance between mutation status and IHC using a modified immunoreactive score for all three antibodies allowing a definitive cut‐point for ARID1A mutant status to be calculated. Comprehensive assessment of concordance of ARID1A IHC and mutation status identified EPR13501 as an optimal antibody, with 100% concordance between ARID1A mutation status and protein expression, across different gynaecological histological subtypes. It delivered the best inter‐rater agreement between all pathologists, as well as a clear cost‐benefit advantage. This could allow patients to be accurately stratified based on their ARID1A IHC status into early phase clinical trials. Gynaecological Cancer Fund The Royal Marsden Cancer Charity Breast Cancer Now . Grant Numbers: PRJNA432413 , PRJNA432343 Cancer Research UK The Monument Trust NHS NIHR Royal Marsden Hospital Biomedical Research Centre NCBI Sequence Read Archive

Published
2018

50. Mutational Genomics for Cancer Pathway Discovery

Author

de Ridder, Jeroen, primary, Kool, Jaap, additional, Uren, Anthony G., additional, Bot, Jan, additional, de Jong, Johann, additional, Rust, Alistair G., additional, Berns, Anton, additional, van Lohuizen, Maarten, additional, Adams, David J., additional, Wessels, Lodewyk, additional, and Reinders, Marcel, additional

Published
2013
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