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1. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Author

Sven Mahner, Robertson Mackenzie, Aline Talhouk, Linda E. Kelemen, Gottfried E. Konecny, Jennifer Alsop, Rosalind Glasspool, Chiu-Chen Tseng, Joy Hendley, Dennis J. Slamon, Jennifer A. Doherty, Andrew Berchuck, Anna H. Wu, Anna M. Piskorz, Chen Wang, Cristina Rodríguez-Antona, D.G.H. de Silva, Valerie Rhenius, Peter A. Fasching, Stacey J. Winham, Gary L. Keeney, Teodora Goranova, Joshy George, Jan Lubinski, Michelle J. Henderson, Rex C. Bentley, Jenny Lester, Sabine Behrens, Joellen M. Schildkraut, Michael E. Carney, Timothy Budden, David G. Huntsman, Oleg Oszurek, Michael S. Anglesio, Jacek Gronwald, Ruby Yun-Ju Huang, Martin Köbel, Javier Benitez, Martin Widschwendter, Melissa C. Larson, Raghwa Sharma, Clara Bodelon, Usha Menon, Janusz Menkiszak, Blake Gilks, María Josefa Mosteiro García, Jesús García-Donas, Wafaa Elatre, Scott H. Kaufmann, Paul Haluska, Pamela J. Thompson, Boris Winterhoff, Susan J. Ramus, Louise A. Brinton, Simon A. Gayther, Mary Anne Rossing, Georgia Chenevix-Trench, Hugh Luk, Jolanta Lissowska, Marc T. Goodman, Billy Chen, Beth Y. Karlan, Naveena Singh, Sian Fereday, Mark E. Sherman, Ana Osorio, Lynne R. Wilkens, Maria P. Intermaggio, Brenda Y. Hernandez, Britton Trabert, Esther Herpel, Mercedes Jimenez-Linan, Janine Senz, Geyi Liu, Celeste Leigh Pearce, Samuel C Y Leong, Iain A. McNeish, Isabelle Ray-Coquard, Susana Banerjee, Malcolm C. Pike, Liz-Anne Lewsley, Helen Steed, Honglin Song, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Holly R. Harris, Tuan Zea Tan, Cezary Cybulski, Alicia Beeghly-Fadiel, A. Toloczko, Nikilyn Nevins, Robert S. Brown, Darren Ennis, Stephanie Chen, Euan A. Stronach, José Palacios, Sandra Orsulic, Anna deFazio, Geoff Macintyre, Kara L. Cushing-Haugen, Mila Volchek, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Paul D.P. Pharoah, Hanwei Sudderuddin, Stefan Kommoss, Derek S. Chiu, Huei San Leong, Peter Sinn, Catherine J. Kennedy, Chloe Karpinskyj, Alison Brand, Amy Lum, Veronica Chow, Nicolas Wentzensen, Tayyebeh M. Nazeran, Nadia Traficante, Dustin Johnson, Yoke-Eng Chiew, Casey S. Greene, Jennifer M Koziak, Renée T. Fortner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Talhouk, Aline [0000-0001-7760-410X], George, Joshy [0000-0001-8510-8229], Wang, Chen [0000-0003-2638-3081], Tan, Tuan Zea [0000-0001-6624-1593], Behrens, Sabine [0000-0002-9714-104X], Bodelon, Clara [0000-0002-6578-2678], Brinton, Louise [0000-0003-3853-8562], Fortner, Renée T [0000-0002-1426-8505], García-Donas, Jesús [0000-0001-7731-3601], Gentry-Maharaj, Aleksandra [0000-0001-7270-9762], Glasspool, Rosalind [0000-0002-5000-1680], Greene, Casey S [0000-0001-8713-9213], Harris, Holly R [0000-0002-2572-6727], Kaufmann, Scott H [0000-0002-4900-7145], Kennedy, Catherine J [0000-0002-4465-5784], Köbel, Martin [0000-0002-6615-2037], Koziak, Jennifer M [0000-0001-5830-0397], Lissowska, Jolanta [0000-0003-2695-5799], McNeish, Iain A [0000-0002-9387-7586], Menkiszak, Janusz [0000-0001-8279-7196], Hinsley, Samantha [0000-0001-6903-4688], Pike, Malcolm C [0000-0003-4891-1199], Rodriguez-Antona, Cristina [0000-0001-8750-7338], Sinn, Peter [0000-0003-2836-6699], Trabert, Britton [0000-0002-1539-6090], Widschwendter, Martin [0000-0002-7778-8380], Winham, Stacey J [0000-0002-8492-9102], Brenton, James D [0000-0002-5738-6683], Brown, Robert [0000-0001-7960-5755], Chang-Claude, Jenny [0000-0001-8919-1971], deFazio, Anna [0000-0003-0057-4744], Fasching, Peter A [0000-0003-4885-8471], Kelemen, Linda E [0000-0003-4362-9784], Menon, Usha [0000-0003-3708-1732], Pharoah, Paul DP [0000-0001-8494-732X], Ramus, Susan J [0000-0003-0005-7798], Doherty, Jennifer A [0000-0002-1454-8187], Anglesio, Michael S [0000-0003-1639-5003], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, Bevacizumab, 03 medical and health sciences, Ovarian tumor, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Ovarian carcinoma, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Stage (cooking), Aged, Ovarian Neoplasms, business.industry, Cystadenoma, Serous, Cancer, Middle Aged, Precision medicine, Omics, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Neoplasm Grading, Transcriptome, business, Algorithms, medicine.drug
Abstract

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Published
2020

2. Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

Author

Tuan Zea Tan, Srinivasaraghavan Kannan, Lingzhi Wang, Thi Bich Uyen Le, Richard Weijie Ong, Giridharan Periyasamy, Chandra S. Verma, Nur Afiqah Binte Mohamed Salleh, Jane Vin Chan, Li Ren Kong, David P. Lane, Matan Thangavelu Thangavelu, Chit Fang Cheok, Wee Joo Chng, Chwee Ming Lim, Lie Yong Judice Koh, Jieying Amelia Lau, Ashok R. Venkitaraman, Miyoung Lee, Boon Cher Goh, Kong, Li Ren [0000-0001-7980-4666], Tan, Tuan Zea [0000-0001-6624-1593], Kannan, Srinivasaraghavan [0000-0002-9539-5249], Lane, David P [0000-0003-0551-3545], Goh, Boon Cher [0000-0002-4107-102X], Apollo - University of Cambridge Repository, and Lane, David P. [0000-0003-0551-3545]

Subjects
0301 basic medicine, 82/29, Mutant, 96, 45/44, General Physics and Astronomy, Apoptosis, Mice, SCID, 13, Hydroxamic Acids, 14, 96/31, Epigenesis, Genetic, 13/2, 13/1, chemistry.chemical_compound, 0302 clinical medicine, Neoplasms, Histone methylation, Protein Isoforms, 14/19, lcsh:Science, 13/89, Regulation of gene expression, 45/70, Sulfonamides, Multidisciplinary, biology, Caspase 3, Chemistry, 82/79, High-throughput screening, NF-kappa B, Acetylation, Chromatin, Ubiquitin ligase, Gene Expression Regulation, Neoplastic, 631/67/1059/602, Gain of Function Mutation, 030220 oncology & carcinogenesis, 38/39, 64/60, Poly(ADP-ribose) Polymerases, Protein Binding, 631/80/82/23, 101, Ubiquitin-Protein Ligases, Science, Antineoplastic Agents, 13/109, Models, Biological, Article, General Biochemistry, Genetics and Molecular Biology, 38, 03 medical and health sciences, Targeted therapies, Cell Line, Tumor, Animals, Humans, 96/1, Nucleotide Motifs, Codon, Cell Proliferation, 49/15, General Chemistry, DNA-binding domain, Xenograft Model Antitumor Assays, 49, 030104 developmental biology, 13/51, Mutation, biology.protein, Cancer research, lcsh:Q, Mutant Proteins, 631/154/1435/2163, Cisplatin, Tumor Suppressor Protein p53, Topotecan, DNA
Abstract

Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically., Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling.

Published
2020

3. A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

Author

Soo Chin Lee, Srinivasaraghavan Kannan, Richard Weijie Ong, Min En Nga, Chandra S. Verma, Li Ren Kong, Joline S.J. Lim, Chee Wai Fhu, Tuan Zea Tan, Yiqing Huang, Yaw Chyn Lim, Boon Cher Goh, Daniel Shao-Weng Tan, Nur Afiqah Binte Mohamed Salleh, Dennis Kappei, Nicholas Syn, H. Phillip Koeffler, Seng Gee Lim, N. Gopalakrishna Iyer, Ross A. Soo, Benedict Yan, Robby Miguel Goh, Jingshan Ho, Kong, Li Ren [0000-0001-7980-4666], Tan, Tuan Zea [0000-0001-6624-1593], Syn, Nicholas L [0000-0002-6343-176X], Kannan, Srinivasaraghavan [0000-0002-9539-5249], Kappei, Dennis [0000-0002-3582-2253], Goh, Boon Cher [0000-0002-4107-102X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Lung Neoplasms, Receptor, ErbB-2, Cell, General Physics and Astronomy, Plasma protein binding, Mice, 0302 clinical medicine, Phosphorylation, Receptor, Head and neck cancer, skin and connective tissue diseases, lcsh:Science, Multidisciplinary, Proto-Oncogene Proteins c-met, Prognosis, Phenotype, Protein-protein interaction networks, medicine.anatomical_structure, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, RNA splicing, Carcinoma, Squamous Cell, Tyrosine kinase, Protein Binding, Signal Transduction, Science, Antineoplastic Agents, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Targeted therapies, Semaphorin, Cell Line, Tumor, medicine, Animals, Humans, Protein Interaction Domains and Motifs, Gene, Protein Kinase Inhibitors, neoplasms, Polymorphism, Genetic, General Chemistry, Xenograft Model Antitumor Assays, 030104 developmental biology, Mutation, Cancer research, Extracellular signalling molecules, lcsh:Q
Abstract

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies., The MET receptor is frequently activated in cancer. Here, the authors show that in head and neck and lung squamous carcinoma, a polymorphic MET variant enhances binding to HER2, resulting in activation of HER2 signalling and progression of the cancers.

Published
2020

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