19 results on '"Patrick Tomboc"'
Search Results
2. Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset
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Jiil, Chung, Logine, Negm, Vanessa, Bianchi, Lucie, Stengs, Anirban, Das, Zhihui Amy, Liu, Sumedha, Sudhaman, Melyssa, Aronson, Ledia, Brunga, Melissa, Edwards, Victoria, Forster, Martin, Komosa, Scott, Davidson, Jodi, Lees, Patrick, Tomboc, David, Samuel, Roula, Farah, Anne, Bendel, Jeffrey, Knipstein, Kami Wolfe, Schneider, Agnes, Reschke, Shayna, Zelcer, Alexandra, Zorzi, Robert, McWilliams, William D, Foulkes, Raymond, Bedgood, Lindsay, Peterson, Sara, Rhode, An, Van Damme, Isabelle, Scheers, Sharon, Gardner, Gabriel, Robbins, Magimairajan Issai, Vanan, M Stephen, Meyn, Rebecca, Auer, Brandie, Leach, Carol, Burke, Anita, Villani, David, Malkin, Eric, Bouffet, Annie, Huang, Michael D, Taylor, Carol, Durno, Adam, Shlien, Cynthia, Hawkins, Gad, Getz, Yosef E, Maruvka, Uri, Tabori, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Pediatrics, Brussels Heritage Lab, and Clinical sciences
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Brain Neoplasms/diagnosis ,Cancer Research ,Oncology ,Germ Cells/pathology ,genomics ,Microsatellite instability ,Humans ,Colorectal Neoplasms/diagnosis ,DNA Mismatch Repair/genetics ,Neoplastic Syndromes, Hereditary/diagnosis ,Microsatellite Repeats - Abstract
PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10−12), immunohistochemistry (86%, P = 4.6 × 10−3), or tumor mutational burden (80%, P = 9.1 × 10−4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10−5). CONCLUSION LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.
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- 2022
3. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
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Lee Yi Yen, Melyssa Aronson, Carol J. Swallow, Cynthia Hawkins, Lara Reichman, Rebecca C. Luiten, Sumita Roy, Michal Zapotocky, Patrick Tomboc, Christian Kratz, Michael Osborn, Junne Kamihara, Ayse Bahar Ercan, Jamie L. Maciaszek, Vanessa Bianchi, Benjamin Oshrine, Hagit N. Baris, Ossama M. Maher, Mohsin Rashid, Sara Rhode, Sharon Gardner, Annika Bronsema, David S. Ziegler, An Van Damme, Monica Newmark, Mithra Ghalibafian, Heather Hampel, Jordan R. Hansford, Vahid Fallah Azad, Michael P. Link, Simon C. Ling, Marc Remke, Shayna Zelcer, Deborah T. Blumenthal, Isabelle Scheers, Rebecca Loret De Mola, Syed Ahmer Hamid, Vanan MagimairajanIssai, Kim E. Nichols, Saunders Hsu, Catherine Goudie, Naureen Mushtaq, Ira Winer, Abeer Al-Battashi, Garth Nicholas, Roula Farah, Kami Wolfe Schneider, Rejin Kebudi, Jan Rapp, Gregory Thomas, Helen Toledano, Alvaro Lassaletta, Anne Bendel, Jeffrey Knipstein, Musa Alharbi, Gadi Abebe-Campino, Rose B. McGee, Anirban Das, Uri Tabori, Donald Basel, Alyssa Reddy, Melissa Edwards, Scott Lindhorst, Craig Harlos, Bailey Gallinger, Elizabeth Cairney, Anita Villani, Valerie Larouche, Rachel Pearlman, Maude Blundell, Gary Mason, David Sumerauer, Magnus Sabel, Aghiad Chamdin, Leslie Taylor, David Malkin, William D. Foulkes, Maura Massimino, Catherine Gilpin, Eric Bouffet, Miriam Bornhorst, Carol Durno, Enrico Opocher, Nobuko Hijiya, Zehavit Frenkel, David Samuel, Michal Lurye, Stefanie Zimmermann, Shani Caspi, Stefano Chiaravalli, David Gass, Eshetu G. Atenafu, Shlomi Constantini, Shay Ben-Shachar, Michal Yalon, Rina Dvir, Daniel Pettee, Bruce Crooks, Santanu Sen, Carl Koschmann, Raymond Bedgood, Theodore Nicolaides, Duncan Stearns, Yael Goldberg, Melissa Galati, Gabriel Robbins, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, and UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,MEDLINE ,DNA Mismatch Repair ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Neoplastic Syndromes, Hereditary ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Child ,Early Detection of Cancer ,Hematology ,Brain Neoplasms ,business.industry ,Cancer predisposition ,Prognosis ,United States ,Survival Rate ,DNA Repair Enzymes ,030104 developmental biology ,Survival benefit ,Child, Preschool ,Population Surveillance ,030220 oncology & carcinogenesis ,MISMATCH REPAIR DEFICIENCY ,Female ,Colorectal Neoplasms ,business ,Follow-Up Studies - Abstract
PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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- 2021
4. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells
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Cynthia Hawkins, Daniel A. Morgenstern, Victoria J. Forster, Scott Lindhorst, Sumedha Sudhaman, Uri Tabori, An Van Damme, Eric Bouffet, Alexander Lossos, Ben George, Annika Bronsema, Anita Villani, Michael Osborn, Annie Huang, Yosef E. Maruvka, Melyssa Aronson, Patrick Tomboc, Michal Yalon-Oren, David S. Ziegler, Reid Hayes, Carol Durno, Vanessa Bianchi, Melissa Galati, Nuno Miguel Nunes, Magimairajan Issai Vanan, Vanja Cabric, Gregory Thomas, Nicholas Light, Scott Davidson, Matthew Zatzman, Michael D. Taylor, A. Sorana Morrissy, Martin Komosa, Melissa Edwards, Gary Mason, Jiil Chung, Adam Shlien, Gad Getz, Shriya Deshmukh, Alyssa Reddy, Karl P. Hodel, Zachary F. Pursell, Robert Siddaway, Maura Massimino, Enrico Opocher, Ledia Brunga, David Malkin, Ben Ho, Jacalyn Kelly, Daniel C. Bowers, Nathaniel D. Anderson, Valerie Larouche, Thomas A. Kunkel, Nicholas J. Haradhvala, Kristina A. Cole, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
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0301 basic medicine ,DNA polymerase ,Somatic hypermutation ,DNA-Directed DNA Polymerase ,DNA Mismatch Repair ,Whole Exome Sequencing ,Article ,Germline ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Exome Sequencing ,medicine ,Humans ,Exome ,Polymerase ,Genetics ,biology ,food and beverages ,Microsatellite instability ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Proofreading ,Microsatellite Instability ,DNA mismatch repair - Abstract
Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. Significance: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995
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- 2020
5. Life without mismatch repair
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Yvette Hooks, Mathijs A. Sanders, Scott Lindhorst, Christoffer Flensburg, Patrick Tomboc, Peter J. Campbell, Michael R. Stratton, Philip S. Robinson, Vanessa Bianchi, Moritz Gerstung, Tim H. H. Coorens, Agnes Reschke, Luiza Moore, Harald Vöhringer, Uri Tabori, Victoria J. Forster, Tim Butler, Brittany Campbell, Henry Lee-Six, Adam Shlien, Ultan McDermott, Duncan Stearns, Rebecca A. Bilardi, Melissa Edwards, Bruce Crooks, Ian J. Majewski, and Elizabeth Cairney
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Genetics ,MSH6 ,Mutation ,Germline mutation ,MSH2 ,medicine ,PMS2 ,Somatic hypermutation ,DNA mismatch repair ,Neoplastic transformation ,Biology ,medicine.disease_cause - Abstract
Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutSα), but not MLH1 or PMS2 (MutLα), caused 5-methylcytosine-dependent hypermutation, indicating that MutSα is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.HighlightsMMR repairs 1-10 lesions/day in every normal cell and thousands more in tumor cellsMMR patterns and rates are shaped by genotype, tissue type and malignant transformationMSH2 and MSH6 are pivotal for repairing spontaneous deamination of methylated cytosineReplication indels and substitutions vary by leading versus lagging strand and genotype
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- 2021
6. Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue
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Theodore W. Laetsch, Luis Alberto Pedroza, Brittany Campbell, Mark L. Bernstein, An Van Damme, Scott Lindhorst, Bruce Crooks, Melyssa Aronson, Jagadeesh Ramdas, Shlomi Constantini, Patrick Tomboc, Ashraf Shamvil, Ben George, Gary Mason, Vanan Magimairajan, Garth Nicholas, Uri Tabori, Kami Wolfe Schneider, William D. Foulkes, Lisa Yu, Kara Semotiuk, David Sumerauer, Cindy Zhang, Rebecca C. Luiten, Sara Carroll, Michal Zapotocky, Stella Lanni, Christopher E. Pearson, Laura Palma, Ariane Mandel, David Malkin, Daniel C. Bowers, Melissa Edwards, Andrew Y. Shuen, Nobuko Hijiya, Rina Dvir, Warren Mason, Gagan B. Panigrahi, Nataliya Zhukova, Roula Farah, Michael Yalon Oren, Oz Mordechai, Eric Bouffet, Helen Toledano, Naureen Mushtaq, Musa Alharbi, Margaret E. Wierman, Kristina A. Cole, Andrea H. Seeley, S. Gallinger, Yi Yen Lee, Valerie Larouche, Carol Durno, David Samuel, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Non neoplastic ,DNA Mismatch Repair ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplastic Syndromes, Hereditary ,Predictive Value of Tests ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Mismatch Repair Endonuclease PMS2 ,Brain Neoplasms ,business.industry ,Cancer predisposition ,Cancer ,medicine.disease ,digestive system diseases ,DNA-Binding Proteins ,DNA Repair Enzymes ,MutS Homolog 2 Protein ,Phenotype ,030104 developmental biology ,Oncology ,chemistry ,Case-Control Studies ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,MISMATCH REPAIR DEFICIENCY ,DNA mismatch repair ,Colorectal Neoplasms ,MutL Protein Homolog 1 ,Penetrant (biochemical) ,business - Abstract
Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
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- 2019
7. Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency
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Uri Tabori, Magnus Sabel, Alexander Lossos, Annika Bronsema, Lauren Sambira, David Gass, Vanan Magimairajan, Gary Mason, Melissa Edwards, Vanja Cabric, Simone Stone, David Malkin, Isabelle Scheers, Ben George, Anita Villani, Deborah T. Blumenthal, An Van Damme, Rose B. McGee, Lee Yen, Sandra Luna-Fineman, John M. Maris, David Sumerauer, Charlotta Fröjd, Sumedha Sudhaman, Michael D. Taylor, Enrico Opocher, Yosef E. Maruvka, Oz Mordechai, Jeffrey Knipstein, Rebecca Loret De Mola, Melyssa Aronson, Shlomi Constantini, Abhaya Kulkarni, Daniel A. Morgenstern, Rina Dvir, Trevor J. Pugh, Patrick Tomboc, Ted Laetsch, Noor Alsafwani, Vanessa Bianchi, Kim E. Nichols, Jordan R. Hansford, Manohar Shroff, Peter B. Dirks, Shani Caspi, Anirban Das, Stefano Chiaravalli, Valerie Larouche, Eric Bouffet, Adam Shlien, Gad Getz, Maura Massimino, Alyssa Reddy, Michal Yalon, Gadi Campino, Anne Bendel, Cynthia Hawkins, Michal Zapotocky, Derek Tsang, Jiil Chung, Tomasz Sarosiek, Lindsey Hoffman, Daniel C. Bowers, Ailish Coblentz, Kristina A. Cole, Stefanie Zimmermann, Scott Lindhorst, Nobuko Hijaya, Michael Osborn, David S. Ziegler, Liana Nobre, Carol Durno, David Samuel, and Pamela Ohashi
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Genetics ,Replication (statistics) ,Mutation (genetic algorithm) ,Microsatellite ,Biology ,Germline - Abstract
Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.
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- 2021
8. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
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Anirban Das, Sumedha Sudhaman, Daniel Morgenstern, Ailish Coblentz, Jiil Chung, Simone C. Stone, Noor Alsafwani, Zhihui Amy Liu, Ola Abu Al Karsaneh, Shirin Soleimani, Hagay Ladany, David Chen, Matthew Zatzman, Vanja Cabric, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Lauren C, Sambira Nahum, Ayse B. Ercan, Arash Nabbi, Shlomi Constantini, Rina Dvir, Michal Yalon-Oren, Gadi Abebe Campino, Shani Caspi, Valerie Larouche, Alyssa Reddy, Michael Osborn, Gary Mason, Scott Lindhorst, Annika Bronsema, Vanan Magimairajan, Enrico Opocher, Rebecca Loret De Mola, Magnus Sabel, Charlotta Frojd, David Sumerauer, David Samuel, Kristina Cole, Stefano Chiaravalli, Maura Massimino, Patrick Tomboc, David S. Ziegler, Ben George, An Van Damme, Nobuko Hijiya, David Gass, Rose B. McGee, Oz Mordechai, Daniel C. Bowers, Theodore W. Laetsch, Alexander Lossos, Deborah T. Blumenthal, Tomasz Sarosiek, Lee Yi Yen, Jeffrey Knipstein, Anne Bendel, Lindsey M. Hoffman, Sandra Luna-Fineman, Stefanie Zimmermann, Isabelle Scheers, Kim E. Nichols, Michal Zapotocky, Jordan R. Hansford, John M. Maris, Peter Dirks, Michael D. Taylor, Abhaya V. Kulkarni, Manohar Shroff, Derek S. Tsang, Anita Villani, Wei Xu, Melyssa Aronson, Carol Durno, Adam Shlien, David Malkin, Gad Getz, Yosef E. Maruvka, Pamela S. Ohashi, Cynthia Hawkins, Trevor J. Pugh, Eric Bouffet, Uri Tabori, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique
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Adult ,DNA Replication ,Male ,Adolescent ,DNA Repair ,Pediatric Cancer ,Immunology ,Cancer immunotherapy ,Medical and Health Sciences ,General Biochemistry, Genetics and Molecular Biology ,B7-H1 Antigen ,Article ,Paediatric cancer ,Tumour biomarkers ,Young Adult ,Rare Diseases ,Neoplasms ,Genetics ,Biomarkers, Tumor ,Tumor Microenvironment ,2.1 Biological and endogenous factors ,Humans ,Prospective Studies ,Aetiology ,Child ,Immune Checkpoint Inhibitors ,Cancer genetics ,Germ-Line Mutation ,Cancer ,Retrospective Studies ,Pediatric ,Tumor ,Neurosciences ,General Medicine ,Survival Analysis ,CNS cancer ,Female ,Biomarkers - Abstract
Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.
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- 2021
9. Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns
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David T.W. Jones, Alexander Lossos, Bruce Crooks, Alexandra Sexton-Oates, Patrick Tomboc, Andrew Dodgshun, Jordan R. Hansford, Alan Mackay, Chris Jones, Vanessa Bianchi, Shlomi Constantini, Cynthia Hawkins, Duncan Stearns, Michal Yalon, Shamvil Ashraf, An Van Damme, Eric Bouffet, David S. Ziegler, Maura Massimino, Enrico Opocher, Uri Tabori, Gregory Thomas, Jagadeesh Ramdas, Valerie Larouche, Michael J. Sullivan, Roula Farah, Warren P. Mason, David Samuel, Stefano Chiaravalli, Scott Lindhorst, Kohei Fukuoka, Anirban Das, Kristina A. Cole, Syed Ahmer Hamid, Vijay Ramaswamy, Melissa Edwards, Gary Mason, and Magimairajan Issai Vanan
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0301 basic medicine ,Adult ,Male ,Adolescent ,DNA Repair ,DNA repair ,Somatic hypermutation ,Gene mutation ,Biology ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Young Adult ,0302 clinical medicine ,Germline mutation ,Humans ,Child ,Germ-Line Mutation ,CpG Island Methylator Phenotype ,Brain Neoplasms ,Methylation ,Glioma ,DNA Methylation ,DNA Repair-Deficiency Disorders ,eye diseases ,030104 developmental biology ,CpG site ,Child, Preschool ,DNA methylation ,Cancer research ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled “Wild type-C” or “Paediatric RTK 1”. Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.
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- 2020
10. HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS
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Eric Bouffet, Warren P. Mason, David Samuel, An Van Damme, Alexander Lossos, Bruce Crooks, Syed Ahmer Hamid, Ashraf Shamvil, Uri Tabori, Kohei Fukuoka, Andrew Dodgshun, Alexandra Sexton-Oates, Jordan R. Hansford, Patrick Tomboc, David R. Jones, Alan Mackay, Vanessa Bianchi, David S. Ziegler, Gregory Thomas, Shlomi Constantini, Duncan Stearns, Michal Yalon, Scott Lindhorst, Jagadeesh Ramdas, Roula Farah, Maura Massimino, Enrico Opocher, Michael J. Sullivan, Vanan Magimairajan, Kristina A. Cole, Valerie Larouche, Stefano Chiaravalli, Chris Jones, Vijay Ramaswamy, Melissa Edwards, Gary Mason, and Cynthia Hawkins
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Cancer Research ,Somatic hypermutation ,Context (language use) ,Methylation ,Epigenome ,Biology ,eye diseases ,Germline mutation ,Oncology ,CpG site ,DNA methylation ,Cancer research ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Epigenetics ,High Grade Glioma - Abstract
Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
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- 2020
11. RARE-17. SURVIVAL BENEFIT FOR INDIVIDUALS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME AND BRAIN TUMORS WHO UNDERGO SURVEILLANCE PROTOCOL. A REPORT FROM THE INTERNATIONAL REPLICATION REPAIR CONSORTIUM
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Scott Lindhorst, Jan Rapp, Deborah T. Blumenthal, Carl Koschmann, Mithra Ghalibafian, Rebecca Loret De Mola, Daniel Pettee, Garth Nicholas, Roula Farah, Raymond Bedgood, Aghiad Chamdin, Donald Basel, Valerie Larouche, Michal Yalon, Michal Lurye, Monica Newmark, Rachel Pearlman, Theodore Nicolaides, William D. Foulkes, Eric Bouffet, Shlomi Constantini, Shayna Zelcer, Maura Massimino, Duncan Stearns, Enrico Opocher, Saunders Hsu, Gabriel Robbins, Michael P. Link, Naureen Mushtaq, Ira Winer, Alyssa Reddy, Ayse Bahar Ercan, Rina Dvir, Zehavit Frenkel, Rebecca C. Luiten, An Van Damme, Miriam Bornhorst, Michal Zapotocky, Syed Ahmer Hamid, Sharon Gardner, Alvaro Lassaletta, Catherine Goudie, Melissa Edwards, Carol Durno, David Samuel, Anne Bendel, Mohsin Rashid, Kim E. Nichols, Sara Carroll, Junne Kamihara, Vahid Fallah Azad, Melyssa Aronson, Craig Harlos, Patrick Tomboc, Jordan R. Hansford, Vanessa Bianchi, Santanu Sen, Michael Osborn, Jamie L. Maciaszek, Benjamin Oshrine, Cathy Gilpin, Isabelle Scheers, Abeer Al-Battashi, David S. Ziegler, Marc Remke, Jeffrey Knipstein, Anirban Das, Uri Tabori, Stefano Chiaravalli, Carol J. Swallow, Magnus Sabel, Ossama M. Maher, Annika Bronsema, Stefanie Zimmerman, Lee Yi Yen, Lara Reichman, Simon C. Ling, Vanan Magimairajan, David Sumerauer, Nobuko Hijiya, Helen Toledano, Musa Alharbi, Leslie Taylor, and Elizabeth Cairney
- Subjects
Medulloblastoma ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,medicine.disease ,Clinical neurology ,Survival benefit ,Internal medicine ,Glioma ,medicine ,MISMATCH REPAIR DEFICIENCY ,AcademicSubjects/MED00300 ,DNA mismatch repair ,AcademicSubjects/MED00310 ,Neurology (clinical) ,business ,Craniopharyngioma and Rare Tumors ,Glioblastoma - Abstract
BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.
- Published
- 2020
12. Bevacizumab as adjuvant therapy for recurrent respiratory papillomatosis in an infant
- Author
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Patrick Tomboc, Michele M. Carr, Andrew Allison, and Christopher Gates
- Subjects
Male ,medicine.medical_specialty ,Bevacizumab ,Angiogenesis Inhibitors ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Tracheostomy ,030225 pediatrics ,medicine ,Adjuvant therapy ,Humans ,030223 otorhinolaryngology ,Respiratory Tract Infections ,Respiratory distress ,business.industry ,Papillomavirus Infections ,Infant ,General Medicine ,Surgery ,Otorhinolaryngology ,Respiratory failure ,Debridement ,Chemotherapy, Adjuvant ,Pediatrics, Perinatology and Child Health ,Breathing ,Recurrent Respiratory Papillomatosis ,Airway ,business ,medicine.drug - Abstract
Recurrent Respiratory Papillomatosis (RRP) is a benign disease of the airway that can result in symptoms ranging from mild dysphonia to respiratory distress to respiratory failure related to colonization of the lung parenchyma. It is a disease that typically begins in childhood and can require treatment indefinitely, though may remit in adolescence. Although treatment includes surgical management, certain cases require adjuvant therapy. Many therapies have been tried over the years with varying levels of success. Our patient presented as a 7 month old male in respiratory distress, who was subsequently diagnosed with RRP. He has required a tracheostomy, ventilation, and frequent surgical debridement for the last 20 months. Due to the aggressiveness of his disease, he was started on systemic bevacizumab (Avastin) in an effort to stabilize his lesions. Though early effect seemed apparent based on Derkay scores, systemic bevacizumab has failed to elicit clinical improvement in our patient. He remains with a tracheostomy receiving bevacizumab 10 mg/kg as an intermittent infusion approximately every 4 weeks along with surgical debridement with little to no clinical improvement thus far. In light of the recent successes with bevacizumab therapy, this case highlights the difficulty in finding new treatment for this disease.
- Published
- 2019
13. IMMU-20. IMMUNE AND TUMOR BIOMARKERS OF OUTCOME IN REPLICATION REPAIR DEFICIENT BRAIN TUMORS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: UPDATES FROM THE INTERNATIONAL REPLICATION REPAIR DEFICIENCY CONSORTIUM
- Author
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Sumedha Sudhaman, Eric Bouffet, Valerie Larouche, Deborah T. Blumenthal, Michael Osborn, Stefan S. Bielack, Ayse Bahar Ercan, Duncan Stearns, Cynthia Hawkins, Kim E. Nichols, Lauren Sambira, David Gass, Sandra Luna-Fineman, Charlotta Fröjd, Lindsey Hoffman, Lee Yi Yen, Gregory Thomas, Daniel C. Bowers, Rebecca Loret De Mola, Shlomi Constantini, Anne Bendel, Michael D. Taylor, David S. Ziegler, Tatiana Lipman, Uri Tabori, Scott Lindhorst, An Van Damme, Ted Laetsch, Jeffrey Knipstein, Brittany Campbell, Carol Durno, Gary Mason, Warren P. Mason, Elisabeth Koustenis, Magnus Sabel, David Samuel, Melyssa Aronson, Alyssa Reddy, Michal Oren, Sumita Roy, Patrick Tomboc, Vanan Magimairajan, Daniel Morgenstern, Ira Winer, Jacalyn Kelly, Cindy Zhang, Sara Carroll, Alvaro Lassaletta, Karen Gauvain, G. Rechavi, Stefanie Zimmermann, David Sumerauer, Melissa Edwards, Ailish Coblentz, Kristina A. Cole, Maura Massimino, Oz Mordechai, Nobuko Hijiya, Enrico Opocher, Trevor J. Pugh, Alexander Lossos, Ben George, Adam Shlien, Stefano Chiaravalli, Kami Wolfe Schneider, Margaret E. Wierman, Annika Bronsema, Jiil Chung, Gavin P. Dunn, Michal Zapotocky, M Remke, Santanu Sen, Rina Dvir, and Peter B. Dirks
- Subjects
Cancer Research ,Cell cycle checkpoint ,business.industry ,medicine.medical_treatment ,Immune checkpoint inhibitors ,T-cell receptor ,Cancer ,Immunotherapy ,Immunology/Immunotherapy ,medicine.disease ,Replication (computing) ,Immune system ,Oncology ,Glioma ,medicine ,Cancer research ,Neurology (clinical) ,business - Abstract
Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond favorably to immune checkpoint inhibition (ICI). We are collecting ongoing clinical and molecular data from patients with RRD hypermutant cancers treated with ICI as a part of our consortium registry study. Companion biomarkers include tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference is obtained from RNAseq. Additionally, T-cell receptor rearrangement data are collected from the tumor and blood throughout treatment. From 2015–2018, 53 patients were treated with ICI and combination therapies. Of these 39 had brain tumors, with 93% having high grade gliomas. Two-year overall survival for the entire cohort is 47+/-8%, which compares favorably with historical controls. Tumor location had major impact on outcome. Non-CNS solid tumor patients have 2-year OS of 78+/-11%, all failures occurring within the first 2 months, and sustained responses are observed for 3 years. In contrast, OS for brain tumors is 39+/-10% with late recurrences observed even after 2 years of therapy (p=0.02). Large tumor size and total tumor burden are associated with higher rates of “flare” and poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens do not correlate with response. However, specific signatures extracted from SNVs and indels are significantly associated with response to ICI and favorable outcome (p=0.005). Notably, RRD IDH1 mutant glioblastomas have particularly poor response to ICI. Interestingly, glioblastomas (n=8) which failed single agent ICI had favorable responses to combination immunotherapies with prolonged survival of 65%+/-8% one year after failure vs 0 for untreated patients (p=0.01). The favorable outcome and responses to ICI are encouraging. Since brain tumors respond less favorably to ICI than other solid tumors, combination therapies based on tumor and immune signatures of these cancers may be beneficial.
- Published
- 2019
14. IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY
- Author
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Duncan Stearns, Rina Dvir, Daniel Morgenstern, Jacalyn Kelly, Ailish Coblentz, Peter B. Dirks, Adam Shlien, Michael Osborn, Nobuko Hijiya, An Van Damme, Gregory Thomas, Anne Bendel, Elisabeth Koustenis, Gavin P. Dunn, Charlotta Fröjd, Sumedha Sudhaman, Lee Yi Yen, Michael D. Taylor, Stefanie Zimmermann, Alexander Lossos, David S. Ziegler, Melyssa Aronson, G. Rechavi, Lauren Sambira, Kami Wolfe Schneider, David Gass, Ben George, Ted Laetsch, Alyssa Reddy, Michal Zapotocky, Eric Bouffet, Cynthia Hawkins, Alberto Broniscer, Scott Lindhorst, Sumita Roy, Patrick Tomboc, Vanan Magimairajan, Maura Massimino, Margaret E. Wierman, Tatiana Lipman, Mark Remke, Karen Gauvain, David Sumerauer, Uri Tabori, Ira Winer, Magnus Sabel, Cindy Zhang, Sara Carroll, Shlomi Constantini, Stefan Bielack, Ayse Bahar Ercan, Valerie Larouche, Stefano Chiaravalli, Lindsey Hoffman, Daniel C. Bowers, Alvaro Lassaletta, Jeffrey Knipstein, Enrico Opocher, Kristina A. Cole, Annika Bronsema, Rebecca Loret De Mola, Jiil Chung, Santanu Sen, Oz Mordechai, Carol Durno, Warren P. Mason, David Samuel, Trevor J. Pugh, Michal Oren, Melissa Edwards, Deborah T. Blumenthal, Sandra Luna-Fineman, and Gary Mason
- Subjects
Cancer Research ,Mutation ,Cell cycle checkpoint ,business.industry ,medicine.medical_treatment ,Cancer ,Immunotherapy ,medicine.disease ,medicine.disease_cause ,Phenotype ,Immune checkpoint ,Immune system ,Oncology ,medicine ,Cancer research ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Favorable outcome ,business - Abstract
Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.
- Published
- 2020
15. Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature
- Author
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Janice Ahn, Patrick Tomboc, Cletus Cheyuo, Rabia Qaiser, Kymberly Gyure, and Walid Radwan
- Subjects
0301 basic medicine ,Male ,Ribonuclease III ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,MLH1 ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,DNA Mismatch Repair ,DEAD-box RNA Helicases ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Arachnoid cyst ,PMS2 ,Medicine ,Humans ,Child ,Mismatch Repair Endonuclease PMS2 ,Genetics ,business.industry ,Corpus Callosum Agenesis ,Hematology ,medicine.disease ,digestive system diseases ,MSH6 ,030104 developmental biology ,Oncology ,MSH2 ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Mutation ,DNA mismatch repair ,Agenesis of Corpus Callosum ,business ,Glioblastoma - Abstract
Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome caused by autosomal recessive biallelic (homozygous) germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The clinical spectrum includes neoplastic and non-neoplastic manifestations. We present the case of a 7-year-old boy who presented with T-lymphoblastic lymphoma and glioblastoma, together with non-neoplastic manifestations including corpus callosum agenesis, arachnoid cyst, developmental venous anomaly, and hydrocephalus. Gene mutation analysis revealed pathogenic biallelic mutations of PMS2 and heterozygous DICER1 variant predicted to be pathogenic. This report is the first to allude to a possible interaction of the mismatch repair system with DICER1 to cause corpus callosum agenesis.
- Published
- 2017
16. HGG-20. DNA METHYLATION ANALYSIS OF HIGH-GRADE GLIOMA IN PATIENTS WITH MISMATCH REPAIR DEFICIENCIES
- Author
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David R. Jones, Shlomi Constantini, Kristina A. Cole, David S. Ziegler, Jagadeesh Ramdas, Roula Farah, Gregory Thomas, Maura Massimino, Uri Tabori, Enrico Opocher, Melissa Edwards, Gary Mason, Warren P. Mason, David Samuel, Michal Oren, Duncan Stearns, Vanan Magimairajan, Brittany Campbell, An Van Damme, Michael J. Sullivan, Patrick Tomboc, Alexander Lossos, Bruce Crooks, Richard Saffery, Stefano Chiaravalli, Andrew Dodgshun, Alexandra Sexton-Oates, Jordan R. Hansford, Kohei Fukuoka, Ashraf Shamvil, Syed Ahmer Hamid, Scott Lindhorst, and Valerie Larouche
- Subjects
Cancer Research ,Mutation ,biology ,Methylation ,medicine.disease_cause ,Abstracts ,Histone ,Mitotic cell cycle ,Oncology ,CpG site ,DNA methylation ,medicine ,biology.protein ,Cancer research ,DNA mismatch repair ,Neurology (clinical) ,Gene - Abstract
Patients with constitutional mismatch repair deficiency (CMMRD) are prone to developing high-grade glioma (HGG). These tumours acquire DNA polymerase mutations and become ultra-hypermutant harbouring hundreds of mutations per megabase. The impact of these mutations on methylation profile and the ability of the tool to differentiate MMRD tumours from others is unknown. In order to answer these questions, we performed either 450k/850K methylation analysis on a cohort of 52 CMMRD-HGG and compared them to 148 non-CMMRD HGG and normal brain controls. CMMRD HGG harbouring classic mutations in histone 3 or IDH genes had a methylation profile which clustered closely with non-MMRD tumours harbouring these mutations. Tumours without these alterations exhibited a tendency to hypomethylation with some tumours being extremely hypomethylated in comparison to other HGG. Hypomethylation was unrelated to mutational burden and type of DNA polymerase mutation present. Gene set analysis of methylation patterns revealed enrichment of hypomethylation for cellular pathways involved in cellular metabolism, organelle maintenance, mitotic cell cycle and gene expression. This pattern persisted in subgroup analysis of IDH mutant tumours in patients with and without MMRD. Importantly, this pattern was present in MMRD HGG with mutational burdens
- Published
- 2018
17. Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway
- Author
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Joseph C. Loftus, Ian T. Mathews, Michael E. Berens, Alison Roos, Nhan L. Tran, Serdar Tuncali, Ashley Chavez, Patrick Tomboc, and Harshil Dhruv
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Cell ,Blotting, Western ,RAC1 ,Apoptosis ,Receptors, Tumor Necrosis Factor ,Article ,Propentofylline ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Tumor Cells, Cultured ,Humans ,Neoplasm Invasiveness ,Protein kinase B ,Cell Proliferation ,Gene knockdown ,Temozolomide ,business.industry ,Brain Neoplasms ,NF-kappa B ,medicine.disease ,Primary tumor ,Surgery ,nervous system diseases ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Neuroprotective Agents ,Neurology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Xanthines ,Cancer research ,Neurology (clinical) ,Signal transduction ,business ,Glioblastoma ,medicine.drug ,Signal Transduction - Abstract
Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. Knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer’s disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. Here we showed that PPF decreased GBM cell expression of TROY, inhibited glioma cell invasion, and sensitized GBM cells to TMZ. Mechanistically, PPF decreased glioma cell invasion by modulating TROY expression and downstream signaling, including AKT, NF-κB, and Rac1 activation. Thus, PPF may provide a pharmacologic approach to targeting TROY to inhibit cell invasion and reduced therapeutic resistance in GBM.
- Published
- 2015
18. An integrated approach to identifying clinically relevant targets in pediatric gliomas
- Author
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Nhan L. Tran, Patrick Tomboc, and Troy A. McEachron
- Subjects
Oncology ,Chemotherapy ,medicine.medical_specialty ,Radiotherapy ,business.industry ,Brain Neoplasms ,medicine.medical_treatment ,Neurosurgery ,Context (language use) ,General Medicine ,Disease ,PDGFRA ,Glioma ,Pediatric cancer ,Pediatrics ,Radiation therapy ,Regimen ,Editorial ,Internal medicine ,Concomitant ,Medicine ,Humans ,business - Abstract
303 ISSN 2045-0907 10.2217/CNS.13.21 © 2013 Future Medicine Ltd CNS Oncol. (2013) 2(4), 303–306 High-grade gliomas (HGGs) are categorized by WHO as grade III–IV glial malignancies and account for roughly 15–20% of all pediatric CNS tumors [1]. For pediatric patients diagnosed with supratentorial HGGs, the 2-year survival rates range from 10 to 30%. The prognosis for patients with diffuse brainstem gliomas is even more dismal, as less than 10% will survive more than 2 years after diagnosis [1]. The current treatment for newly diagnosed pediatric HGGs is safe maximal surgical resection and radiotherapy. The addition of chemotherapy to this regimen is debatable, reflecting the lack of consensus among pediatric neuro-oncologists regarding the optimal protocol/treatment plan for newly diagnosed patients [2]. Despite these efforts, marginal impact has been made on the overall survival rates of these patients. This begs the question: ‘how do we change the way in which we view and treat pediatric HGGs?’ To fully understand the complexities of pediatric HGGs and subsequently identify therapeutic vulnerabilities, we must first understand the full molecular, cellular and physiological context of these malignancies. While it has long been thought that both pediatric and adult gliomas are the same disease affecting different patient populations, recently, multiple groups including the Canadian Paediatric Cancer Genome Consortium and the St Jude Children’s Research Hospital–Washington University in St Louis Pediatric Cancer Genome Project have challenged this notion by revealing striking differences in the mutation spectrum and frequencies between pediatric and adult HGGs [3–11]. The use of high-resolution genomic approaches has uncovered potential therapeutic targets for pediatric gliomas such as PDGFRA, MET and IGF1R (recurrent focal amplification in HGGs and pontine gliomas) [7,10,12], BRAF and CDK2NA (BRAF-V600E mutations with concomitant CDKN2A loss in a subset of malignant astrocytomas) [11] and FGFR1 (intragenic duplications of the tyrosine kinase domain in low-grade gliomas) [3]. Alone, the identification and characterization of the somatic DNA alterations is insufficient. Pediatric HGGs harbor
- Published
- 2014
19. Abstract 5366: Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells
- Author
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Patrick Tomboc, Alison Roos, Michael E. Berens, Joseph C. Loftus, Ashley Chavez, Nathan M. Jameson, Nhan L. Tran, Serdar Tuncali, and Harshil Dhruv
- Subjects
Cancer Research ,Temozolomide ,business.industry ,Cancer ,RAC1 ,Glial tumor ,medicine.disease ,Primary tumor ,Propentofylline ,chemistry.chemical_compound ,Oncology ,chemistry ,Glioma ,Immunology ,medicine ,Cancer research ,business ,Protein kinase B ,medicine.drug - Abstract
Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. TROY expression increases with glial tumor grade and inversely correlates with patient survival. TROY stimulates GBM cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. Conversely, knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. In this study, we demonstrated that PPF decreases TROY protein expression in glioma cells, and subsequently suppress activation downstream signaling effectors including AKT, NF-κB, and Rac1. PPF treatment of glioma cells also suppressed glioma cell migration and invasion, demonstrated by transwell migration assay and reduced membrane ruffling. Finally, PPF treatment increased vulnerability of glioma cells to Temozolomide (TMZ) and radiation. In summary, this study demonstrates that PPF provides a pharmacologic approach to target TROY to inhibit glioma cell invasion and reduce therapeutic resistance to TMZ and radiation. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Alison Roos, Patrick Tomboc, Nathan Jameson, Ashley Chavez, Joseph Loftus, Michael E. Berens, Nhan L. Tran. Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5366. doi:10.1158/1538-7445.AM2015-5366
- Published
- 2015
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