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3. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Author

Torchia, Jonathon, Golbourn, Brian, Feng, Shengrui, Ho, Ching, Sin-Chan, Patrick, Vasiljevic, Alexandre, Norman, Joseph D, Guilhamon, Paul, Garzia, Livia, Agamez, Natalia R, Lu, Mei, Chan, Tiffany S, Picard, Daniel, de Antonellis, Pasqualino, Khuong-Quang, Dong-Anh, Planello, Aline C, Zeller, Constanze, Barsyte-Lovejoy, Dalia, Lafay-Cousin, Lucie, Letourneau, Louis, Bourgey, Mathieu, Yu, Man, Gendoo, Deena MA, Dzamba, Misko, Barszczyk, Mark, Medina, Tiago, Riemenschneider, Alexandra N, Morrissy, A Sorana, Ra, Young-Shin, Ramaswamy, Vijay, Remke, Marc, Dunham, Christopher P, Yip, Stephen, Ng, Ho-keung, Lu, Jian-Qiang, Mehta, Vivek, Albrecht, Steffen, Pimentel, Jose, Chan, Jennifer A, Somers, Gino R, Faria, Claudia C, Roque, Lucia, Fouladi, Maryam, Hoffman, Lindsey M, Moore, Andrew S, Wang, Yin, Choi, Seung Ah, Hansford, Jordan R, Catchpoole, Daniel, Birks, Diane K, Foreman, Nicholas K, Strother, Doug, Klekner, Almos, Bognár, Laszló, Garami, Miklós, Hauser, Péter, Hortobágyi, Tibor, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Hwang, Eugene I, Gajjar, Amar, Chiou, Shih-Hwa, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheinemann, Katrin, Fleming, Adam J, Johnston, Donna L, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Afzal, Samina, Ramsay, David A, Sirachainan, Nongnuch, Hongeng, Suradej, Larbcharoensub, Noppadol, Grundy, Richard G, Lulla, Rishi R, Fangusaro, Jason R, Druker, Harriet, Bartels, Ute, Grant, Ronald, Malkin, David, McGlade, C Jane, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Majewski, Jacek, Montpetit, Alexandre, Bourque, Guillaume, Bader, Gary D, Reddy, Alyssa T, Gillespie, G Yancey, and Warmuth-Metz, Monika

Subjects
Genetics, Human Genome, Rare Diseases, Orphan Drug, Cancer, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Aetiology, 5.1 Pharmaceuticals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Central Nervous System Neoplasms, Chromatin, DNA Methylation, Dasatinib, Epigenesis, Genetic, Epigenomics, Humans, Mutation, Protein Kinase Inhibitors, Pyrimidines, Receptor, Platelet-Derived Growth Factor beta, Rhabdoid Tumor, SMARCB1 Protein, Teratoma, ATRT, enhancer, epigenomics, genomics, rhabdoid tumors, subgroup-specific therapeutics, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Published
2016

6. Performance of the eHealth decision support tool, MIPOGG, for recognising children with Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin syndromes.

Author

Hebert, Robyn, Cullinan, Noelle, Armstrong, Linlea, Blood, Katherine A., Brossard, Josee, Brunga, Ledia, Cacciotti, Chantel, Caswell, Kimberly, Cellot, Sonia, Coltin, Hallie, Deyell, Rebecca J., Felton, Kathleen, Fernandez, Conrad V., Fleming, Adam J., Gibson, Paul, Hammad, Rawan, Jabado, Nada, Johnston, Donna L., Lafay-Cousin, Lucie, and Larouche, Valérie

Abstract

Background Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation. Methods This study assessed MIPOGG’s performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period. Results MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG’s ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS. Conclusion This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG’s strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

Author

Torchia, Jonathon, Picard, Daniel, Lafay-Cousin, Lucie, Hawkins, Cynthia E, Kim, Seung-Ki, Letourneau, Louis, Ra, Young-Shin, Ho, King Ching, Chan, Tiffany Sin Yu, Sin-Chan, Patrick, Dunham, Christopher P, Yip, Stephen, Ng, Ho-keung, Lu, Jian-Qiang, Albrecht, Steffen, Pimentel, José, Chan, Jennifer A, Somers, Gino R, Zielenska, Maria, Faria, Claudia C, Roque, Lucia, Baskin, Berivan, Birks, Diane, Foreman, Nick, Strother, Douglas, Klekner, Almos, Garami, Miklos, Hauser, Peter, Hortobágyi, Tibor, Bognár, Laszló, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheineman, Katrin, Johnston, Donna, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Ramsay, David A, Fleming, Adam J, Lulla, Rishi R, Fangusaro, Jason R, Sirachainan, Nongnuch, Larbcharoensub, Noppadol, Hongeng, Suradej, Barakzai, Muhammad Abrar, Montpetit, Alexandre, Stephens, Derek, Grundy, Richard G, Schüller, Ulrich, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Taylor, Michael D, Rutka, James T, Dirks, Peter, Bader, Gary D, Warmuth-Metz, Monika, Rutkowski, Stefan, Pietsch, Torsten, Judkins, Alexander R, Jabado, Nada, Bouffet, Eric, and Huang, Annie

Published
2015
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10. Analysis of surgical and MRI factors associated with cerebellar mutism

Author

Sergeant, Anjali, Kameda-Smith, Michelle Masayo, Manoranjan, Branavan, Karmur, Brij, Duckworth, JoAnn, Petrelli, Tina, Savage, Katey, Ajani, Olufemi, Yarascavitch, Blake, Samaan, M. Constantine, Scheinemann, Katrin, Alyman, Cheryl, Almenawer, Saleh, Farrokhyar, Forough, Fleming, Adam J., Singh, Sheila Kumari, and Stein, Nina

Published
2017
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15. Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes

Author

Goudie, Catherine, primary, Witkowski, Leora, additional, Cullinan, Noelle, additional, Reichman, Lara, additional, Schiller, Ian, additional, Tachdjian, Melissa, additional, Armstrong, Linlea, additional, Blood, Katherine A., additional, Brossard, Josée, additional, Brunga, Ledia, additional, Cacciotti, Chantel, additional, Caswell, Kimberly, additional, Cellot, Sonia, additional, Clark, Mary Egan, additional, Clinton, Catherine, additional, Coltin, Hallie, additional, Felton, Kathleen, additional, Fernandez, Conrad V., additional, Fleming, Adam J., additional, Fuentes-Bolanos, Noemi, additional, Gibson, Paul, additional, Grant, Ronald, additional, Hammad, Rawan, additional, Harrison, Lynn W., additional, Irwin, Meredith S., additional, Johnston, Donna L., additional, Kane, Sarah, additional, Lafay-Cousin, Lucie, additional, Lara-Corrales, Irene, additional, Larouche, Valerie, additional, Mathews, Natalie, additional, Meyn, M. Stephen, additional, Michaeli, Orli, additional, Perrier, Renée, additional, Pike, Meghan, additional, Punnett, Angela, additional, Ramaswamy, Vijay, additional, Say, Jemma, additional, Somers, Gino, additional, Tabori, Uri, additional, Thibodeau, My Linh, additional, Toupin, Annie-Kim, additional, Tucker, Katherine M., additional, van Engelen, Kalene, additional, Vairy, Stephanie, additional, Waespe, Nicolas, additional, Warby, Meera, additional, Wasserman, Jonathan D., additional, Whitlock, James A., additional, Sinnett, Daniel, additional, Jabado, Nada, additional, Nathan, Paul C., additional, Shlien, Adam, additional, Kamihara, Junne, additional, Deyell, Rebecca J., additional, Ziegler, David S., additional, Nichols, Kim E., additional, Dendukuri, Nandini, additional, Malkin, David, additional, Villani, Anita, additional, and Foulkes, William D., additional

Published
2021
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16. Childhood head trauma and the risk of childhood brain tumours: a case‐control study in Ontario, Canada

Author

Cheng, Sierra, primary, McLaughlin, John R., additional, Brown, M. Catherine, additional, Al‐Sawaihey, Hamad, additional, Rutka, James, additional, Bouffet, Eric, additional, Hawkins, Cynthia, additional, Cairney, Beth, additional, Ranger, Adrianna, additional, Fleming, Adam J., additional, Johnston, Donna, additional, Greenberg, Mark, additional, Malkin, David, additional, and Hung, Rayjean J., additional

Published
2021
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17. Leptin is Associated with the Tri-Ponderal Mass Index in Children: A Cross-Sectional Study

Author

Empringham,Brianna, Jennings,William J, Rajan,Raeesha, Fleming,Adam J, Portwine,Carol, Johnston,Donna L, Zelcer,Shayna M, Rassekh,Shahrad Rod, Tran,Victoria, Burrow,Sarah, Thabane,Lehana, Samaan,M Constantine, Empringham,Brianna, Jennings,William J, Rajan,Raeesha, Fleming,Adam J, Portwine,Carol, Johnston,Donna L, Zelcer,Shayna M, Rassekh,Shahrad Rod, Tran,Victoria, Burrow,Sarah, Thabane,Lehana, and Samaan,M Constantine

Abstract

Brianna Empringham,1,2 William J Jennings,1,2 Raeesha Rajan,1– 3 Adam J Fleming,1,4 Carol Portwine,1,4 Donna L Johnston,5 Shayna M Zelcer,6 Shahrad Rod Rassekh,7 Victoria Tran,1,2 Sarah Burrow,8 Lehana Thabane,3,9– 11 M Constantine Samaan1– 3 1Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; 2Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 3Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada; 4Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 5Division of Pediatric Hematology/Oncology, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 6Pediatric Hematology Oncology, Children’s Hospital, London Health Sciences Center, London, Ontario, Canada; 7Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, British Columbia’s Children’s Hospital, Vancouver, BC, Canada; 8Division of Orthopedic Surgery, Department of Surgery, McMaster University Medical Centre, Hamilton, Ontario, Canada; 9Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada; 10Centre for Evaluation of Medicines, St. Joseph’s Health Care, Hamilton, Ontario, Canada; 11Biostatistics Unit, St Joseph’s Healthcare-Hamilton, Hamilton, Ontario, CanadaCorrespondence: M Constantine SamaanDepartment of Pediatrics, McMaster University, Division of Pediatric Endocrinology, McMaster Children’s Hospital, 1280 Main Street West, 3A-57, Hamilton, Ontario, L8S 4K1 Tel +001-905-521-2100, ext. 75926Fax +001-905-308-7548Email samaanc@mcmaster.caBackground: Obesity is characterized by the disproportionate expansion of the fat mass and is most commonly diagnosed using the Body Mass Index (BMI) z-score or percentile in children. However, these measures associate poorly with the fat mass. This i

Published
2021

19. Leptin is Associated with the Tri-Ponderal Mass Index in Children: A Cross-Sectional Study

Author

Empringham, Brianna, primary, Jennings, William J, additional, Rajan, Raeesha, additional, Fleming, Adam J, additional, Portwine, Carol, additional, Johnston, Donna L, additional, Zelcer, Shayna M, additional, Rassekh, Shahrad Rod, additional, Tran, Victoria, additional, Burrow, Sarah, additional, Thabane, Lehana, additional, and Samaan, M Constantine, additional

Published
2021
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20. Childhood head trauma and the risk of childhood brain tumours: A case‐control study in Ontario, Canada.

Author

Cheng, Sierra, McLaughlin, John R., Brown, M. Catherine, Al‐Sawaihey, Hamad, Rutka, James, Bouffet, Eric, Hawkins, Cynthia, Cairney, A. Elizabeth, Ranger, Adrianna, Fleming, Adam J., Johnston, Donna, Greenberg, Mark, Malkin, David, and Hung, Rayjean J.

Subjects
BRAIN tumors, ADVERSE childhood experiences, NECK injuries, SKULL fractures, CASE-control method, PEDIATRIC oncology, COMPUTED tomography
Abstract

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population‐based and hospital‐based case‐control study of children 0 to 15 years with newly diagnosed CBTs from 1997 to 2003 recruited across Ontario through paediatric oncology centres was conducted. Controls were frequency‐matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education and maternal pack‐years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, or head or neck X‐rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X‐ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research. What' s new? : Head trauma in early childhood has been hypothesised as a potential risk factor for childhood brain tumours (CBTs). However, existing studies have yielded conflicting results. In this case‐control study of children aged 0–15 years with newly diagnosed brain tumours in Ontario, Canada, no overall association was observed between head trauma and CBTs among the total population of 280 cases and 919 controls. There was an association between head trauma within the first year of life and CBTs, which became non‐significant after adjusting for X‐ray and CT exposures to the head and neck in the same time period. [ABSTRACT FROM AUTHOR]

Published
2022
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22. 42 - The Prevalence of Diabetes Mellitus in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis

Author

Chen, Sondra S., primary, Nadarajah, Ajantha, additional, Wang, Kuan-Wen, additional, Kay, Stephanie, additional, Banfield, Laura, additional, Foroutan, Farid, additional, Johnston, Donna, additional, Zelcer, Shayna, additional, Rassekh, S. Rod, additional, Thabane, Lehana, additional, Fleming, Adam J., additional, Portwine, Carol, additional, and Constantine Samaan, M., additional

Published
2020
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23. Analysis of factors that influence neurosurgical length of hospital stay among newly diagnosed pediatric brain tumor patients

Author

Hasan, Muhammad, primary, Diep, Dion, additional, Manoranjan, Branavan, additional, Maharaj, Arjuna, additional, Chaudhry, Sabrina, additional, Shaheen, Saqib, additional, Farrokhyar, Forough, additional, Fleming, Adam J., additional, Ajani, Olufemi, additional, Singh, Sheila K., additional, and Yarascavitch, Blake, additional

Published
2019
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24. Urine biomarkers of acute kidney injury in noncritically ill, hospitalized children treated with chemotherapy

Author

Sterling, Maya, primary, Al-Ismaili, Zubaida, additional, McMahon, Kelly R., additional, Piccioni, Melissa, additional, Pizzi, Michael, additional, Mottes, Theresa, additional, Lands, Larry C., additional, Abish, Sharon, additional, Fleming, Adam J., additional, Bennett, Michael R., additional, Palijan, Ana, additional, Devarajan, Prasad, additional, Goldstein, Stuart L., additional, O'Brien, Maureen M., additional, and Zappitelli, Michael, additional

Published
2017
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26. Identification of nonferritin mitochondrial iron deposits in a mouse model of friedreich ataxia

Author

National Health and Medical Research Council (Australia), Muscular Dystrophy Association (US), Canadian Institutes of Health Research, Whitnall, Megan, Suryo Rahmanto, Yohan, Huang, Michael L. H., Saletta, Federica, Chuen Lok, Hiu, Gutiérrez, Lucía, Lázaro, Francisco J., Fleming, Adam J., Pierre, Timothy G. St., Mikhael, Marc R., Ponka, Prem, Richardson, Des R., National Health and Medical Research Council (Australia), Muscular Dystrophy Association (US), Canadian Institutes of Health Research, Whitnall, Megan, Suryo Rahmanto, Yohan, Huang, Michael L. H., Saletta, Federica, Chuen Lok, Hiu, Gutiérrez, Lucía, Lázaro, Francisco J., Fleming, Adam J., Pierre, Timothy G. St., Mikhael, Marc R., Ponka, Prem, and Richardson, Des R.

Abstract

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich ataxia (FA). This disease is due to decreased expression of the mitochondrial protein, frataxin, which leads to alterations in mitochondrial iron (Fe) metabolism. The identification of potentially toxic mitochondrial Fe deposits in FA suggests Fe plays a role in its pathogenesis. Studies using the muscle creatine kinase (MCK) conditional frataxin knockout mouse that mirrors the disease have demonstrated frataxin deletion alters cardiac Fe metabolism. Indeed, there are pronounced changes in Fe trafficking away from the cytosol to the mitochondrion, leading to a cytosolic Fe deficiency. Considering Fe deficiency can induce apoptosis and cell death, we examined the effect of dietary Fe supplementation, which led to body Fe loading and limited the cardiac hypertrophy in MCK mutants. Furthermore, this study indicates a unique effect of heart and skeletal muscle-specific frataxin deletion on systemic Fe metabolism. Namely, frataxin deletion induces a signaling mechanism to increase systemic Fe levels and Fe loading in tissues where frataxin expression is intact (i.e., liver, kidney, and spleen). Examining the mutant heart, native size-exclusion chromatography, transmission electron microscopy, Mössbauer spectroscopy, and magnetic susceptibility measurements demonstrated that in the absence of frataxin, mitochondria contained biomineral Fe aggregates, which were distinctly different from isolated mammalian ferritin molecules. These mitochondrial aggregates of Fe, phosphorus, and sulfur, probably contribute to the oxidative stress and pathology observed in the absence of frataxin.

Published
2012

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