Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

Autor:	Ercan AB; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Aronson M; Zane Cohen Centre for Digestive Diseases, Sinai Health System, Toronto, ON, Canada., Fernandez NR; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Chang Y; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Levine A; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada., Liu ZA; Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Negm L; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Edwards M; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Bianchi V; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Stengs L; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Chung J; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada., Al-Battashi A; Department of Pediatric Hematology and Oncology, The Royal Hospital, Muscat, Oman., Reschke A; Division of Pediatric Hematology/Oncology, Stanford Medicine, Stanford, CA, USA., Lion A; Department of Pediatric Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA., Ahmad A; University of Child Health Sciences, Children's Hospital Lahore, Lahore, Pakistan., Lassaletta A; Department of Pediatric Hematology-Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain., Reddy AT; University of California, San Francisco, CA, USA., Al-Darraji AF; College of Medicine, University of Baghdad, Paediatric Oncology Unit, Baghdad, Iraq., Shah AC; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Van Damme A; Division of Pediatric Hematology and Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, Brussels, Belgium., Bendel A; Children's Minnesota, Minneapolis, MN, USA., Rashid A; Department of Pediatric Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan., Margol AS; Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA, USA., Kelly BL; CHI-Saint Joseph Health Cancer Care, Lexington, KY, USA., Pencheva B; Alfac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA., Heald B; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA., Lemieux-Anglin B; Departments of Oncology and Human Genetics, McGill University Health Centre, Cancer Genetics Program, Montreal, QC, Canada., Crooks B; Division of Hematology-Oncology, IWK Health, Halifax, NS, Canada., Koschmann C; Department of Pediatric Hematology-Oncology, University of Michigan Medical School, Ann Arbor, MI, USA., Gilpin C; Children's Hospital of Eastern Ontario, Genetics, Ottawa, ON, Canada., Porter CC; Alfac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA., Gass D; Department of Pediatric Hematology and Oncology, Atrium Health, Charlotte, NC, USA., Samuel D; Valley Children's Hospital, Madera, CA, USA., Ziegler DS; Kid's Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Australia., Blumenthal DT; Neuro-Oncology Division, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel., Kuo DJ; Division of Pediatric Hematology/Oncology, University of California, San Diego, CA, USA., Hamideh D; Division of Pediatric Hematology-Oncology, American University of Beirut, Beirut, Lebanon., Basel D; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA., Khuong-Quang DA; Children's Cancer Centre, The Royal Children's Hospital, Melbourne, VIC, Australia., Stearns D; UH Rainbow Babies and Children's Hospital Division of Pediatrics, Pediatric Neuro-oncology, Cleveland, OH, USA., Opocher E; Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy., Carceller F; Children and Young People's Unit, Royal Marsden NHS Foundation Trust, London, UK; Division of Clinical Studies, The Institute of Cancer Research, London, UK., Baris Feldman H; The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Toledano H; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel., Winer I; Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA., Scheers I; Division of Pediatric Gastroenterology and Hepatology, Cliniques Universitaires Saint-Luc, IREC Universite Catholique de Louvain, Brussels, Belgium., Fedorakova I; Clinic of Pediatric Oncology and Hematology, University Children's Hospital, Banská Bystrica, Slovakia., Su JM; Department of Pediatrics, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA., Vengoechea J; Associate Professor of Human Genetics, Emory University, Atlanta, GA, USA., Sterba J; Pediatric Oncology Department, University Hospital Brno, Masaryk Univerzity, Faculty of Medicine, Brno, Czech Republic., Knipstein J; Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Medical College of Wisconsin, Milwaukee, WI, USA., Hansford JR; Michael Rice Children's Hematology and Oncology Centre, Women's and Children's Hospital, Adelaide, SA, Australia; South Australia Health and Medical Research Institute Adelaide, SA, Australia; South Australia Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia., Gonzales-Santos JR; De La Salle Medical and Health Sciences Institute, Dasmariñas, Philippines., Bhatia K; Children's Cancer Centre, The Royal Children's Hospital, Melbourne, VIC, Australia., Bielamowicz KJ; Department of Pediatrics, Division of Hematology/Oncology, University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, AR, USA., Minhas K; Division of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan., Nichols KE; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA., Cole KA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Penney L; Division of Medical Genetics, Department of Pediatrics, IWK Health Centre, Halifax, NS, Canada., Hjort MA; Children's Clinic, St Olavs University Hospital, Trondheim, Norway., Sabel M; Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Gil-da-Costa MJ; Pediatric Oncology Department, University Hospital de São João, Porto, Portugal., Murray MJ; Department of Pathology, University of Cambridge, Cambridge, UK., Miller M; Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA., Blundell ML; Sutter Health, Cancer Risk Program, Sacramento, CA, USA., Massimino M; Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Al-Hussaini M; King Hussein Cancer Center, Amman, Jordan., Al-Jadiry MF; College of Medicine, University of Baghdad, Paediatric Oncology Unit, Baghdad, Iraq., Comito MA; Golisano Children's Hospital, SUNY Upstate, Syracuse, NY, USA., Osborn M; Michael Rice Children's Hematology and Oncology Centre, Women's and Children's Hospital, Adelaide, SA, Australia., Link MP; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Zapotocky M; Department of Paediatric Haematology and Oncology, University Hospital Motol and Second Faculty of Medicine, Charles University, Prague, Czech Republic., Ghalibafian M; MAHAK Pediatric Cancer Treatment and Research, Tehran, Iran., Shaheen N; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan., Mushtaq N; Aga Khan University Hospital, Karachi, Pakistan., Waespe N; Division of Pediatric Oncology and Hematology, Department of Pediatrics, Inselspital, Bern University Hospital, Bern, Switzerland., Hijiya N; Pediatric Hematology Oncology and Stem Cell Transplant, Columbia University Irving Medical Center, New York, NY, USA., Fuentes-Bolanos N; Kid's Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Australia., Ahmad O; Hopp Children's Cancer Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia., Chamdine O; Department of Pediatric Hematology Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia., Roy P; Department of Pathology, Tata Medical Center, Rajarhat, Kolkata, India., Pichurin PN; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Nyman P; Crown Princess Victoria Children's Hospital, Linköping University Hospital, Linköping, Sweden; Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden., Pearlman R; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Auer RC; Ottawa Hospital Research Institute, Ottawa, ON, Canada., Sukumaran RK; Department of Pediatric Hemato-oncology, Tata Medical Center, Kolkata, India., Kebudi R; Department of Pediatric Hematology-Oncology, Istanbul University, Oncology Institute, Istanbul, Türkiye., Dvir R; Department of Pediatric Hemato-Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Raphael R; UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA., Elhasid R; Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel., McGee RB; St Jude Children's Research Hospital, Memphis, TN, USA., Chami R; Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada., Noss R; Center for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, USA., Tanaka R; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA., Raskin S; Department of Pediatrics, Federal University of Parana, Curitiba, Parana., Sen S; Department of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India., Lindhorst S; Department of Neurosurgery, Division of Neuro-Oncology, Medical University of South Carolina, Charleston, SC, USA., Perreault S; Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada., Caspi S; Sheba Medical Center, Cancer Research Center, Tel Hashomer, Israel., Riaz S; Department of Hematology and Oncology, The Children's Hospital and University of Child Health Sciences, Lahore, Pakistan., Constantini S; Department of Pediatric Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Albert S; Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, QC Canada., Chaleff S; Maine Children's Cancer Program, Portland, ME, USA., Bielack S; Padiatrie 5 (Onkologie, Hamatologie, Immunologie), Zentrum fur Kinder-, Jugend- und Frauenmedizin, Stuttgart Cancer Center, Klinikum Stuttgart-Olgahospital, Stuttgart, Germany., Chiaravalli S; Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Cramer SL; Department of Pediatric Hematology/Oncology, Prisma Health, Columbia, SC, USA., Roy S; Central Michigan University, Mount Pleasant, MI, USA; Division of Genetics, Genomic & Metabolic Disorders, Pediatric Cancer Genetics Clinic, Children's Hospital of Michigan, Detroit, MI, USA., Cahn S; Winship Cancer Institute, Emory University Hospital, Atlanta, GA, USA., Penna S; Division of Rehabilitation Neuropsychology, Emory University School of Medicine, Atlanta, GA, USA., Hamid SA; Indus Hospital and Health Network, Karachi, Pakistan., Ghafoor T; Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center, National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan., Imam U; Pediatric Oncology Department, National Institute of Child Health, Karachi, Pakistan., Larouche V; Department of Hematology-Oncology, CHU de Quebec-Universite Laval, Quebec, QC, Canada., Magimairajan Issai V; Department of Pediatric Hematology-Oncology, CancerCare Manitoba, Winnipeg, MB, Canada., Foulkes WD; Departments of Oncology and Human Genetics, McGill University Health Centre, Cancer Genetics Program, Montreal, QC, Canada., Lee YY; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan., Nathan PC; Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada., Maruvka YE; Faculty of Biotechnology and Food Engineering, The Lokey Center for Life Science and Engineering, TECHNION-Israel Institute of Technology, Haifa, Israel., Greer MC; Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, Toronto, ON, Canada., Durno C; Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada., Shlien A; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada., Ertl-Wagner B; Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, Canada., Villani A; Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada., Malkin D; Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada., Hawkins C; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada., Bouffet E; Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada., Das A; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada; Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada., Tabori U; Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, ON, Canada; Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: uri.tabori@sickkids.ca.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2024 May; Vol. 25 (5), pp. 668-682. Date of Electronic Publication: 2024 Mar 26.
DOI:	10.1016/S1470-2045(24)00026-3
Abstrakt:	Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center. Competing Interests: Declaration of interests ALa reports payment from Alexion, support from Servier and stock from Gilead, outside of the submitted work. AV is co-lead role of the Consortium for Childhood Cancer Predisposition, outside of the submitted work. BH reports payment and stock from Invitae, outside of the submitted work. BC reports participation as data safety and monitoring board member in ReRad Study, participation in the chapter advisory board for Make a Wish Canada Nova Scotia, and participation in the medical advisory committee for Make a Wish Canada, outside of the submitted work. CCP reports grants from St Baldrick's Foundation, outside of the submitted work. DSZ reports consulting fees for Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Alexion, Amgen, and Norgine, outside of the submitted work. DTB reports grants from MSD and Novocure, consulting fees from Nanocarry Therapeutics and Servier, and payment from Servier, outside of the submitted work. EO reports payment and support from Alexion for educational event, outside of the submitted work. EB reports grants from Roche and board participation for Novartis, Alexion and Gilead, outside of the submitted work. FC reports grants from Hall Hunter Foundation (UK), outside of the submitted work. HBF reports payments from Illumina and Sanofi Genzyme, support from Illumina, participation as scientific advisory committee for Sanofi Genzyme, International Gaucher Alliance and Igentify, stock from Igentify, and receipt of materials from Illumina, outside of the submitted work. IW reports grants from Chimerix and payment from COG Partners, outside of the submitted work. IS reports grants from Fondation Saint-Luc and FNRS-CDR, outside of the submitted work. JK reports other financial interests at Servier and PRA Health Sciences, outside of the submitted work. JRG-S reports participation on the board of the Philippine Society of Pediatric Oncology and Philippine Board of Pediatric Oncology, and stock in Macrogenics, Moderna, Mirati Therapeutics, CRISPR Therapeutics, Repligen, Quidelortho, and Shockwave Medical, outside of the submitted work. KJB reports consulting fees from US WorldMeds, Springworks Therapeutics, Alexion, and YmAbs, and payment from Alexion, outside of the submitted work. MS reports grants and support from the Swedish Childhood Cancer Fund, participation as a data safety and monitoring board member for clinical trial NCT05230758, and participation in the Swedish Pediatric CNS tumour group, outside of the submitted work. MAC reports financial support from SUNY Upstate Department of Pediatrics and board participation for Paige's Butterfly Run, outside of the submitted work. MO reports payment from Aptitude Health and participation on a data safety monitoring board or advisory board for Ultragenyx and Abeona, outside of the submitted works. MZ reports payment and support from and board participation for AstraZeneca. NW reports grants from CANSEARCH Foundation, Childhood Cancer Research Switzerland, and the Foundation for Children and Adolescents with Cancer; payment, support, and advisory board participation for Swedish Orphan Biovitrum; and board participation for Childhood Cancer Switzerland, outside of the submitted work. NH reports grants from the National Institutes of Health (NIH) and board participation for Incyte and Pfizer, outside of the submitted work. PCN reports grants from the Canadian Institutes for Health Research (CIHR) Foundation, US Department of Defense, and Garron Family Cancer Centre, outside of the submitted work. RP reports participation in the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, outside of the submitted work. RT reports consulting fees from Fennec Pharmaceuticals and Day One Biopharmaceuticals and payment from Fennec Pharmaceuticals, outside of the submitted work. SS reports payments from Sanofi Pharmaceuticals and Mylan Pharmaceutical, and board participation for Sanofi Pharmaceuticals, outside of the submitted work. SB reports consulting fees from Hoffmann-La Roche, YmAbs, MAP Biopharma and SERB SAS, and payment from Zschimmer & Schwarz Mohsdorf, outside of the submitted work. UI reports board participation in Pakistan Society of Pediatric Oncology, outside of the submitted work. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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