Doua Bakry1, Melyssa Aronson2, Carol Durno3, Hala Rimawi4, Roula Farah5, Qasim Kholaif Alharbi6, Musa Alharbi7, Ashraf Shamvil8, Shay Ben-Shachar9, Matthew Mistry10, Shlomi Constantini11, Rina Dvir12, Ibrahim Qaddoumi13, Steven Gallinger2, Jordan Lerner-Ellis14, Aaron Pollett15, Derek Stephens16, Steve Kelies17, Elizabeth Chao17, David Malkin1, Eric Bouffet18, Cynthia Hawkins19, Uri Tabori20. 1. Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. 2. The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada. 3. The Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre for Digestive Disease and Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Nutrition and Hepatology, The Hospital for Sick Children, Toronto, Canada. 4. Faculty of Medicine, Jordan University of Science & Technology, Irbid, Jordan. 5. Saint George Hospital University Medical Center, Beirut, Lebanon. 6. King Fahad Specialist Hospital, Department of Pediatric Hematology/Oncology and Stem Cell Transplant, Dammam, Saudi Arabia. 7. King Fahad City Center, Riyahd, Saudi Arabia. 8. Children Cancer Hospital, Karachi, Pakistan. 9. The Gilbert Israeli Neurofibromatosis Center (GINFC), Tel-Aviv Medical Center, Tel-Aviv, Israel. 10. Genetic and Genomic Program, Institute of Medical Sciences, The University of Toronto, Israel. 11. Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel-Aviv, Israel. 12. Pediatric Hemato-Oncology Department, Tel Aviv Medical Center, Tel-Aviv, Israel. 13. St. Jude Children's Research Hospital, Memphis, TN, USA. 14. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada; Dept of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Ontario Institute of Cancer Research, Genome Technologies Platform, Canada. 15. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada; Dept of Lab Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 16. Dalla Lana School of Public Health University of Toronto, Canada; Clinical Research, The Hospital for Sick Children, Canada. 17. Ambry Genetics, Aliso Viejo, CA, USA. 18. Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Arthur and Sonia Labbatt Brain Tumor Research Center, Toronto, Ontario, Canada. 19. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada. 20. Division of Hematology/Oncology, The Hospital for Sick Children, Institute of Medical Sciences, The University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Arthur and Sonia Labbatt Brain Tumor Research Center, Toronto, Ontario, Canada. Electronic address: uri.tabori@sickkids.ca.
Abstract
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. METHODS: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. RESULTS: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. DISCUSSION: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. METHODS: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. RESULTS: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. DISCUSSION: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.
Authors: A Kerpel; M Yalon; M Soudack; J Chiang; A Gajjar; K E Nichols; Z Patay; S Shrot; C Hoffmann Journal: AJNR Am J Neuroradiol Date: 2020-04-30 Impact factor: 3.825
Authors: Matthew Mistry; Nataliya Zhukova; Daniele Merico; Patricia Rakopoulos; Rahul Krishnatry; Mary Shago; James Stavropoulos; Noa Alon; Jason D Pole; Peter N Ray; Vilma Navickiene; Joshua Mangerel; Marc Remke; Pawel Buczkowicz; Vijay Ramaswamy; Ana Guerreiro Stucklin; Martin Li; Edwin J Young; Cindy Zhang; Pedro Castelo-Branco; Doua Bakry; Suzanne Laughlin; Adam Shlien; Jennifer Chan; Keith L Ligon; James T Rutka; Peter B Dirks; Michael D Taylor; Mark Greenberg; David Malkin; Annie Huang; Eric Bouffet; Cynthia E Hawkins; Uri Tabori Journal: J Clin Oncol Date: 2015-02-09 Impact factor: 44.544
Authors: Chen Yang; Frances Austin; Hope Richard; Michael Idowu; Vernell Williamson; Fernanda Sabato; Andrea Ferreira-Gonzalez; Scott A Turner Journal: Cold Spring Harb Mol Case Stud Date: 2019-10-23
Authors: Melissa A Galati; Karl P Hodel; Zachary F Pursell; Uri Tabori; Miki S Gams; Sumedha Sudhaman; Taylor Bridge; Walter J Zahurancik; Nathan A Ungerleider; Vivian S Park; Ayse B Ercan; Lazar Joksimovic; Iram Siddiqui; Robert Siddaway; Melissa Edwards; Richard de Borja; Dana Elshaer; Jiil Chung; Victoria J Forster; Nuno M Nunes; Melyssa Aronson; Xia Wang; Jagadeesh Ramdas; Andrea Seeley; Tomasz Sarosiek; Gavin P Dunn; Jonathan N Byrd; Oz Mordechai; Carol Durno; Alberto Martin; Adam Shlien; Eric Bouffet; Zucai Suo; James G Jackson; Cynthia E Hawkins; Cynthia J Guidos Journal: Cancer Res Date: 2020-09-16 Impact factor: 12.701
Authors: Erika K S M Leenders; Harm Westdorp; Roger J Brüggemann; Jan Loeffen; Christian Kratz; John Burn; Nicoline Hoogerbrugge; Marjolijn C J Jongmans Journal: Eur J Hum Genet Date: 2018-06-14 Impact factor: 4.246