Title

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes

Authors

Catherine Goudie, Division of Hematology-Oncology, Department of Pediatrics, McGill University Health Centre, Montreal, Quebec, Canada.
Leora Witkowski, McGill University Health Centre, Department of Human Genetics, Montreal, Quebec, Canada.
Noelle Cullinan, Department of Haematology-Oncology, Children's Health Ireland, Crumlin, Dublin, Ireland.
Lara Reichman, Department of Child Health and Human Development, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
Ian Schiller, Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Melissa Tachdjian, Department of Child Health and Human Development, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
Linlea Armstrong, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Katherine A. Blood, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Josée Brossard, Division of Pediatric Hematology-Oncology, Department of Pediatrics, CIUSSS de l'Estrie - CHUS, Sherbrooke, Quebec, Canada.
Ledia Brunga, Department of Genetics and Genome Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Chantel Cacciotti, Department of Pediatric Oncology-Hematology, Children's Hospital-London Health Sciences Centre, London, Ontario, Canada.
Kimberly Caswell, Department of Genetics and Genome Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Sonia Cellot, Charles-Bruneau Cancer Centre, Pediatric Hematology-Oncology Division, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, Montreal, Quebec, Canada.
Mary Egan Clark, Cancer Predisposition Division, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Catherine Clinton, Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
Hallie Coltin, Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Kathleen Felton, Pediatric Hematology/Oncology, Jim Pattison Children's Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Conrad V. Fernandez, Division of Hematology/Oncology, Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.
Adam J. Fleming, Division of Pediatric Hematology/Oncology, McMaster Children's Hospital, Hamilton, Ontario, Canada.
Noemi Fuentes-Bolanos, Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales Sydney, Kensington, New South Wales, Australia.
Paul Gibson, Division of Pediatric Hematology/Oncology, McMaster Children's Hospital, Hamilton, Ontario, Canada.
Ronald Grant, Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Rawan Hammad, Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Lynn W. Harrison, Cancer Predisposition Division, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Meredith S. Irwin, Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Donna L. Johnston, Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Sarah Kane, Division of Clinical Genetics, Department of Hereditary Cancer and Genetics, Memorial Sloan-Kettering Cancer Center, Basking Ridge, New Jersey.
Lucie Lafay-Cousin, Section of Pediatric Hematology Oncology and Bone Marrow Transplantation, Alberta Children's Hospital, Calgary, Alberta, Canada.
Irene Lara-Corrales, Section of Dermatology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Valerie Larouche, Department of Pediatrics, Centre mère-enfant Soleil du CHU de Québec-Université Laval, Québec City, Quebec, Canada.
Natalie Mathews, Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
M Stephen Meyn, Center for Human Genomics and Precision Medicine, University of Wisconsin School of Medicine and Public Health, Madison.
Orli Michaeli, Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Abstract

IMPORTANCE: Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. OBJECTIVE: To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. DESIGN, SETTING, AND PARTICIPANTS: In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. EXPOSURES: Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. MAIN OUTCOMES AND MEASURES: The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. RESULTS: In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. CONCLUSIONS AND RELEVANCE: In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Publication Title

JAMA oncology

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