Original Title: État des connaissances - Panels des prédispositions aux cancers pédiatriques par séquençage de nouvelle génération

Authors' objectives: The mandate of the Réseau québécois de diagnostic moléculaire (RQDM), of which the Centre québécois de génomique clinique (CQGC) is a part of, is to meet the current and future needs of the health and social services system in the field of molecular diagnostics and personalized medicine, particularly with regard to the diagnosis of rare diseases and oncology. To this end, the RQDM, with the support of the Ministère de la Santé et des Services sociaux (MSSS), has undertaken a vast project to upgrade technology and develop and repatriate next-generation sequencing (NGS) tests performed outside Québec. The rollout of this project undoubtedly entails opportunities and risks for the overall offer of NGS services and will require reflection in this regard. At the MSSS’s request, the Institut national d'excellence en santé et en services sociaux (INESSS) carried out a rapid assessment of the relevance and challenges of the tests developed by the RQDM and, where advisable, how best to implement them from the overall perspective of Québec’s healthcare system. The information on each test gathered by INESSS is consolidated in individual reports like this one. This report concerns virtual panels of genes associated with the predisposition to pediatric cancers analyzed by NGS.

Authors' results and conclusions: RESULTS (#1 CLINICAL CONTEXTS AND PROPOSED TESTS): Predispositions to pediatric hereditary cancers constitute a heterogeneous group of syndromes associated with the development of pediatric signature cancers. It is estimated that at least 10 % of patients with a pediatric cancer carry a mutation in one of the genes associated with a cancer predisposition syndrome. Diagnosing these syndromes can influence the management of childhood cancers and the preventive follow-up that would be done afterwards. (#2 CLINICAL VALIDITY): In hereditary genetics, the clinical validity of a multigene panel analyzed by sequencing is determined, among other things, by the correspondence of the genes in the panel with the target disease. The panel should therefore include all the genes for which variants have been clearly identified as being responsible for the disease (pathogenic variants). The genes included in each virtual panel were selected by the RQDM’s working group on the molecular investigation of hereditary pediatric cancer predisposition syndromes on the basis of the scientific evidence available when they were evaluated. The contents of the two virtual panels proposed by the requester were compared with those of the hereditary cancer predisposition panels recommended by ClinGen and PanelApp. In all, more than 75 % of the genes in each of the virtual panels are in one of the panels recommended by these two organizations. The validity of the KLLN (solid tumour panel) and BRAF, CSF3R, FANCM, LZTR1, NRAS, RAD51C and RIT1 (hematologic cancer panel) genes is uncertain, as they are not classified as being clinically relevant in these organizations’ panels. Lastly, the diagnostic performance of the proposed tests has been estimated at 10 %, which is the proportion of pediatric cancer cases in which germline mutations in an oncogene have been observed. (#3 CLINICAL UTILITY): Based on the data provided by the requester and on the reviewed literature, the analysis of germline predispositions to hereditary pediatric cancers is useful primarily for managing cancer patients. Indeed, the discovery of germline variants associated with hereditary cancer predisposition syndromes will also determine the choice of cancer therapy and how these patients will be followed in the long-term. The family members of a patient in whom a pathogenic variant has been identified could be carriers as well and thus benefit from increased medical surveillance. (#4 IMPLEMENTATION CONSIDERATIONS): The experts shared several issues involved in medical genetics services. Firstly, the reports produced will need to be user-friendly to make their interpretation by the professionals who order the tests easier and to limit the number of medical genetics requests. At the moment, the wait time for accessing medical genetics consultations is very long because of the limited resources and growing needs. Opening germline testing to all cases of pediatric cancer will necessarily increase the number of requests for medical genetics services and the strain on staff. An increase in the volume of test requests for relatives of a person with a germline pathogenic variant should also be considered in resource planning, particularly for genetic counselling. The risk of incidental findings is not negligible, given the number of genes included in each virtual panel and the high genetic heterogeneity of pediatric cancers. The experts consulted stressed the importance of obtaining informed consent and offering genetic counseling before and after pediatric germline genetic testing. The impact of a positive result on the cancer patient and their family can be considerable and must be clearly stated and understood.(#5 ECONOMIC ANALYSIS): A rapid review of the scientific literature was carried out. However, no cost-effectiveness studies on the use of the whole exome to molecularly diagnose a hereditary predisposition to pediatric cancers were selected. It should be noted that, given the nature of the MSSS’s request to INESSS, no modeling was done. Nevertheless, considering that their clinical benefits are at least equivalent to those of the commercial panels currently sent outside Québec, the proposed virtual panels could be cost-effective, since they are less expensive. However, the cost-effectiveness of the commercial panels sent outside Québec has never been evaluated by INESSS. Even if major economic uncertainties remain, particularly with regard to the costs associated with implementing and organizing the services, the budget impact analysis suggests that including the two gene panels in question in the Répertoire des panels de gènes associés aux cancers pédiatriques could result in a cost increase of approximately $ 449,000 over the first three years. This would essentially be due to the higher volume of requests following repatriation. CONCLUSION: The findings and conclusions of this report are based on a rapid review of the scientific and grey literature, and on contextual data and experiential knowledge. The approach consists of a summary risk analysis to guide the MSSS’s decision regarding testing for hereditary pediatric cancer predisposition syndromes by next-generation sequencing. Certain issues were raised concerning the age limits, clinical algorithms and access to medical genetics services, including genetic counselling. Implementing the proposed tests would help harmonize molecular diagnostic practices for pediatric cancer cases. Organizational improvements in sample transport and in biological specimen and test report traceability could, however, improve the current situation. It is essential that the impact of a positive germline genetic test result are clearly explained to patients and their families. The proposed panels have a lower per-test cost than those currently performed in the same clinical context but outside Québec. However, their implementation could generate additional costs of approximately $ 449,000 over the first three years.

Authors' methods: The approach included a rapid review of the scientific and grey literature for the clinical and economic aspects, a budget impact analysis, and consultations with Québec experts. Only items containing synthesis data or recommendations relating to the use of NGS to diagnose pediatric cancer predisposition syndromes were selected. INESSS set up an advisory committee whose members were invited to express their views on the various clinical implementation issues and aspects relating to the proposed test. The final findings stem from the triangulation of the scientific data, the positions of the main learned societies consulted, and the contextual data and experiential knowledge that were gathered.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panels-des-predispositions-aux-cancers-pediatriques-par-sequencage-de-nouvelle-generation.html

Year Published: 2023

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panels-des-predispositions-aux-cancers-pediatriques-par-sequencage-de-nouvelle-generation.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)