Original Title: État des connaissances - Panel pour la recherche de mutations myéloïdes 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, is to meet the current and future needs of the health and social services network in the fields of molecular diagnostics and personalized medicine, particularly regarding the diagnosis of rare diseases and cancer. To this end, 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) analyses. The implementation of this project undoubtedly entails both opportunities and risks for the overall NGS service offering and requires careful consideration. At the request of the MSSS, the Institut national d'excellence en santé et en services sociaux (INESSS) carried out a rapid assessment of the relevance, issues and, where applicable, optimal implementation modalities associated with the analyses developed by RQDM, from a global perspective of the Quebec healthcare system. The information gathered by INESSS on each analysis is consolidated in individual, self-supporting documents such as this one. This report deals specifically with SNG gene panels to detect myeloid mutations.

Authors' results and conclusions: (#1 CLINICAL CONTEXTS AND PROPOSED ANALYSES): The three groups of conditions covered by the myeloid mutations panel are myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and clonal cytopenias of undetermined significance (CCUS). Diagnosis of these conditions is currently mainly supported by cytomorphological analysis, pathology, flow cytometry, specific mutation testing and cytogenetics. However, the search for mutations in a larger number of genes may contribute to the diagnosis or prognostic stratification of the disease. These mutations are covered by the gene panel currently used for prognostic stratification of acute myeloid leukemia (AML); a test available from the Répertoire québécois et système de mesure des procédures de biologie médicale (hereinafter referred to as Répertoire) since 2015. This is a commercial kit of 143 genes associated with myeloid cancers, from which the results of 46 genes will be reported in the context of current knowledge in hematological oncology. Sequencing will be performed on DNA extracted from bone marrow, blood, or fixed tissue samples. (#2 VALIDITY AND CLINICAL UTILITY): In somatic genetics, the clinical validity of a multigene analysis performed by SNG is defined by its ability to establish the sequence of genes or loci of clinical interest from tissues or cells. The allele frequency detection limit with the selected technology is approximately 5% at 500X coverage, for both substitutions and microdeletions. The selection of genes for the panel was based on published scientific literature and recommendations from learned societies. Most genes and mutations to be analyzed are associated with a favorable or unfavorable prognosis in the context of MDS and MPN or allow clonality to be determined. A few genes help to clarify the diagnosis or are associated with an inherited predisposition to myeloid hemopathies. It should be noted that there are few recommendations from learned societies for the diagnosis and prognostic stratification of CCUS, which only entered the official WHO classification in 2022. In this classification, CCUS are defined by cytopenias associated with clonal hematopoiesis, with the presence of mutations associated with myeloid cancers at an allelic frequency greater than or equal to 2%. (#3 IMPLEMENTATION CONSIDERATIONS ): Members of the Advisory Committee stressed the complexity of diagnosis and prognostic stratification of hematological malignancies. In their view, signs and symptoms, blood and bone marrow aspirate results are all integral to diagnosis. Moreover, to ensure that results are available within an acceptable timeframe, traditional cytogenetic tests are often performed in parallel, and in some cases, it may be difficult to wait for the results of one test before proceeding with the second. To ensure the relevance of requests for evaluation, and to avoid transferring the entire responsibility for managing requests to the laboratory, members of the Advisory Committee propose authorizing prescriptions by other specialists, such as internists, but that such prescriptions be validated by a hematologist, without requiring a consultation for the patient. (#4 ECONOMIC ANALYSIS): A rapid review of the scientific literature was conducted. However, no cost-effectiveness studies regarding the use of a gene panel for the diagnostic and prognostic characterization of myeloid hematological cancers were retained. Given the nature of the mandate given to INESSS by the MSSS, no economic modeling was done. Nevertheless, compared with commercial panels currently sent outside Quebec, the proposed panel is less costly. It should be noted that the efficiency of commercial panels sent outside Quebec has never been evaluated by INESSS. CONCLUSION: The findings and conclusions of this report are based on a rapid review of the scientific and grey literature, as well as contextual data and experiential knowledge. This state of the art is intended to support the MSSS in its decision to make available an analysis for the diagnosis and prognostic stratification of hematological malignancies. During this exercise, no major concerns were identified, and the information gathered supports the relevance of offering this analysis. However, uncertainties related to the availability of resources and the organization of services surrounding the performance of this analysis in the province of Quebec were highlighted and should be explored to ensure optimal implementation.

Authors' methods: The approach includes a rapid review of the scientific and grey literature for the clinical and economic aspects, a budget impact analysis, and consultations with Quebec experts. Only documents presenting synthesis data or recommendations related to the use of N testing for myeloid mutations were retained. INESSS set up an advisory committee where members were invited to express their views on the various issues associated with the repatriation of the proposed test. The final findings are based on the triangulation of scientific data, the positions taken by the main learned societies consulted, and the contextual data and experiential knowledge gathered.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panel-pour-la-recherche-de-mutations-myeloides-par-sequencage-de-nouvelle-generation.html

Year Published: 2023

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panel-pour-la-recherche-de-mutations-myeloides-par-sequencage-de-nouvelle-generation.html

English language abstract: An English language summary is available

Publication Type: Other

Country: Canada

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)