Cascading After Peridiagnostic Cancer Genetic Testing: An Alternative to Population-Based Screening
Ce dossier présente deux études menées aux Etats-Unis, l'une évaluant la faisabilité d'une nouvelle stratégie, comportant une consultation de conseil génétique par téléphone et l'envoi d'un test génétique utilisant l'ADN salivaire, pour améliorer le taux d'utilisation de tests génétiques chez les parents de patients atteints d'un cancer ayant pour origine une mutation constitutionnelle (30 patients et 102 parents de patients ; âge médian : 51 ans), l'autre estimant le délai nécessaire pour identifier, à l'aide d'une stratégie favorisant l'utilisation de tests génétiques au sein des familles des patients, l'ensemble des porteurs de variants constitutionnels de susceptibilité au cancer, en fonction de différents facteurs (taille de la famille, taux de diffusion des informations génétiques, taux de couverture des parents au premier, deuxième ou troisième degré)
PURPOSE : Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information.
METHODS : Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size.
RESULTS : The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations.
CONCLUSION : Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.
Journal of Clinical Oncology , article en libre accès, 2019