C van Marcke1, A Collard2, M Vikkula3, F P Duhoux4. 1. Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc and Institut de Recherche Expérimentale et Clinique (Pôle MIRO), Université catholique de Louvain, Brussels, Belgium; Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium. 2. Statistical Support Unit, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium. 3. Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium. 4. Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc and Institut de Recherche Expérimentale et Clinique (Pôle MIRO), Université catholique de Louvain, Brussels, Belgium; Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium. Electronic address: francois.duhoux@uclouvain.be.
Abstract
BACKGROUND: Gene-panels are used to assess predisposition to breast cancer by simultaneous testing of multiple susceptibility genes. This approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We performed a systematic review of published studies to calculate the prevalence of VUS and pathogenic variants (PV) in routinely tested breast cancer susceptibility genes in patients at high risk of breast cancer. METHODS: We comprehensively searched the literature using Medline through May 23, 2017 for studies conducting gene-panel testing on germline DNA of women with familial breast cancer and reporting on both PVs and VUSs. A meta-analysis of the collected data was carried out to obtain pooled VUS and PV prevalence estimates per gene using a generalized linear mixed model with logit link for binomial distribution. RESULTS: Of 602 publications, 4 were eligible and included 1870 patients. The panels encompassed 4-27 considered genes. Overall, the estimated probability per gene of a PV and VUS was 55% (95% confidence interval (CI) 26%-81%) and 91% (95% CI 78%-97%), respectively (p = 0.0066). The estimated probability per patient of a PV and VUS was 8% (95% CI 1%-34%) and 23% (95% CI 7%-52%), respectively (p = 0.0052). The ratio of VUS to PV was highest in the mismatch repair genes MLH1, MSH2, MSH6, PMS2 (18.7), CDH1 (13.4) and ATM (9.5). Amongst the 1468 patients tested for BRCA1 and BRCA2, only these two genes had a VUS to PV ratio of less than one (0.2 and 0.6, respectively). CONCLUSION: With the current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a PV. Better classification of VUSs is therefore critical and requires gene-specific VUS-assessment in every future study of gene-panel testing in patients at high risk of breast cancer.
BACKGROUND: Gene-panels are used to assess predisposition to breast cancer by simultaneous testing of multiple susceptibility genes. This approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We performed a systematic review of published studies to calculate the prevalence of VUS and pathogenic variants (PV) in routinely tested breast cancer susceptibility genes in patients at high risk of breast cancer. METHODS: We comprehensively searched the literature using Medline through May 23, 2017 for studies conducting gene-panel testing on germline DNA of women with familial breast cancer and reporting on both PVs and VUSs. A meta-analysis of the collected data was carried out to obtain pooled VUS and PV prevalence estimates per gene using a generalized linear mixed model with logit link for binomial distribution. RESULTS: Of 602 publications, 4 were eligible and included 1870 patients. The panels encompassed 4-27 considered genes. Overall, the estimated probability per gene of a PV and VUS was 55% (95% confidence interval (CI) 26%-81%) and 91% (95% CI 78%-97%), respectively (p = 0.0066). The estimated probability per patient of a PV and VUS was 8% (95% CI 1%-34%) and 23% (95% CI 7%-52%), respectively (p = 0.0052). The ratio of VUS to PV was highest in the mismatch repair genes MLH1, MSH2, MSH6, PMS2 (18.7), CDH1 (13.4) and ATM (9.5). Amongst the 1468 patients tested for BRCA1 and BRCA2, only these two genes had a VUS to PV ratio of less than one (0.2 and 0.6, respectively). CONCLUSION: With the current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a PV. Better classification of VUSs is therefore critical and requires gene-specific VUS-assessment in every future study of gene-panel testing in patients at high risk of breast cancer.
Authors: Elena Bueno-Martínez; Lara Sanoguera-Miralles; Alberto Valenzuela-Palomo; Ada Esteban-Sánchez; Víctor Lorca; Inés Llinares-Burguet; Jamie Allen; Alicia García-Álvarez; Pedro Pérez-Segura; Mercedes Durán; Douglas F Easton; Peter Devilee; Maaike Pg Vreeswijk; Miguel de la Hoya; Eladio A Velasco-Sampedro Journal: J Pathol Date: 2022-07-15 Impact factor: 9.883
Authors: Li Sun; Adam Brentnall; Shreeya Patel; Diana S M Buist; Erin J A Bowles; D Gareth R Evans; Diana Eccles; John Hopper; Shuai Li; Melissa Southey; Stephen Duffy; Jack Cuzick; Isabel Dos Santos Silva; Alec Miners; Zia Sadique; Li Yang; Rosa Legood; Ranjit Manchanda Journal: JAMA Oncol Date: 2019-10-03 Impact factor: 31.777