Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)

Fecha de publicación: 18/01/2019

Autores de IIS La Fe

• Inmaculada De Juan Jiménez

  Autor

• Sarai Palanca Suela

  Autor

• Juan Silvestre Oltra Soler

  Autor

• Ángel Agustín Segura Huerta

  Autor

Participantes ajenos a IIS La Fe

• Ramirez-Calvo, M
• Garcia-Casado, Z
• Fernandez-Serra, A
• Soto, JL
• Castillejo, A
• Barbera, VM
• Juan-Fita, MJ
• Chirivella, I
• Sanchez, AB
• Tena, I
• Chaparro, C
• Salas, D
• Lopez-Guerrero, JA

Grupos

• Investigación Clínica y Traslacional en Cáncer

  

  Leader

  José Gómez Codina

• Investigación Traslacional en Genética

  

  Leader

  Francisco Martínez Castellano

Abstract

BackgroundApproximately 5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS). In the context of the Program of Hereditary Cancer of the Valencia Community, individuals belonging to specific HCS and their families receive genetic counselling and genetic testing according to internationally established guidelines. The current diagnostic approach is based on sequencing a few high-risk genes related to each HCS; however, this method is time-consuming, expensive and does not achieve a confirmatory genetic diagnosis in many cases. This study aims to test the level of improvement offered by a Next Generation Sequencing (NGS) gene-panel compared to the standard approach in a diagnostic reference laboratory setting.MethodsA multi-gene NGS panel was used to test a total of 91 probands, previously classified as non-informative by analysing the high-risk genes defined in our guidelines.ResultsNineteen deleterious mutations were detected in 16% of patients, some mutations were found in already-tested high-risk genes (BRCA1, BRCA2, MSH2) and others in non-prevalent genes (RAD51D, PALB2, ATM, TP53, MUTYH, BRIP1).ConclusionsOverall, our findings reclassify several index cases into different HCS, and change the mutational status of 14 cases from non-informative to gene mutation carriers. In conclusion, we highlight the necessity of incorporating validated multi-gene NGS panels into the HCSs diagnostic routine to increase the performance of genetic diagnosis.

Keywords

• Hereditary Cancer syndrome; Genetic counselling; Next generation sequencing; Multi-gene panel; Diagnostic accuracy