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.
Highlights
5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS)
The identification of gene mutation carriers constitutes a challenge for the Public Health System in terms of prevention and early diagnosis of tumours associated with each HCS
Our better understanding of tumour genetics together the availability of cutting-edge sequencing technologies requires a continuous evaluation of clinical guidelines and analytical procedures to improve the performance of genetic counselling programmes
Summary
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 identification of gene mutation carriers constitutes a challenge for the Public Health System in terms of prevention and early diagnosis of tumours associated with each HCS. The identification of gene mutation carriers in relatives of HCS families has important implications in the field of cancer prevention, early diagnosis and in reproductive decision-making. In order to manage these high-risk individuals, clinical practice guidelines and specific genetic counselling programmes have been incorporated in the context of health care institutions. Our better understanding of tumour genetics together the availability of cutting-edge sequencing technologies requires a continuous evaluation of clinical guidelines and analytical procedures to improve the performance of genetic counselling programmes
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