Dataset Information

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

ABSTRACT:

Background

In the context of our Regional Program of Hereditary Cancer, individuals fulfilling the criteria are tested for germline mutations to subsequently establish the clinical management. Our standard diagnostic approach focuses on sequencing a few classic high-risk genes, a method that frequently renders uninformative genetic results. This study aims to examine the improved yield offered by an On-Demand panel.

Methods

We designed an On-Demand panel for the analysis of 35-genes associated with inherited cancer susceptibility in a total of 128 cases of Hereditary Breast and Ovarian Cancer (HBOC) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC).

Results

Eighteen deleterious mutations were detected, in both routinely (BRCA2, MLH1, MSH2, PMS2) and non-routinely (ATM, BLM, BRIP1, CHEK2, MUTYH) tested genes. The screening extended to 35 genes rendered by patients carrying several- up to 6-Variants of Unknown Significance (VUS). Moreover, we confirmed the splicing disruption at RNA level for a not previously reported BRIP1 splicing mutation. Using an On-Demand panel, we identified 18 pathogenic mutation carriers, seven of which would have gone unnoticed with traditional analysis.

Conclusions

Our results reinforce the utility of NGS gene panels in the diagnostic routine to increase the performance of genetic testing, especially in individuals from families with overlapping cancer phenotypes.

SUBMITTER: Velazquez C

PROVIDER: S-EPMC7288470 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

Velázquez Carolina C Lastra Enrique E Avila Cobos Francisco F Abella Luis L de la Cruz Virginia V Hernando Blanca Ascensión BA Hernández Lara L Martínez Noemí N Infante Mar M Durán Mercedes M

Journal of translational medicine 20200610 1

<h4>Background</h4>In the context of our Regional Program of Hereditary Cancer, individuals fulfilling the criteria are tested for germline mutations to subsequently establish the clinical management. Our standard diagnostic approach focuses on sequencing a few classic high-risk genes, a method that frequently renders uninformative genetic results. This study aims to examine the improved yield offered by an On-Demand panel.<h4>Methods</h4>We designed an On-Demand panel for the analysis of 35-gen ...[more]

PMID: 32522261

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Project description:BackgroundIn a considerable number of patients with a suspected hereditary tumor syndrome (HTS), no underlying germline mutation is detected in the most likely affected genes. The present study aimed to establish and validate a large gene panel for HTS, and determine its diagnostic yield and clinical utility.MethodsThe study cohort comprised 173 patients with suspected, but unexplained, HTS (group U) and 64 HTS patients with a broad spectrum of known germline mutations (group K). All patients in group U presented with early age at onset, multiple tumors, and/or a familial clustering of various tumor types; no germline mutation had been identified during routine diagnostics. Sequencing of leukocyte DNA was performed for the 94 HTS genes of the Illumina TruSight™Cancer Panel and 54 additional HTS genes.ResultsThe sensitivity of the panel to identify known germline variants was 99.6%. In addition to known mutations, a total of 192 rare, potentially pathogenic germline variants in 86 genes were identified. Neither the proportion of rare variants per patient (group K: 0.9 variants; group U: 0.8 variants) nor the proportion of variants in the most frequently mutated, moderately penetrant genes CHEK2 and ATM showed significant inter-group difference. Four of the five patients from group U with a truncating CHEK2 mutation had thyroid cancer, pointing to a broader tumor spectrum in patients with pathogenic CHEK2 variants. In 22% of patients from group K, a further potential causative variant was identified. Here, the most interesting finding was an NF1 nonsense mutation in a child with a known TP53 frameshift mutation. In 17% of patients from group U, potential causative variants were identified. In three of these patients (2%), mutations in PMS2, PTEN, or POLD1 were considered to be causative. In both groups, incidental findings with presumptive predictive value were generated.ConclusionsThe gene panel identified the genetic cause in some prescreened, unexplained HTS patients and generated incidental findings. Some patients harbored predicted pathogenic mutations in more than one established HTS gene, rendering interpretation of the respective alterations challenging. Established moderate risk genes showed an almost equal distribution among patients with known and unexplained disease.

Project description:BackgroundNext generation sequencing (NGS) has been a handy tool in clinical practice, mainly due to its efficiency and cost-effectiveness. It has been widely used in genetic diagnosis of several inherited diseases, and, in clinical oncology, it may enhance the discovery of new susceptibility genes and enable individualized care of cancer patients. In this context, we explored a pan-cancer panel in the investigation of germline variants in Brazilian patients presenting clinical criteria for hereditary cancer syndromes or familial history.MethodsSeventy-one individuals diagnosed or with familial history of hereditary cancer syndromes were submitted to custom pan-cancer panel including 16 high and moderate penetrance genes previously associated with hereditary cancer syndromes (APC, BRCA1, BRCA2, CDH1, CDKN2A, CHEK2, MSH2, MSH6, MUTYH, PTEN, RB1, RET, TP53, VHL, XPA and XPC). All pathogenic variants were validated by Sanger sequencing.ResultsWe identified a total of eight pathogenic variants among 12 of 71 individuals (16.9%). Among the mutation-positive subjects, 50% were diagnosed with breast cancer and had mutations in BRCA1, CDH1 and MUTYH. Notably, 33.3% were individuals diagnosed with polyposis or who had family cases and harbored pathogenic mutations in APC and MUTYH. The remaining individuals (16.7%) were gastric cancer patients with pathogenic variants in CDH1 and MSH2. Overall, 54 (76.05%) individuals presented at least one variant uncertain significance (VUS), totalizing 81 VUS. Of these, seven were predicted to have disease-causing potential.ConclusionOverall, analysis of all these genes in NGS-panel allowed the identification not only of pathogenic variants related to hereditary cancer syndromes but also of some VUS that need further clinical and molecular investigations. The results obtained in this study had a significant impact on patients and their relatives since it allowed genetic counselling and personalized management decisions.

Dataset Information

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

Background

Methods

Results

Conclusions

Publications

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

Similar Datasets

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