Prevalence and characteristics of likely-somatic variants in cancer susceptibility genes among individuals who had hereditary pan-cancer panel testing
| Autor: | Thomas P. Slavin, Hannah C. Cox, Susan L. Neuhausen, Jeffrey N. Weitzel, Guido Marcucci, Bradford Coffee, Debora Mancini-DiNardo, Ryan Bernhisel, Jennifer Logan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Cancer Research Somatic cell Ataxia Telangiectasia Mutated Proteins Biology DNA sequencing Germline Article 03 medical and health sciences 0302 clinical medicine Gene Frequency Neoplastic Syndromes Hereditary Genetics medicine Humans Mass Screening Genetic Predisposition to Disease Molecular Biology Allele frequency Gene CHEK2 Germ-Line Mutation Aged Base Sequence Cancer High-Throughput Nucleotide Sequencing Middle Aged medicine.disease Checkpoint Kinase 2 030220 oncology & carcinogenesis Tumor Suppressor Protein p53 Likely somatic |
| Zdroj: | Cancer Genet |
| Popis: | Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.22%) individuals. They were most frequent in TP53, CHEK2 and ATM, commonly as C-to-T transitions. Among individuals who carried a likely-somatic variant and reported no personal cancer history, 54.2% (78/144) carried a variant in TP53, CHEK2 or ATM. With a reported cancer history, this percentage increased to 81.1% (494/609), predominantly in CHEK2 and TP53. Their presence was associated with age (OR=3.1, 95% CI 2.5, 3.7; p0.001) and personal history of cancer (OR=3.3, 95% CI 2.7, 4.0; p0.001), particularly ovarian cancer. Germline ATM pathogenic variant carriers showed significant enrichment of likely-somatic variants (OR=2.8, 95% CI 1.6, 4.9; p = 0.005), regardless of cancer status. The appearance of likely-somatic variants is consistent with clonal hematopoiesis, possibly influenced by cancer treatment. These findings highlight the precision required of diagnostic laboratories to deliver accurate germline testing results. |
| Databáze: | OpenAIRE |
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