Targeted Next-Generation Sequencing of Thyroid Fine-Needle Aspirates Identifies Incidental Germline Findings

  • Background/Purpose.
    Identification of individuals at high-risk for cancer can help cancer prevention and early detection and can guide cancer treatment. Aim of this study was to describe incidental germline mutations identified through in-house FNA testing of thyroid nodule patients who underwent somatic genotyping.

    FNA thyroid samples (n=123) from 117 patients with thyroid nodules were tested for mutations in 19 thyroid cancer drivers using NGS. Genes with hereditary cancer associations as defined in ACMG (American College of Medical Genetics and Genomics) list (RET, PTEN, TP53) were included1. After variant calling and annotation, only rare variants (MAF<0.005 in European population) suspected to be of germline origin (allele fraction 40% to 60%) were considered. Germline status of each variant was confirmed by Sanger sequencing on normal thyroid tissues of patients who underwent thyroidectomy.

    Fifty-seven nodules harbored at least 1 germline and rare variant. Overall, 71variants in 14 genes were identified in 54 patients (46%), with TG mutations being the most common (30%). Thirty-nine variants were previously annotated in Clin Var dataset, with three of them identified as pathogenic (3%) and clinically associated with familial breast cancer or Cowden disease. Among the 32 unreported variants, further likely pathogenic variants may be found, including a novel RET mutation in a young woman with no current evidence of disease.

    Discussion & Conclusion
    Our findings provide evidence that cancer predisposition mutations can be identified also from FNA samples testing, thus allowing the enrollment of at-risk patients in routine follow-up. However, patients should be previously informed that FNA testing may identify incidental findings.


Leave a Reply