High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

Abstract

The close association between pre-existing Hashimoto’s thyroiditis and thyroid cancer is well established. The simultaneous occurrence of multiple neoplastic foci within the same organ suggests a common genotoxic effect potentially contributing to carcinogenesis, the nature of which is still not clear. Next-generation sequencing (NGS) provides a potent tool to demonstrate and compare the mutational profile of the independent neoplastic foci. Our collection of 47 cases with thyroid carcinoma and Hashimoto’s thyroiditis included 14 with at least two tumorous foci. Detailed histological analysis highlighted differences in histomorphology, immunoprofile, and biological characteristics. Further, a 67-gene NGS panel was applied to demonstrate the mutational diversity of the synchronic tumors. Significant differences could be detected with a wide spectrum of pathogenic gene variants involved (ranging between 5 and 18, cutoff >5.0 variant allele frequencies (VAF)). Identical gene variants represented in both synchronous tumors of the same thyroid gland were found in only two cases (BRAF and JAK3 genes). An additional set of major driver mutations was identified at variable allele frequencies in a highly individual setup suggesting a clear clonal independence. The different BRAF statuses in coincident thyroid carcinoma foci within the same organ outline a special challenge for molecular follow-up and therapeutic decision-making.

Association of Chronic Lymphocytic Thyroiditis with the Surgical Diseases of the Thyroid Gland

“…Despite this, the presence of CLT had a negative effect on the accuracy rate of cytological diagnoses and increased the suspicious diagnosis rate. In the literature, gene expression classifiers and next-generation sequencing have been used with an attempt to improve the poor accuracy of FNAB in the presence of CLT, but convincing results have not yet been reported (20,21). We consider that studies in the field of molecular and genetics can make important contributions to the development of new methods for the accurate diagnosis of malignancies, especially in cases with CLT coexistence.…”

Genome‐wide DNA methylation analysis of Hashimoto's thyroiditis during pregnancy

“…Similarly, Molnar et al . [20] demonstrated the up‐regulated level of NOTCH1 in HT using a next‐generation sequencing analysis. Moreover, the role of the gene in several autoimmune diseases through modulating T‐cell activation has been reported [21,22].…”

“…Moreover, the significantly enriched KEGG pathways included the FoxO signaling pathway (Figure 4C). [20]. Moreover, the role of the gene in several autoimmune diseases through modulating T cell activation has been reported [21,22].…”

Next-Generation Sequencing in Tumor Diagnosis and Treatment

“…An NGS approach identified pathogenic variants of 41 genes in carcinomas associated with Hashimoto’s thyroiditis, and several genes harbored multiple variants. Identical gene variants represented in both synchronous tumors of the same thyroid gland were found only in a small fraction of cases [ 3 ]. Common gene variants were found in BRAF (1 case) and JAK3 (1 case); however, each tumor pair featured several other additional dominant variants, which were unrelated [ 3 ].…”

“…Identical gene variants represented in both synchronous tumors of the same thyroid gland were found only in a small fraction of cases [ 3 ]. Common gene variants were found in BRAF (1 case) and JAK3 (1 case); however, each tumor pair featured several other additional dominant variants, which were unrelated [ 3 ]. This massive parallel analysis suggests the presence of characteristic genetic patterns for different thyroid carcinoma etiologies.…”