Mutations of TSHR and TP53 Genes in an Aggressive Clear Cell Follicular Carcinoma of the Thyroid

Abstract

Clear cell follicular carcinoma is a rare type of thyroid cancer and some with aggressive biological behavior. The cytoplasmic clearing of the neoplastic cells has been attributed to the accumulation of various substances, such as glycogen, lipid, mucin, and thyroglobulin, or distension of mitochondria or endoplasmic reticulum. However, the molecular mechanisms responsible for the characteristic appearance of the cell cytoplasm and the biological behavior remain unknown. We report here a case of aggressive clear cell follicular carcinoma of the thyroid with molecular profile using targeted next generation sequencing (NGS) that presented as a metastatic tumor in a woman with a history of breast carcinoma. The NGS data revealed the coexisting of a well-characterized loss-of-function TP53 R248Q mutation and a putative gain-of-function mutation of TSHR L272V, which was suggested by the overexpression of thyroglobulin and SLC5A5 (NIS) genes in this tumor. TP53 mutations are usually related with dedifferentiation, progression, and metastasis of thyroid carcinomas. Identification of TP53 R248Q in this tumor correlated with its aggressive clinical behavior. Gain-of-function mutation of TSHR can overstimulate the thyroid follicular cells as the elevated level of TSH does and might have contributed to the development of clear cell morphology in this tumor. This report represents the first case of clear cell follicular carcinoma of the thyroid with NGS analysis and more molecular characterization is needed to elucidate the pathogenesis and provide more prognosis-relevant information for this uncommon variant of thyroid carcinomas.

BRAFwild papillary thyroid carcinoma has two distinct mRNA expression patterns with different clinical behaviors

“…Subsequently, we tried to select genes that were differentially expressed between PTCs in cluster 1 and BRAF wild PTCs in cluster 2 (see Figure ). Unfortunately, we did not observe high expression of well‐known genes, such as BRAF , TERT , RAS , RET , TP53 , NTRK1 , or NTRK3 . We selected 100 differentially expressed genes by statistical analysis using paired the t test.…”

“…Unfortunately, we did not observe high expression of well-known genes, such as BRAF, TERT, RAS, RET, TP53, NTRK1, or NTRK3. [32][33][34][35][36][37] We selected 100 differentially expressed genes by statistical analysis using paired the t test. Although certain genes might not have significant functional roles, if the functional location of that gene is just upstream or just downstream of functionally important genes, such functionally insignificant genes can be selected as prediction markers.…”

Pitfalls in Challenging Thyroid Tumors: Emphasis on Differential Diagnosis and Ancillary Biomarkers

“…Gain-of-function mutation of TSHR might also contribute to the development of clear cell appearance in thyroid tumors [42]. Clear cell variants of follicular adenoma/carcinoma, oncocytic cell tumors, and papillary and medullary thyroid carcinoma have been recognized in the 2017 World Health Organization classification [2].…”

“…Traditionally, clear cell variants of thyroid carcinomas have not been linked to any biological aggressiveness. However, an aggressive clear cell variant of follicular thyroid carcinoma combining a putative gain of function of TSHR and a loss-of-function TP53 has also been reported [ 42 ].…”

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“…TERT promoter mutations have been observed in 5% to 25% of DTC, and it’s been reported that TERT promoter mutations contribute to aggressive behavior in DTC ( 20 , 21 , 22 ). These mutations have a significantly higher prevalence in aggressive thyroid tumor types such as widely invasive oncocytic carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas (ATC) ( 23 ). Similarly, TP53 mutations are prevalent in advanced tumors with a higher recurrence ( 24 ).…”