title: 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.
authors.affiliation: Department of Pathology, Staten Island University Hospital, 475 Seaview Avenue, New York, NY, 10305, USA. tongguoxia@gmail.com.
authors.forename: Guo-Xia
authors.initials: GX
authors.lastname: Tong
authors.affiliation: Department of Pathology, Staten Island University Hospital, 475 Seaview Avenue, New York, NY, 10305, USA.
authors.forename: Kokila
authors.initials: K
authors.lastname: Mody
authors.affiliation: Department of Pathology, Staten Island University Hospital, 475 Seaview Avenue, New York, NY, 10305, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Hamele-Bena
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, 3477 Euler Way, Pittsburgh, PA, 15213, USA.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, 3477 Euler Way, Pittsburgh, PA, 15213, USA.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics*; D018263:Adenocarcinoma, Follicular / Q000235:genetics*; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D011989:Receptors, Thyrotropin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Clear cell carcinoma of the thyroid; Next generation sequencing (NGS); TP53; TSHR