Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

Cancers

Uberto Pagotto¹  Andrea Pession¹  Davide Bianchi²  Daniela Turchetti³  Giovanni Innella³  Maria Romagnoli³  Cesare Rossi³  Lea Godino³  Davide Martorana⁴  Antonio Percesepe⁴  MariaElena Cantarini⁵  Andrea Repaci⁶ 

[1] Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;Division of Endocrinology, Ospedale di Bentivoglio, 40010 Bentivoglio (BO), Italy;Division of Medical Genetics, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;Division of Medical Genetics, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy;Division of Pediatric Oncology, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;Endocrinology and Diabetes Prevention and Care Unit, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;

关键词: RET;    medullary thyroid carcinoma;    clinical management;    variants of uncertain significance;   

DOI  :  10.3390/cancers12113268

来源: DOAJ

【 摘 要 】

Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively.

【 授权许可】

Unknown