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6124185 
Journal Article 
High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas 
Simbolo, M; Mian, C; Barollo, S; Fassan, M; Mafficini, A; Neves, D; Scardoni, M; Pennelli, G; Rugge, M; Pelizzo, MR; Cavedon, E; Fugazzola, L; Scarpa, A 
2014 
1 
Virchows Archiv
ISSN: 0945-6317
EISSN: 1432-2307 
SPRINGER 
NEW YORK 
465 
1 
73-78 
English 
24828033 
WOS:000338728000008 
Sporadic medullary thyroid carcinoma (MTC) harbors RET gene somatic mutations in up to 50 % of cases, and RAS family gene mutations occur in about 10 %. A timely and comprehensive characterization of molecular alterations is needed to improve MTC diagnostic stratification and design-tailored therapeutic approaches. Twenty surgically resected sporadic MTCs, previously analyzed for RET mutations by Sanger sequencing using DNA from formalin-fixed paraffin-embedded samples, were investigated for intragenic mutations in 50 cancer-associated genes applying a multigene Ion AmpliSeq next-generation sequencing (NGS) technology. Thirteen (65 %) MTCs harbored a RET mutation; 10 were detected at both Sanger and NGS sequencing, while 3 undetected by Sanger were revealed by NGS. One of the 13 RET-mutated cases also showed an F354L germline mutation in STK11. Of the seven RET wild-type MTCs, four cases (57.1 %) harbored a RAS mutation: three in HRAS (all Q61R) and one in KRAS (G12R). The three remaining MTCs (15 %) resulted as wild-type for all the 50 cancer-related genes. Follow-up was available in all but one RET-mutated case. At the end of follow-up, 7 of 12 (58 %) RET-mutated patients had relapsed, while the 4 RAS-mutated MTC patients were disease-free. Two of the three patients with MTC wild-type for all 50 genes relapsed during the follow-up period. Detection of mutations by NGS has the potential to improve the diagnostic stratification of sporadic MTC.