High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas.
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.
ARC-Net Research Centre, University and Hospital Trust of Verona, 37134, Verona, Italy.
Michele
M
Simbolo
Caterina
C
Mian
Susi
S
Barollo
Matteo
M
Fassan
Andrea
A
Mafficini
Diogo
D
Neves
Maria
M
Scardoni
Gianmaria
G
Pennelli
Massimo
M
Rugge
Maria Rosa
MR
Pelizzo
Elisabetta
E
Cavedon
Laura
L
Fugazzola
Aldo
A
Scarpa
D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics*; D018278:Carcinoma, Neuroendocrine; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012189:Retrospective Studies; D013964:Thyroid Neoplasms / Q000235:genetics*
D051096:Proto-Oncogene Proteins c-ret; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)