RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.
A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR gamma rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPAR gamma rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPAR gamma typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hürthle cell tumors infrequently had PAX8-PPAR gamma rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement.
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529, USA.
Marina N
MN
Nikiforova
Roy A
RA
Lynch
Paul W
PW
Biddinger
Erik K
EK
Alexander
Gerald W
GW
Dorn
Giovanni
G
Tallini
Todd G
TG
Kroll
Yuri E
YE
Nikiforov
D018263:Adenocarcinoma, Follicular / Q000235:genetics*; D018249:Adenoma, Oxyphilic / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D003062:Codon; D004268:DNA-Binding Proteins / Q000235:genetics*; D037502:Galectin 3 / Q000032:analysis; D015321:Gene Rearrangement; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000951:Antigens, Neoplasm
D014408:Biomarkers, Tumor; D003062:Codon; D004268:DNA-Binding Proteins; D037502:Galectin 3; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C432845:HBME-1 antigen; D000951:Antigens, Neoplasm; C083325:PAX8 protein, human