Endocrinol Metab.  2012 Mar;27(1):45-53. 10.3803/EnM.2012.27.1.45.

Frequency of RAS Mutations and PAX8/PPARgamma Rearrangement in Follicular Thyroid Tumors in Korea

• Kim HJ
• Jang HW
• Sohn SY
• Choi YL
• Kim HJ
• Oh YL
• Kim SW
• Chung JH

• KMID: 2134817
• DOI: http://doi.org/10.3803/EnM.2012.27.1.45

Abstract

BACKGROUND
Follicular thyroid tumors harbor several genetic alterations such as RAS mutations and PAX8/PPARgamma rearrangement. The aims of our study were to investigate the prevalence of RAS mutations and PAX8/PPARgamma rearrangement in follicular thyroid tumors and to correlate RAS mutations and/or PAX8/PPARgamma rearrangement with clinicopathologic features in Korean patients with follicular thyroid carcinomas.
METHODS
RAS mutations were investigated by polymerase chain reaction and DNA sequencing in surgical specimens of 37 follicular thyroid carcinomas (FTCs) and 16 follicular thyroid adenomas (FTAs). PAX8/PPARgamma rearrangement was analyzed by fluorescent in situ hybridization in surgical specimens of 31 FTCs and 13 FTAs.
RESULTS
RAS mutations were detected in 30% (11 of 37) of FTCs and 19% (three of 16) of FTAs. Three of 11 FTC patients with RAS mutations died of thyroid cancer, but none of the 26 FTC patients without RAS mutations. PAX8/PPARgamma rearrangement was found in 10% (three of 31) of FTCs, but in none of the 13 FTAs. All three FTC patients with PAX8/PPARgamma rearrangement remained in complete remission during follow-up. There were no FTC patients with both RAS mutations and PAX8/PPARgamma rearrangement.
CONCLUSION
The prevalence of RAS mutations in our series of follicular tumors was similar to previous studies. The frequency of PAX8/PPARgamma rearrangements in our group of FTC was lower than previous western reports, but higher than Japanese reports. RAS mutations may be associated with hematogeneous metastasis and poor survival while PAX8/PPARgamma rearrangement may be related to more favorable prognosis in Korean patients with FTCs.

Keyword

Mutations; PAX8-PPARgamma fusion protein; Ras; Follicular thyroid cancer

MeSH Terms

Adenocarcinoma, Follicular
Asian Continental Ancestry Group
Follow-Up Studies
Humans
In Situ Hybridization, Fluorescence
Korea
Neoplasm Metastasis
Polymerase Chain Reaction
Prevalence
Prognosis
Sequence Analysis, DNA
Thyroid Gland
Thyroid Neoplasms

Figure

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  Fig. 1 Sequence chromato-gram of NRAS exon-2 encompassing codon 61 shows a heterozygosity composed of an altered nucleotide 'A' and a wild-type nucleotide 'C', resulting in Q61K mutation.

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  Fig. 2 Interphase fluorescence in situ hybridization (FISH) analysis demonstrating the absence of a t(2;3)(q13;p25) translocation and its presence in a follicular thyroid carcinoma (FTC). The locations of the BAC probes used for the FISH fusion assays are shown in relation to PAX8 and PPARγ next to the ideograms of normal chromosomes 2 and 3. A 2q13 probe (83_K08), centromeric of PAX8, was labeled with fluorescein-12-dUTP (green), and a 3p25 probe (26_O22), telomeric of PPARγ, was labled with Texas Red-5-dUTP (red). Nuclei from a follicular thyroid adenoma in which t(2;3)(q13;p25) is absent are shown in A, whereas B demonstrates nuclei form an FTC in which t(2;3)(q13;p25) is present (arrow), as demonstrated by the adjacently located green (83_K08) and red (26_O22) hybridization signals.

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  Fig. 3 Clinical outcomes at last follow-up between RAS point mutations (+) and RAS point mutation (-) in patients with follicular thyroid carcinomas.

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  Fig. 4 PAX8/PPARγ rearrangement with or without other aberrant signal patterns revealed by fluorescence in situ hybridization (F, fusion signal; G, green signal; O, orange signal). A. PAX8/PPARγ rearrangement with the 1F1G1O signal. B. PAX8/PPARγ rearrangement with the 1F1G1O signal. C. PAX8/PPARγ rearrangement with the 2F2G1O signal pattern. D. PAX8/PPARγ rearrangement along with different numerical gains (2F1G1O [left], 2F2G1O [middle], and 2F1G1O [right]). E. PAX8/PPARγ rearrangement with the gains of signals, showing 3G3O (upper two cells), and 3G4O (lower two cells) signal patterns. F. PAX8/PPARγ rearrangement with the gains of signals showing multiple O signals (white arrow), indicating the amplification of the PPARγ.

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