Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

Abstract

In a 59-year-old patient, thyroid follicular cancer was diagnosed in two right-sided toxic thyroid nodules, which had presented clinically as unilateral thyroid autonomy. In addition, the patient had histologically proven lung metastases of thyroid cancer; however, these failed to exhibit iodine uptake and were resistant to radioiodine treatment. The functional activity of the thyroid nodules prompted us to screen for TSH receptor (TSHR) mutations, and the histological diagnosis of follicular carcinoma led us to search for the PAX8-PPARγ1 rearrangement and mutations in the ras genes. Each thyroid nodule harboured a different TSHR mutation (large nodule, Asp633Tyr; small nodule, Phe631Ile). Presence of both mutations in one sample suggestive of local invasion of a thyroid carcinoma could not be demonstrated, although several specimens from different nodule locations were screened. Only the wild-type TSHR sequence was identified in the histologically normal left thyroid lobe, and no genetic alterations were found in the other investigated genes. No TSHR mutations were detected in the pulmonary metastases. This is the first case report of a patient with toxic follicular thyroid carcinoma harbouring two different TSHR mutations and presenting with non-functional lung metastases.

Follicular Adenoma and Carcinoma of the Thyroid Gland

“…Mutations in the phosphatase and tensin homologue suppressor gene and the phosphatidylinositol 3-kinase pathway may be an important factor in the development of more aggressive thyroid cancers and may be more common in follicular cancer [21]. Other factors that have been implicated in the pathogenesis of follicular thyroid cancer include gene mutations in p53, c-myc, c-fos, and the thyrotropin (TSH) receptor [22,23].…”

Somatic mutations of the thyroid-stimulating hormone receptor gene in feline hyperthyroidism: parallels with human hyperthyroidism

“…The remaining two mutations, Asp-632<Tyr (S8a) and Asp-632<His (S8b), have both been previously reported at human codon locus 633 in human hyperfunctioning adenomas/nodules and thyroid carcinomas as somatic, heterozygous mutations (Kosugi et al 1994, Porcellini et al 1994, Van Sande et al 1995, Russo et al 1996, Parma et al 1997, Trulzsch et al 2001, Fuhrer et al 2003 but neither have been reported in FH. Only one cat with the S8a or S8b mutation had a concurrent blood sample: DNA from this blood sample did not harbour either mutation, and neither mutation was detected in blood from non-hyperthyroid cats.…”

“…Five of the 10 mis-sense mutations have previously been identified in human hyperthyroidism (Kosugi et al 1994, Porcellini et al 1994, Van Sande et al 1995, De Roux et al 1996, Russo et al 1996, Spambalg et al 1996, Tonacchera et al 1996, 2000, Duprez et al 1997a, Parma et al 1997, Lavard et al 1999, Mircescu et al 2000, Trulzsch et al 2001, Vanvooren et al 2002, Fuhrer et al 2003, Georgopoulos et al 2003.…”

“…Hyperplastic nodules are surrounded by apparently normal paranodular thyroid tissue (Ferguson et al 1990), and therefore DNA extracted from the whole thyroid lobe will represent both diseased and normal tissue, the latter causing dilution of the diseased tissue DNA, potentially masking any mutations. In addition, different mutations have been found in different nodules taken from individual human thyroid glands (Fuhrer et al 1996, Holzapfel et al 1997a, Duprez et al 1997a, Parma et al 1997, Tonacchera et al 1998a, 2000, Fuhrer et al 2003, and such mutations would also be masked by extraction of DNA from whole thyroid lobes.…”

Dissecting Molecular Events in Thyroid Neoplasia Provides Evidence for Distinct Evolution of Follicular Thyroid Adenoma and Carcinoma

“…12 Polyethylene glycol-purified PCR products were sequenced using BigDye terminator sequencing chemistry (Applied Biosystems, Carlsbad, CA), and sequence analysis was performed on the Genetic Analyzer ABI 377 (Applied Biosystems) as previously described. 13 Positive controls were cDNA from plasmids carrying the H1047R (provided by Dr. Bert Vogelstein, Johns Hopkins University Medical Institutions, Baltimore, MD) and the PAX8/PPAR␥ rearrangement (provided by Dr. Todd Kroll, University of Chicago Medical Center, Chicago, IL). 14 The H-RASV12 mutation was generated in human cDNA (from NT tissue) using the Stratagene Quick-Change site-directed mutagenesis kit according to the manufacture's description and the following primers: RASV12F 5=-AAGCTGGTGGTG-GTGGGCGCCGTCGGTGTGGGCAA-3= and RASV12R 5=-TTGCCCACACCGACGGCGCCCACCACCACCAGCTT-3=.…”