Journal of the National Cancer Institute Advance Access originally published online on January 27, 2009
JNCI Journal of the National Cancer Institute 2009 101(3):162-175; doi:10.1093/jnci/djn471
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© The Author 2009. Published by Oxford University Press.
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A Germline Mutation (A339V) in Thyroid Transcription Factor-1 (TITF-1/NKX2.1) in Patients With Multinodular Goiter and Papillary Thyroid Carcinoma
Affiliations of authors: Department of Surgery, Centre for Cancer Research, Centre for Reproduction, Development and Growth (ESWN), Department of Surgery (BHHL, TL, CKYS, M-TS, DKCL, TYYL, C-YL), Department of Surgery, Centre for Reproduction, Development and Growth (PKHT), Department of Surgery, Centre for Reproduction, Development and Growth (M-MG-B), Department of Pathology (U-SK), Department of Psychiatry (SSC), Genome Research Centre (SSC), University of Hong Kong, Pokfulam, Hong Kong; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX (SYT)
Correspondence to: Elly S. W. Ngan, PhD, Department of Surgery, University of Hong Kong, Pokfulam, Faculty of Medicine Building, 21 Sassoon Rd, Hong Kong, SAR, China (e-mail: engan{at}hku.hk).
Background: The genetic factors that determine the risk of papillary thyroid carcinoma (PTC) among patients with multinodular goiter (MNG) remain undefined. Because thyroid transcription factor-1 (TTF-1) is important to thyroid development, we evaluated whether the gene that encodes it, TITF-1/NKX2.1, is a genetic determinant of MNG/PTC predisposition.
Methods: Twenty unrelated PTC patients with a history of MNG (MNG/PTC), 284 PTC patients without a history of MNG (PTC), and 349 healthy control subjects were screened for germline mutation(s) in TITF-1/NKX2.1 by sequencing of amplified DNA from blood. The effects of the mutation on the growth and differentiation of thyroid cells were demonstrated by ectopic expression of wild-type (WT) and mutant proteins in PCCL3 normal rat thyroid cells, followed by tests of cell proliferation, activation of cell growth pathways, and transcription of TTF-1 target genes. All statistical tests were two-sided.
Results: A missense mutation (1016C>T) was identified in TITF-1/NKX2.1 that led to a mutant TTF-1 protein (A339V) in four of the 20 MNG/PTC patients (20%). These patients developed substantially more advanced tumors than MNG/PTC or PTC patients without the mutation (P = .022, Fisher exact test). Notably, this germline mutation was dominantly inherited in two families, with some members bearing the mutation affected with MNG, associated with either PTC or colon cancer. The mutation encoding the A339V substitution was not found among the 349 healthy control subjects nor among the 284 PTC patients who had no history of MNG. Overexpression of A339V TTF-1 in PCCL3 cells, as compared with overexpression of WT TTF-1, was associated with increased cell proliferation including thyrotropin-independent growth (average A339V proliferation rate = 134.27%, WT rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0% to 47.7%, P = .010), enhanced STAT3 activation, and impaired transcription of the thyroid-specific genes Tg, TSH-R, and Pax-8.
Conclusion: This is the first germline mutation identified in MNG/PTC patients. It could contribute to predisposition for MNG and/or PTC and to the pathogenesis of PTC.
| Context and Caveats Prior knowledge Some multinodular goiter (MNG) patients develop papillary thyroid carcinoma (PTC), but the genetic basis is not understood. Study design A screen was performed in Hong Kong to identify mutations in the gene for thyroid transcription factor-1 (TTF-1) among 284 patients with PTC, 20 patients with MNG and PTC, and 349 healthy volunteers. Subsequently, the effects of overexpression of mutant A339V TTF-1 on growth properties and transcription in the nonmalignant rat thyroid cell line, PCCL3, were tested relative to the wild-type protein. Contribution The germline missense mutation A339V was found in TTF-1 from four of the 20 MNG/PTC patients studied and showed autosomal dominant inheritance in two families. In stably transfected PCCL3 cells that overexpressed the mutant protein, proliferation was approximately doubled in culture medium with and without thyrotropin, STAT3 and Akt were activated, cyclin D2 expressed at higher levels, and transcription of three TTF-1 response genes decreased relative to wild type–overexpressing control cells. Implications The A339V mutation may predispose some MNG patients to development of PTC. Limitations The patients studied were limited in number, so prevalence of the mutation and cancer risk cannot be predicted for the Chinese population as a whole. Functional studies were limited to overexpression of the human protein in rat normal thyroid cells. From the Editors
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Manuscript received June 4, 2008; revised October 29, 2008; accepted November 18, 2008.
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