SFEBES2016 Poster Presentations Thyroid (26 abstracts)
ESR2 mutations in RET mutation-negative familial medullary thyroid carcinoma
Wazir K. Afghan 1 , Donato Iacovazzo 1 , Maria Alevizaki 2 , William Foulkes 3 , Francesca Lugli 4 , Maralyn Druce 1 , Pinaki Dutta 5 , Mary N. Dang 1 , Plamena Gabrovska 1 , Patrick J. Morrison 6 , Martina Owens 7 , Sian Ellard 7 , Julian Sampson 8 , Laura De Marinis 4 & Márta Korbonits 1
1Centre for Endocrinology, Barts and The London School of Medicine, London, UK; 2Endocrine Unit, Athens University Medical School, Athens, Greece; 3Departments of Medicine, Oncology and Human Genetics, McGill University, Montreal, Canada; 4Endocrinology, Università Cattolica Del Sacro Cuore, Rome, Italy; 5Endocrinology, PGIMER, Chandigarh, India; 6Centre for Cancer Research and Cell Biology, Queens University, Belfast, UK; 7Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; 8Institute of Medical Genetics, Cardiff University, Cardiff, UK.
Introduction: Approximately 25% of medullary thyroid cancer (MTC) cases arise in a familial setting, either as MEN2 or fMTC. While most of these are caused by mutations in the RET gene, a few families have unidentified mutations. Recently, a frameshift mutation in the ESR2 gene (coding oestrogen receptor beta) was found in a family with RET-negative fMTC associated with C-cell hyperplasia. In vitro, transfection of mutant ESR2 led to unopposed oestrogen receptor alpha-mediated RET expression. Tissue samples showed RET overexpression. The aim of this study was to investigate the prevalence of ESR2 mutations in RET-negative fMTC/CCH kindreds and patients diagnosed with RET-negative sporadic MTC.
Methods: DNA samples from six RET-negative fMTC/CCH families and 12 RET-negative sporadic MTC patients were collected. The eight ESR2 coding exons and exon-intron boundaries were amplified by PCR and sequenced through Sanger sequencing. In silico prediction tools were used to assess the functional impact of identified variants. Immunohistochemistry for RET was performed in samples of RET-negative fMTC and in a series of sporadic MTC controls.
Results: No ESR2 variants were identified in five RET-negative fMTC/CCH families, while two common single nucleotide polymorphisms were found in the proband from one other family. Two rare missense variants (c.748G>A p.G250S, minor allele frequency (MAF) 0.08% and c.1508G>A p.C503Y, MAF 0.01%) were found in two patients with sporadic MTC. In silico predictions did not support a pathogenic role for these variants. Immunohistochemistry in RET-negative fMTC samples showed either absent or weak RET expression, significantly lower compared with sporadic controls.
Conclusion: No pathogenic ESR2 mutations were identified in our RET negative fMTC/CCH families, suggesting that ESR2 is not commonly involved in RET-negative fMTC. Lack of RET overexpression suggests that RET-independent mechanisms underlie the pathogenesis of MTC in these families. Further studies are needed to identify alternative causative mutations in RET-negative fMTC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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