AHR over-expression in papillary thyroid carcinoma

Clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow-up

Caterina Mian, Filippo Ceccato, Susi Barollo, Sara Watutantrige-Fernando, Nora Albiger, Daniela Regazzo, Paola De Lazzari, Gianmaria Pennelli, Sandra Rotondi, Davide Nacamulli, Maria Rosa Pelizzo, Marie Lise Jaffrain-Rea, Franco Grimaldi, Gianluca Occhi, Carla Scaroni

Research output: Contribution to journalArticle

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Abstract

Aim: Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3-7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. Methods: Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. Results: 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. Conclusions: The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.

Original languageEnglish
Article numbere101560
JournalPLoS One
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 14 2014

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Aryl Hydrocarbon Receptors
Acromegaly
Thyroid Neoplasms
carcinoma
hydrocarbons
receptors
Factor IX
mutation
Proteins
Insulin-Like Growth Factor I
Thyroid Gland
Germ-Line Mutation
Mutation
proteins
Growth Hormone-Secreting Pituitary Adenoma
Carcinoma, Papillary, Follicular
germ cells
protein synthesis
Tumors
goiter

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

AHR over-expression in papillary thyroid carcinoma : Clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow-up. / Mian, Caterina; Ceccato, Filippo; Barollo, Susi; Watutantrige-Fernando, Sara; Albiger, Nora; Regazzo, Daniela; De Lazzari, Paola; Pennelli, Gianmaria; Rotondi, Sandra; Nacamulli, Davide; Pelizzo, Maria Rosa; Jaffrain-Rea, Marie Lise; Grimaldi, Franco; Occhi, Gianluca; Scaroni, Carla.

In: PLoS One, Vol. 9, No. 7, e101560, 14.07.2014.

Research output: Contribution to journalArticle

Mian, C, Ceccato, F, Barollo, S, Watutantrige-Fernando, S, Albiger, N, Regazzo, D, De Lazzari, P, Pennelli, G, Rotondi, S, Nacamulli, D, Pelizzo, MR, Jaffrain-Rea, ML, Grimaldi, F, Occhi, G & Scaroni, C 2014, 'AHR over-expression in papillary thyroid carcinoma: Clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow-up', PLoS One, vol. 9, no. 7, e101560. https://doi.org/10.1371/journal.pone.0101560
Mian, Caterina ; Ceccato, Filippo ; Barollo, Susi ; Watutantrige-Fernando, Sara ; Albiger, Nora ; Regazzo, Daniela ; De Lazzari, Paola ; Pennelli, Gianmaria ; Rotondi, Sandra ; Nacamulli, Davide ; Pelizzo, Maria Rosa ; Jaffrain-Rea, Marie Lise ; Grimaldi, Franco ; Occhi, Gianluca ; Scaroni, Carla. / AHR over-expression in papillary thyroid carcinoma : Clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow-up. In: PLoS One. 2014 ; Vol. 9, No. 7.
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abstract = "Aim: Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3-7{\%}. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. Methods: Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. Results: 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70{\%} of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. Conclusions: The prevalence of DTC in acromegaly is around 11{\%} and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.",
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T2 - Clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow-up

AU - Mian, Caterina

AU - Ceccato, Filippo

AU - Barollo, Susi

AU - Watutantrige-Fernando, Sara

AU - Albiger, Nora

AU - Regazzo, Daniela

AU - De Lazzari, Paola

AU - Pennelli, Gianmaria

AU - Rotondi, Sandra

AU - Nacamulli, Davide

AU - Pelizzo, Maria Rosa

AU - Jaffrain-Rea, Marie Lise

AU - Grimaldi, Franco

AU - Occhi, Gianluca

AU - Scaroni, Carla

PY - 2014/7/14

Y1 - 2014/7/14

N2 - Aim: Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3-7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. Methods: Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. Results: 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. Conclusions: The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.

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