title: AHR over-expression in papillary thyroid carcinoma: clinical and molecular assessments in a series of Italian acromegalic patients with a long-term follow-up.
abstract: OBJECTIVE
  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.
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Ceccato
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Watutantrige-Fernando
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Nora
authors.initials: N
authors.lastname: Albiger
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Regazzo
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: de Lazzari
authors.affiliation: II Pathology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Pennelli
authors.affiliation: Department of Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rotondi
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Nacamulli
authors.affiliation: Surgical Pathology Unit, Department of Surgery, University-Hospital of Padua, Padua, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pelizzo
authors.affiliation: Department of Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila, Italy; Neuromed Institute, Department of Neurological Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Jaffrain-Rea
authors.affiliation: Endocrinology and Metabolism Unit, University-Hospital "Santa Maria della Misericordia," Udine, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Grimaldi
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Occhi
authors.affiliation: Endocrinology Unit, Department of Medicine, University-Hospital of Padua, Padua, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Scaroni
mesh_terms: D000172:Acromegaly / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D002291:Carcinoma, Papillary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D048493:Proto-Oncogene Proteins B-raf; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C482119:BRAF protein, human