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Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene

¹ , Endocrinology ² Genetics Laboratory, Galliera Hospital, 16128 Genova, Italy³ Laboratory of Molecular Genetics, G Gaslini Institute, 16148 Genova, Italy⁴ Department of Oncology, Biology and Genetics/Medical Genetics Service, University of Genova, 1632 Genova, Italy⁵ Pathology Unit, ⁶ , Division of Surgery and ⁷ Nuclear Medicine, Galliera Hospital, 16128 Genova, Italy

(Correspondence should be addressed to L Foppiani who is now at S S D Endocrinologia, Mura delle Cappuccine 14, 16128 Genova, Italy;; Email: luca.foppiani{at}galliera.it)

Abstract

Introduction: Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed.

Case: We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.