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

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.

RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management

“…In contrast to majority of RET 804 (non-cysteine) mutation carriers who remain biochemically normal till the third decade of life (54), individuals with classical cysteine mutations (codon 634) show a positive pentagastrin test during the first decade of life (6,(62)(63)(64). Additional studies have also described HPTH in association with V804M (50,59,69,99) and V804L mutations (58,60). Their results differed from earlier findings in that the authors found no statistically significant difference between the groups in mean age at diagnosis and stage of C-cell disease including size of MTC (macroscopic or microscopic), bilaterality, presence of CCH and regional node involvement.…”

“…In 2004, Gibelin et al first reported HPTH in a French MEN 2A family harboring a V804M mutation (69). Additional studies have also described HPTH in association with V804M (50, 59, 69, 99) and V804L mutations (58, 60). Another extrathyroidal feature of MEN 2 is CNT, a feature of MEN 2B and less commonly MEN 2A (70).…”

CDKN2A gene mutations and genetic interactions in the pathogenesis of melanoma

“…It was first detected in an Italian pancreatic cancer patient 37 , then later in an Italian multiple primary melanoma patient 42 , and in a Brazilian familial melanoma patient with Italian ancestors 43 . Foppiani et al 44 detected the P48T mutation in an Italian patient with multiple endocrine neoplasia 2A (MEN 2A) syndrome and papillary thyroid carcinoma along with a RET proto-oncogene mutation. The patient had past history of melanoma and family history of melanoma, pancreatic carcinoma and several other malignancies.…”