title: Novel RET mutations in macedonian patients with medullary thyroid carcinoma: genotype-phenotype correlations.
abstract: Medullary thyroid carcinomas (MTCs) are rare neoplasms comprising 2-10% of all thyroid malignnancies. More than 75% are sporadic tumors and the remainder is familial and MEN2 related. Both sporadic and syndromic MTCs frequently show mutations in the RET proto-oncogene. It has been noted that some MTC cases present an indolent, and some an aggressive clinical course. Ki-67 expression is generally low, with documented exceptions, whereas high expression of Bcl-2 has been reported in majority of the cases. Some studies have shown that Ki-67 and Bcl-2 expressions have prognostic value, as well as RET mutational status. We analyzed 20 unrelated MTC cases for Ki-67, Bcl-2 expression and RET mutations and tested their intercorrelations, correlations to the morphologic features and stage of the tumors, as well as their influence on survival. In 13 of the 20 analyzed cases we found 23 sequence changes distributed in exons 8, 10-13 and 16. There were 11 different missense mutations, single nucleotide deletion with frameshift, and 8 different synonymous mutations. Only 4 of the sequence changes have been previously published. Twelve patients (60%) had tumors expressing one or more missense mutations or single nucleotide deletion and 7 of them (35%) had at least one damaging or possibly damaging RET mutation. Most of the tumors had low Ki-67 expression (mean 6.48% of cells) and high Bcl-2 expression (mean 68.3%). Significantly better survival was observed in cases with low Ki-67 (< 6.5%; p < 0.05), high Bcl-2 expression (> 68.3%; p < 0.01) and younger age at diagnosis (< 51 years; p < 0.05).
authors.affiliation: Institute of Pathology, Medical Faculty, Skopje, R. Macedonia.
authors.forename: R
authors.initials: R
authors.lastname: Jovanovic
authors.affiliation: Institute of Pathology, Medical Faculty, Skopje, R. Macedonia.
authors.forename: S
authors.initials: S
authors.lastname: Kostadinova-Kunovska
authors.affiliation: Institute of Pathology, Medical Faculty, Skopje, R. Macedonia.
authors.forename: V
authors.initials: V
authors.lastname: Janevska
authors.affiliation: Institute of Pathology, Medical Faculty, Skopje, R. Macedonia.
authors.forename: B
authors.initials: B
authors.lastname: Bogoeva
authors.affiliation: Institute of Pathology, Medical Faculty, Skopje, R. Macedonia.
authors.forename: L
authors.initials: L
authors.lastname: Spasevska
authors.affiliation: Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, Skopje, R. Macedonia.
authors.forename: D
authors.initials: D
authors.lastname: Miladinova
authors.affiliation: Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, Skopje, R. Macedonia.
authors.forename: A
authors.initials: A
authors.lastname: Ugrinska
authors.affiliation: Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, Skopje, R. Macedonia.
authors.forename: M
authors.initials: M
authors.lastname: Zdraveska-Kochovska
authors.affiliation: Institute of Immunobiology and Human Genetics, Medical Faculty, Skopje, R. Macedonia.
authors.forename: D
authors.initials: D
authors.lastname: Trajkov
authors.affiliation: Institute of Pathology, Medical Faculty, Skopje, R. Macedonia.
authors.forename: G
authors.initials: G
authors.lastname: Petrusevska
mesh_terms: D000328:Adult; D000368:Aged; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: C000595707:BCL2 protein, human; D019394:Ki-67 Antigen; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human