P.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy. Issue 7 (29th April 2019)

• Record Type: Journal Article
• Authors: Giacché, Mara; Panarotto, Alessandra; Tacchetti, Maria Chiara; Tosini, Rossella; Campana, Federica; Mori, Luigi; Cappelli, Carlo; Pirola, Ilenia; Lombardi, Davide; Pezzola, Diego Cesare; Casella, Claudio; Castellano, Maurizio
• Is Part Of: Human mutation. Volume 40:Issue 7(2019)
• Page Start: 926
• Page End: 937
• Publication Date: 2019-04-29
• Subjects: medullary thyroid cancer -- founder effect -- prophylactic thyroidectomy -- RET -- Ser891Ala; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23754
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Applying genetic screening in medullary thyroid cancer (MTC) patients we identified an unexpectedly high frequency of c.2671T>G, p.Ser891Ala RET mutation carriers. Our aim was to: (a) deeply characterize the clinical expression of this mutation, (b) identify the presence of a founder effect in our region. Genetic analysis was performed in 251 relatives from 28 Ser891Ala kindreds, among 108 p.Ser891Ala asymptomatic carriers, 64 were submitted to thyroidectomy: mean age for 10 subjects presenting C‐cells hyperplasia was 30.2 ± 13.7 years, raising to 37.9 ± 10.3 in 14 subjects with micro‐MTC and to 55.0 ± 14.7 years in 39 subjects with MTC. Age‐related progression across histopathological groups CCH/microMTC and MTC were statistically significant: genetic screening in Ser891Ala families could be safely postponed at the age of 14. To investigate the hypothesis of a common ancestor for Ser891Ala mutation we genotyped for 18 polymorphic microsatellite markers encompassing RET locus all subjects belonging to Ser891Ala families and we identified a founder effect, estimating the age of a common ancestor, dating back to 1493 AD. Ethnographic data collected in historical archives support laboratory results; the high prevalence of this mutation in our region could suggest the hypothesis of a population study to realize a preventive intervention in a rare neoplastic disease.