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

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.

GLOBAL ENDOCRINOLOGY: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review

“…The hypothesis of a common ancestor was then investigated, and a common haplotype identified, as demonstrated by accurate research on church and municipal archives and regional clustering of mutations in kindreds in two areas, the Seriana Valley, in the province of Bergamo, and the Plain of Brescia. The reconstruction of the genealogical tree confirmed that family residents in Brescia were descendants of immigrants from the Seriana Valley in the 1600s, supporting the hypothesis that the p.Ser891Ala variant was most likely introduced by a founder pathogenic variant (58). Recent studies from Italy (not included in Table 1) from two distinct centers have shed light on these observations.…”

“…Another interesting observation in these series is that the pathogenic variant p.Ser891Ala is more prevalent in Italy (9.7%) than in Germany or France (4.7 and 4.6%, respectively). This is apparently due to a founder effect in an isolated mountainous region in northern Italy (58). The authors noticed an impressive percentage of patients harboring the p.Ser891Ala variant in their local series (54.9%) when compared with the percentage found in Italy for p.Val804Met (13.7%).…”

Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study

“…In our overall cohort, the most frequently mutated codon was 634, followed by codons 804, 618, 620, 790, 611, 891, 609, 768 and other rarely mutated codons. With only minor differences, likely accounted for by founder effects, the distribution of mutations in our cohort is, by and large, comparable to that of series in the literature (7,17,19,20,21,38,39,40,41,42,43,44,45).…”

Medullary Thyroid Carcinoma and Associated Endocrinopathies in Slovenia from 1995 to 2021

“…As expected, lower frequencies of variants V804M (9.5%) and S891A (4.8%) were observed. Those variants have been described as founder variants in northern Italy and Sardinia and are rare elsewhere [ 7 , 20 , 21 ]. These findings demonstrate national specific distribution of RET PVs.…”