Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers

Abstract

The findings propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.

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

“…Patients with tumors confined to the thyroid gland have at 10‐year survival rate of 95–96%, survival rate decreases to 75.5–77% in patients with nodal involvement, and only 40–44% patients with distant metastases at diagnosis survive more than 10 years (respectively citation, Randle et al, ; Roman, Lin, & Sosa, ). This study describe our 18 years’ experience of RET genetic screening in a large unselected series of consecutive MTC patients observed at a single institution in Northern Italy: We observed an unexpected prevalence of c.2671T>G, p.Ser891Ala substitution in exon 15, compared to prevalence observed in population‐based studies from other countries in Europe where Ser891Ala accounts for 4.1% of all RET mutation in France (Lebeault et al, ) and 4.4% in Germany (Machens, Lorenz, Weber, & Dralle, ). Purpose of our study was: (a) to deeply characterize this mutation, evaluating clinical phenotype, stage of thyroid disease at time of therapeutic/prophylactic thyroidectomy in a large series of subjects, (b) to explore and date back in time, a putative Ser891Ala founder mutation in a distinct geographic region in Northeast Italy.…”

“…The main reason for such differences between our and previous studies is attributable to the high prevalence in our series of Ser891Ala mutation (54.9%), a noncysteine codon variant that has been reported in other populations at a much lower frequency: From 2% of all RET mutations in EUROMEN Study Group (Machens et al, ), to 9.6% in ITAMEN Study (Romei et al, ) and 14,8% in the French Medullary Study Group (Niccoli‐Sire et al, ). In more recent study, Ser891Ala accounts for 4.4% of all RET mutation in France (Lebeault et al, ) and for 4,1% in Germany (Machens et al, ).…”

Genotype-specific progression of hereditary medullary thyroid cancer

“…Because they are less disruptive than frameshift mutations or deletions leading to protein truncation, nonsynonymous missense sequence variants of medically actionable genes have an intrinsic element of uncertainty in relation to their clinical effects (Weber, & Eng, ). The rapid advance of gene sequencing technologies has produced an unprecedented rate of discovery of genome variation in humans, including new RET sequence variants (Lebeault et al., ; Toledo et al., ). Some of those variants were misclassified as pathogenic owing to limited genetic analyses of highly selected patients and small numbers of controls often consisting of no more than 100 samples (Erlic et al., ).…”

“…It emerged only recently that RET sequence variants p.Ser649Leu, p.Tyr791Phe, and p.Ile852Met were not pathogenic contrary to initial belief (Erlic et al., ; Mathiesen et al., ; Toledo et al., ). This came as a surprise because many, albeit not all, in vitro focus formation assays and computer‐based in silico predictive models implicated a causative role for these gene variants in the progression of MTC (Cosci et al., ; Crockett et al., ; Lebeault et al., ), raising concerns as to the generalizability of in vitro and in silico findings to man.…”

65 YEARS OF THE DOUBLE HELIX: Exploiting insights on the RET receptor for personalized cancer medicine

“…In addition to MEN2-RET pathogenic mutations, there are several polymorphic sequence variants that act as modifiers of RET mutation genotype. Combinations of polymorphic RET coding or intronic sequence variants have been suggested to increase MTC or MEN2A-PCC risk (McWhinney et al 2003, Ceolin et al 2012, Siqueira et al 2014, Lebeault et al 2017. The Y791F non-synonymous variant lies within the RET kinase domain and was originally thought to be a pathogenic mutation, while the G691S variant lies in the juxtamembrane region of RET (Fig.…”