RET Y791F: alone or accompanied?

Abstract

W e read with interest the article "Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism" recently published in this Journal (1).The article was written by Brazilian endocrinologists and surgeons and consists of a consensus of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM). As a full version of it is also available in Portuguese language and free for download, it is definitely a valuable reference to Brazilian doctors in residency trainings and medical specialists in the fields of endocrinology, surgery, oncology and others.Virtually all individuals carrying a germline mutation in the RET proto-oncogene will develop medullary thyroid carcinoma (MTC) and therefore total prophylactic thyroidectomy is indicated at early ages, based on the specific RET mutations (1-3).In this context, we would like to make a comment regarding to the Y791F variant located at the exon 13 of RET. Although initial data regarding this variant indicated that it could be a weak mutation associated with mild forms of the disease (4,5), recent studies have shown no association of this variant with an increased susceptibility to MTC. Erlic and cols. (6) and Toledo and cols. (7) have analyzed the frequencies of RET Y791F in large cohorts of tumor free individuals and showed that the variant behaves as a rare non-pathogenic polymorphism rather than a disease-causing mutation. In addition, a thorough review of the literature does not document a link of Y791F (alone) with familial MTC. On the contrary, the reported Y791F carriers who inadvertently underwent thyroidectomy presented no histopathological signs of disease (5,6).These data indicate that thyroidectomy should not be recommended to cases with genetic testing results showing RET Y791F (alone). However, especial attention should be taken by Brazilian doctors, geneticists and surgeons, as the RET Y791F variant has been identified in combination with the strong RET C634Y (exon 11) mutation in more than 15 Brazilian families with MTC/MEN2 (7,8). Noteworthy, this combination changes completely the clinical scenario, and patients with RET C634Y/ Y791F should be treated accordingly to the recommendations to cases carrying RET C634 mutations, in which early total thyroidectomy is needed to be performed (1-3). Therefore, when receiving a genetic testing showing the presence of the RET Y791F variant, it is crucial to make sure that the remaining exons of the gene were completely sequenced as well, to fully certify whether is a Y791F-alone or a RET C634Y/Y791F patient (6).In conclusion, we would like to congratulate the authors for the SBEM consensus and invite all the Brazilian medical doctors and geneticists to read our extended study and review of the literature about RET Y791F, a variant that need to be well understood by the health professionals of our country to the better management of Brazilian patients with MTC and their relatives (6).

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

“…Surprisingly, 8 of 92 patients with melanoma (9%) harboured germline SNVs, which resulted in amino‐acid modifications that previously were associated with cancer predisposition phenotypes or growth abnormalities (Fig. A,B) . According to data from the “1000 Genomes” project, all variants occur at a frequency of less than 5 per 1000 in the general population.…”

“…In the melanoma samples from each patient, germline variants are accompanied by the indicated oncogenic drivers. Superscript numerals in the column headed “Effect” indicate the following references: 1) Liu et al, 2) Kress et al, 3) Mantelli et al, 4) Ghiorzo et al 5) Berndt et al, 6) Toledo et al, 7) Plaza Menacho et al, and 8) Frank et al SNVs correspond to the following Single‐Nucleotide Polymorphism Database (dbSNP) identifiers and reference SNP (rs) numbers: MET [T1010I], rs56391007; FGFR1 [I300T], rs121909633; CDKN2A [G101W], rs104894094; RET [Y791F], rs77724903; and ERBB2 [I654V], rs1801201. For patient MS126, the tumor content in the sequenced tissue was below 5%, but the patient was still included because of the reliable detection of oncogenic drivers ( www.cbioportal.org, 09/18).…”

“…2A,B). [25][26][27][28][29][30][31][32] According to data from the "1000 Genomes" project, all variants occur at a frequency of less than 5 per 1000 in the general population. Two patients carried the CDKN2A glycine-to-tryptophan mutation at codon 101 (G101W) variant, which is considered oncogenic because of an impaired interaction with CDK4/CDK6.…”

“…5) Berndt et al,29 6) Toledo et al,30 7) Plaza Menacho et al,31 and 8) Frank et al32 SNVs correspond to the following Single-Nucleotide Polymorphism Database (dbSNP) identifiers and reference SNP (rs) numbers: MET [T1010I], rs56391007; FGFR1 [I300T], rs121909633; CDKN2A [G101W], rs104894094; RET [Y791F], rs77724903; and ERBB2 [I654V], rs1801201. For patient MS126, the tumor content in the sequenced tissue was below 5%, but the patient was still included because of the reliable detection of oncogenic drivers (www.cbioportal.org, 09/18).…”

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

“…The variant, first reported in patients with Hirschsprung disease [27], MTC [28,29] and PCC [30], involves a highly conserved amino acid and used to be regarded as pathogenic based on in silico predictions. More recently, the evidence that the variant has similar frequencies in affected and unaffected subjects [31,32] is more common in the population than expected for a disease-causing variant [33,34], fails to co-segregate with the disease in some families [35,36] and co-occurred with a pathogenic variant in some patients [37,38] led researchers to reconsider it as likely benign. In our patient, however, the young age at MTC diagnosis raises the suspicion that this variant may have, to some extent, favored the development of MTC, possibly interacting with other factors in a multifactorial context, or that she carries a pathogenic variant undetected by the multigene test performed.…”