Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic RET p.Cys634Arg mutation (a known MTC driver). A germ-line RET substitution (p.Cys630=) had also been found but was considered clinically irrelevant because of its synonymous nature. Next generation sequencing (NGS) of the tumor tissues revealed that the RET mutations were in cis. There was no evidence of gene amplification. Expression analysis found an increase of RET transcript in p.Cys630=;p.Cys634Arg patient compared with that found in 7 MTCs harboring p.Cys634 mutations. Minigene expression assays demonstrated that the presence of the synonymous RET mutation was sufficient to explain the increased RET mRNA level. In silico analyses and RNA immunoprecipitation experiments showed that the p.Cys630 = variant created new exonic splicing enhancer motifs that enhanced SRp55 recruitment to the mutant allele, leading to more efficient maturation of its pre-mRNA and an increased abundance of mature mRNA encoding a constitutively active RET receptor. These findings document a novel mechanism by which synonymous mutations can contribute to cancer progression.

A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency / Pecce, Valeria; Sponziello, Marialuisa; Damante, Giuseppe; Rosignolo, Francesca; Durante, Cosimo; Lamartina, Livia; Grani, Giorgio; Russo, Diego; di Gioia, Cira Rosaria; Filetti, Sebastiano; Verrienti, Antonella. - In: PLOS GENETICS. - ISSN 1553-7404. - 14:10(2018), p. e1007678. [10.1371/journal.pgen.1007678]

A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency

Pecce, Valeria
Co-primo
;
Sponziello, Marialuisa
Co-primo
;
Rosignolo, Francesca;Durante, Cosimo;Lamartina, Livia;Grani, Giorgio;di Gioia, Cira Rosaria;Filetti, Sebastiano;Verrienti, Antonella
Ultimo
2018

Abstract

Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic RET p.Cys634Arg mutation (a known MTC driver). A germ-line RET substitution (p.Cys630=) had also been found but was considered clinically irrelevant because of its synonymous nature. Next generation sequencing (NGS) of the tumor tissues revealed that the RET mutations were in cis. There was no evidence of gene amplification. Expression analysis found an increase of RET transcript in p.Cys630=;p.Cys634Arg patient compared with that found in 7 MTCs harboring p.Cys634 mutations. Minigene expression assays demonstrated that the presence of the synonymous RET mutation was sufficient to explain the increased RET mRNA level. In silico analyses and RNA immunoprecipitation experiments showed that the p.Cys630 = variant created new exonic splicing enhancer motifs that enhanced SRp55 recruitment to the mutant allele, leading to more efficient maturation of its pre-mRNA and an increased abundance of mature mRNA encoding a constitutively active RET receptor. These findings document a novel mechanism by which synonymous mutations can contribute to cancer progression.
2018
Ecology, Evolution, Behavior and Systematics; Molecular Biology; Genetics; Genetics (clinical); Cancer Research
01 Pubblicazione su rivista::01a Articolo in rivista
A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency / Pecce, Valeria; Sponziello, Marialuisa; Damante, Giuseppe; Rosignolo, Francesca; Durante, Cosimo; Lamartina, Livia; Grani, Giorgio; Russo, Diego; di Gioia, Cira Rosaria; Filetti, Sebastiano; Verrienti, Antonella. - In: PLOS GENETICS. - ISSN 1553-7404. - 14:10(2018), p. e1007678. [10.1371/journal.pgen.1007678]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1184125
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