ArticlePLoS genetics2018
A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- The role of miR-335-5p in the redifferentiation of BRAF p.V600E thyroid cancers.Molecular oncology · 2026Article
- DRP-PSM: Multi-Level Feature Integration Reveals Hierarchical Contributions to Pathogenic Synonymous Mutation Prediction.ACS omega · 2025Article
- A Novel Synonymous Variant of PAX2 in Monochorionic Diamniotic Twins With Bilateral Renal Agenesis: A Case Report and Literature Review.Molecular genetics & genomic medicine · 2025Review
- The role of miR-139-5p in radioiodine-resistant thyroid cancer.Journal of endocrinological investigation · 2023Article
- Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes.Journal of the National Cancer Institute · 2022Review
- Article
- Precision oncology forFrontiers in oncology · 2022Review
- Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility.Endocrine · 2021Article
- The role of FOSL1 in stem-like cell reprogramming processes.Scientific reports · 2021Article
- Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN.Journal of experimental & clinical cancer research : CR · 2021Article
- Folding Stability of Pax9 Intronic G-Quadruplex Correlates with Relative Molar Size in Eutherians.Molecular biology and evolution · 2021Article
- Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China.BMC cancer · 2021Article
- Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.GigaScience · 2021Article
- Targeting Splicing Factor SRSF6 for Cancer Therapy.Frontiers in cell and developmental biology · 2021Review
- Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid.Cancers · 2020Article
- Case report for an adolescent with germline RET mutation and alveolar rhabdomyosarcoma.Cold Spring Harbor molecular case studies · 2020Article
- Somatic synonymous mutations in regulatory elements contribute to the genetic aetiology of melanoma.BMC medical genomics · 2020Article
- Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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