In-silico analysis of highly pathogenic variants of RET gene associated with thyroid cancer
DOI:
https://doi.org/10.48047/HM.10.2.2024.1490-1501Keywords:
Bioinformatics Tools, Thyroid Cancer, RET gene, Precision Medicine, Pathogenic VariantsAbstract
The proto-oncogene RET is composed of 21 exons located on chromosome 10 (10q11.2) and encodes for a transmembrane receptor tyrosine kinase for members of the glial cell line–derived neurotrophic factor family (GDNF) and associated ligands, and mutations in this gene can cause Thyroid cancer in humans. Therefore, we anticipated studying the consequences of RET non-synonymous variations using advanced bioinformatics tools. Analysis of the genetic mutations in the gene, accomplished using computational methods. The functional and pathogenic effect of missense variations and the deleterious tendency of amino acid substitutions of a gene was investigated using the gnomAD database, SIFT, MutPred, MAESTRO, UCSF Chimera, and cBioportal and survival analysis of a gene was investigated by GEPHA database. This study revealed that “C609Y”,"C618R", “C634R”,"C634F","C634W","L790F, "V804L" and "R813W" variants were predicted to be the most harmful/damaging mutations in RET gene and the survival of patients with thyroid cancer was strongly impacted by the downregulated RET (low expression). This research renders the next generation of precision medicine approaches possible and provides simple but precious tools for use in clinical settings.
Downloads
References
Cabanillas, M.E., D.G. McFadden, and C. Durante, Thyroid cancer. The Lancet, 2016. 388(10061): p. 2783-2795.
Goodfellow, P.J. and S.A. Wells Jr, RET gene and its implications for cancer. JNCI: Journal of the National Cancer Institute, 1995. 87(20): p. 1515-1523.
Romei, C., R. Ciampi, and R. Elisei, A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nature Reviews Endocrinology, 2016. 12(4): p. 192.
Mulligan, A.M., et al., Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res, 2011. 13(6): p. R110.
5Bolino, A., et al., RET mutations in exons 13 and 14 of FMTC patients. Oncogene, 1995. 10(12): p. 2415-2419.
Durbec, P., et al., GDNF signalling through the Ret receptor tyrosine kinase. Nature, 1996. 381(6585): p. 789-793.
Santoro, M. and F. Carlomagno, Central role of RET in thyroid cancer. Cold Spring Harbor perspectives in biology, 2013. 5(12): p. a009233.
Kodama, Y., et al., The RET proto‐oncogene: a molecular therapeutic target in thyroid cancer. Cancer science, 2005. 96(3): p. 143-148.
Amiel, J., et al., Hirschsprung disease, associated syndromes and genetics: a review. Journal of medical genetics, 2008. 45(1): p. 1-14.
Gartner, W., et al., A newly identified RET proto-oncogene polymorphism is found in a high number of endocrine tumor patients. Human genetics, 2005. 117(2): p. 143-153.
Myers, S.M., et al., Characterization of RET proto-oncogene 3'splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene, 1995. 11(10): p. 2039-2045.
Elisei, R., et al., RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. The Journal of Clinical Endocrinology & Metabolism, 2004. 89(7): p. 3579-3584.
Doss, C.G.P., et al., In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach. Molecular BioSystems, 2014. 10(3): p. 421-436.
Sim, N.-L., et al., SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic acids research, 2012. 40(W1): p. W452-W457.
Li, B., et al., Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics, 2009. 25(21): p. 2744-2750.
Laimer, J., et al., MAESTRO-multi agent stability prediction upon point mutations. BMC bioinformatics, 2015. 16(1): p. 1-13.
Shao, C., et al., Optical diagnostic imaging and therapy for thyroid cancer. Materials Today Bio, 2022: p. 100441.
Tural, S., et al., Novel RET Proto-oncogene variants identified in Turkish patients with thyroid carcinoma. Gene, 2020. 746: p. 144611.
Elisei, R., et al., Somatic Ret Indels In Sporadic Medullary Thyroid Cancer: Prevalence And Response To Selpercatinib. The Journal of Clinical Endocrinology & Metabolism, 2022.
Mi, X.
Jimenez, C., et al., A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma. The Journal of Clinical Endocrinology & Metabolism, 2004. 89(7): p. 3521-3526.
Kouvaraki, M.A., et al., RET proto-oncogene: a review and update of genotype–phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid, 2005. 15(6): p. 531-544.
Feldman, G.L., et al., Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG→ ATG) mutation. Surgery, 2000. 128(1): p. 93-98.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Author
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format for any purpose, even commercially.
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
- The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms:
- Attribution — You must give appropriate credit , provide a link to the license, and indicate if changes were made . You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Notices:
You do not have to comply with the license for elements of the material in the public domain or where your use is permitted by an applicable exception or limitation .
No warranties are given. The license may not give you all of the permissions necessary for your intended use. For example, other rights such as publicity, privacy, or moral rights may limit how you use the material.
