Non-Synonymous Snps in The Human Erbb2 Gene: Insilico Prediction and Functional Analysis
DOI:
https://doi.org/10.52783/jns.v14.2972Keywords:
HER-2- neu, Gene, SNPs, Computational analysisAbstract
Introduction: ERBB2 is altered by mutations and amplifications in a variety of cancer types. A small number of drugs have been approved by the Food and Drug Administration (FDA) to treat ERBB2 variants. Determining the expected impact of gene mutations and the protein-protein interactions involved in various cancer types was the aim of the in silico study, which evaluated the ERBB2 gene using bioinformatics techniques.
Methods: The single nucleotide polymorphisms (SNPs) of the ERBB2 gene were investigated in silico using the accession IDs and FASTA amino acid sequences obtained from the National Center for Biotechnology Information (NCBI). Scale-Invariant Feature Transform (SIFT), Polymorphism Phenotyping version 2 (Polyphen-2), Combined Annotation Dependent Depletion (CADD) score, meta-analytic logistic regression (MetaLR), and mutation assessor were among the bioinformatics tools utilized for the study. Protein-protein interactions were evaluated using a string database.
Results: 8298 SNPs are examined. According to SIFT analysis of the SNPs in the ERBB2 gene, 35.7% of the mutations were acceptable and 63.3% were detrimental. The Polyphen study found that 54.1% of SNPs were dangerous mutations and 45.1% were benign. According on metaLR analysis, 63.5% of the SNPs were tolerated, while 36.1% had detrimental mutations. A total of 10.8%, 33.4%, 35%, and 20.3% of the mutations were classified as high, low, medium, and neutral respectively, based on the mutation assessor tool.
Conclusion: The current in silico investigation aims to elucidate the significance of ERBB2 gene variants and their correlation with various disease states. According to our study majority of the SNPswere found to be deleterious. Future studies on pathological conditions connected to ERBB 2 may consider this analysis of detrimental nsSNPs. This study may have significant implications for precision medicine as well.
Downloads
Metrics
References
Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 20142014:852748. doi: 10.1155/2014/852748. Epub 2014 Sep 7. PMID: 25276427; PMCID: PMC4170925.
Aroian RV, Koga M, Mendel JE, Ohshima Y, Sternberg PW. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature. 1990 Dec 27;348(6303):693-9.
Padhy LC, Shih C, Cowing D, Finkelstein R, Weinberg RA. Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell. 1982;28(4):865–871. doi: 10.1016/0092-8674(82)90065-4.
Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: An erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513–516. doi: 10.1038/312513a0.
Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5(4):317–28.
King CR, Kraus MH, Aaronson SA. Amplifcation of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985;229(4717):974.
Ménard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene (2003) 22:6570–8. doi: 10.1038/sj.onc.1206779.
Slamon, D. J., et al. (1987). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 235(4785), 177–182.
Yarden, Y., &Sliwkowski, M. X. (2001). Untangling the ErbBsignalling network. Nature Reviews Molecular Cell Biology, 2(2), 127–137.
Coussens, L. M., & Yang, F. (1994). The role of HER2/neu in breast cancer. Seminars in Oncology, 21(4), 50–55.
Schulze, A., & Downward, J. (2001). Network crosstalk: The interconnections between the Ras, PI3K, and Raf signaling pathways. Cancer Cell, 10(1), 41–49. https://doi.org/10.1016/S1535-6108(01)00192-X.
Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene (2007) 26:6469–87. doi: 10.1038/sj.onc.1210477.
Burstein HJ. The distinctive nature of HER2-positive breast cancers. The New England Journal of Medicine. 2005;353(16):1652–1654. doi: 10.1056/NEJMp058197.
Galogre M, Rodin D, Pyatnitskiy M, Mackelprang M, Koman I. A review of HER2 overexpression and somatic mutations in cancers. Crit Rev Oncol Hematol. 2023;186(103997):103997. Available from: http://dx.doi.org/10.1016/j.critrevonc.2023.103997
Shastry, B.S. SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet 52, 871–880 (2007). https://doi.org/10.1007/s10038-007-0200-z.
Frank B, Hemminki K, Wirtenberger M, et al. The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk. Carcinogenesis. 2005-26:643–7. doi: 10.1093/carcin/bgh342.
Adiga U, Adiga S, Rai T, Desy TM D, Honnalli NM. Bioinformatics Approach to Evaluate GRIN2B Gene in Depression–An in silico Study. Int J Pharm Investigation. 2023 Sep 21;13(4):852–7. Available from: http://dx.doi.org/10.5530/ijpi.13.4.107.
Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, Gao YT, Jin F, Zheng W. Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. Journal of the National Cancer Institute. 2000 Mar 1;92(5):412-7.
Kallel I, Kharrat N, Al-fadhly S, Rebai M, Khabir A, Boudawara TS, Rebai A. HER2 polymorphisms and breast cancer in Tunisian women. Genetic testing and molecular biomarkers. 2010 Feb 1;14(1):29-35.
Siddig A, Mohamed AO, Kamal H, Awad S, Hassan AH, Zilahi E, Al‐Haj M, Bernsen R, Adem A. HER‐2/neu Ile655Val Polymorphism and the Risk of Breast Cancer: A Case–Control Study. Annals of the New York Academy of Sciences. 2008 Sep;1138(1):84-94.
Alaoui-Jamali MA, Morand GB, da Silva SD. ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics. Front Genet. 2015;6. Available from: http://dx.doi.org/10.3389/fgene.2015.00017
Hisayuki Shigematsu, Takao Takahashi, Masaharu Nomura, Kuntal Majmudar, Makoto Suzuki, Huei Lee, Ignacio I. Wistuba, Kwun M. Fong, Shinichi Toyooka, Nobuyoshi Shimizu, Takehiko Fujisawa, John D. Minna, Adi F. Gazdar; Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas. Cancer Res 1 March 2005; 65 (5): 1642–1646. https://doi.org/10.1158/0008-5472.CAN-04-4235.
Riyue, Bao., Anita, Ng., Mark, M., Sasaki., Myvizhi, Esai, Selvan., Alyna, Katti., Hyesan, Lee., Lei, Huang., Andrew, D., Skol., Cinzia, Lavarino., Hector, Salvador., Robert, J., Klein., Zeynep, H., Gümüş., Jaume, Mora., Kenan, Onel., Kenan, Onel. 1. Functional Common and Rare ERBB2 Germline Variants Cooperate in Familial and Sporadic Cancer Susceptibility. Cancer Prevention Research, (2021). doi: 10.1158/1940-6207.CAPR-20-0094
Yan, Ju., Lifeng, Wang., Shengjun, Ta., Rui, Shu., Shanling, Yang., Xican, Gao., Hongping, Song., Liwen, Liu. 3. A germline alteration of ERBB2 increases the risk of breast cancer in Chinese Han women with a familial history of malignant tumors.. Oncology Letters, (2019). doi: 10.3892/OL.2019.10646
Xiangyu, Su., Hongmei, Zhao. 4. Abstract 5014: The landscape of ERBB2 mutations in Chinese patients with solid tumors. Cancer Research, (2022). doi: 10.1158/1538-7445.am2022-5014
Sinead, Toomey., Stephen, F., Madden., Simon, J., Furney., Yue, Fan., Mark, McCormack., Carragh, Stapleton., Mattia, Cremona., Gianpiero, L., Cavalleri., Malgorzata, Milewska., Naomi, Elster., Aoife, Carr., Joanna, Fay., Elaine, W., Kay., Susan, Kennedy., John, Crown., William, M., Gallagher., Bryan, T., Hennessy., Alex, J, Eustace. 5. The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer. Oncotarget, (2016). doi: 10.18632/ONCOTARGET.12782.
Downloads
Published
How to Cite
Issue
Section
License
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
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
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.
