Mutations in the TP53 gene are among the most common genetic alterations in many cancers, and they are also suspected to play a role in the development of cataracts. TP53 is a tumor suppressor gene, and its alteration can dysregulate the expression of genes directly or indirectly controlled by the p53 protein. This may lead to impaired DNA damage repair, defective cell-cycle arrest, altered chromatin remodeling, and disrupted apoptosis. Cataracts, the leading cause of blindness, and cancer, the second leading cause of death worldwide, are still often diagnosed at late stages. This study aimed to evaluate the involvement of TP53 mutations in cataracts and in breast, prostate, and oral cavity cancers in Senegalese patients. A total of 116 patients were included: cataract (n = 29), oral cavity cancer (n = 33), prostate cancer (n = 15), breast cancer (n = 16), and controls (n = 23). Tissue samples were collected during biopsy after informed consent. DNA extraction, PCR amplification, and sequencing were performed. Mutation Surveyor was used to detect mutations; Mutation Taster, SIFT, and PolyPhen-2 were used to predict pathogenicity. DynaMut2 and I-Mutant were used to evaluate the impact of pathogenic variants on protein stability, and Missense3D was used to assess effects on the three-dimensional structure of p53. Cataract and oral cavity cancer tissues harbored more pathogenic variants (19 and 14, respectively) than breast and prostate cancer tissues (7 and 11, respectively). The variants c.506T > G (p. Met169Arg), c.652G > A (p. Val218Met), and c.672 + 1G > T were shared by prostate and breast cancers. The variants c.576G > C (p. Gln192His), c.642T > G (p. His214Gln), c.644G > A (p. Ser215Asn), and c.645T > G (p. Ser215Arg) were common to cataracts and oral cavity cancers. Structural analysis using Missense3D showed that some mutations caused no detectable structural damage, whereas significant conformational alterations were observed at codons 175 and 196 (variants c.524G > C and c.587G > C). These findings suggest that TP53 mutations may occur early in the development of cataract as well as in oral cavity, breast, and prostate cancers. This study provides baseline molecular data that could contribute to improving early detection and clinical management of these diseases in Senegalese patients.
References
[1]
Olivier, M., Hollstein, M. and Hainaut, P. (2009) TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harbor Perspectives in Biology, 2, a001008. https://doi.org/10.1101/cshperspect.a001008
[2]
Tornesello, M.L. (2024) TP53 Mutations in Cancer: Molecular Features and Therapeutic Opportunities (Review). International Journal of Molecular Medicine, 55, Article No. 7. https://doi.org/10.3892/ijmm.2024.5448
[3]
Guha, T. and Malkin, D. (2017) Inherited TP53 Mutations and the Li-Fraumeni Syndrome. Cold Spring Harbor Perspectives in Medicine, 7, a026187. https://doi.org/10.1101/cshperspect.a026187
[4]
Dunn, J. (2023) It Is Time to Close the Gap in Cancer Care. JCO Global Oncology, 9, e2200429. https://doi.org/10.1200/go.22.00429
[5]
Bouri, N., Ba, O., Dieme, J., Mbengue, M., Boye, A., Fall, T., et al. (2017) État des lieux du registre des tumeurs au Sénégal: Bilan à 6ans d’enregistrement en ligne. Revue des Maladies Respiratoires, 34, A75. https://doi.org/10.1016/j.rmr.2016.10.156
[6]
Le Soleil (2021) Cataract Surgery in Senegal. https://exphar.sn/info/chirurgie-de-la-cataracte/
[7]
Ferlay, J., Colombet, M., Soerjomataram, I., Parkin, D.M., Piñeros, M., Znaor, A. and Bray, F. (2021) Cancer Statistics for the Year 2020: An Overview. International Journal of Cancer, 149, 778-789. https://doi.org/10.1002/ijc.33588
[8]
Payen, A. (2015) Physiopathologie du cancer du sein. L’Aide-Soignante, 29, 12-14. https://doi.org/10.1016/j.aidsoi.2014.12.003
[9]
WHO (2025) Breast Cancer. https://www.who.int/news-room/fact-sheets/detail/breast-cancer
[10]
Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I. and Jemal, A. (2024) Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer Journal for Clinicians, 74, 229-263. https://doi.org/10.3322/caac.21834
[11]
Tarle, M. and Lukšić, I. (2024) Pathogenesis and Therapy of Oral Carcinogenesis. International Journal of Molecular Sciences, 25, Article 6343. https://doi.org/10.3390/ijms25126343
[12]
Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. https://doi.org/10.3322/caac.21660
[13]
Gueunoun, F. (2023) More Than 800 Cases of Prostate Cancer Are Recorded Annually in Senegal. https://ouestactu.net/2023/11/27/plus-de-800-cas-de-cancer-de-la-prostate-enregistres-annuellement-au-senegal/
[14]
Mbemi, A., Khanna, S., Njiki, S., Yedjou, C.G. and Tchounwou, P.B. (2020) Impact of Gene-Environment Interactions on Cancer Development. International Journal of Environmental Research and Public Health, 17, Article 8089. https://doi.org/10.3390/ijerph17218089
[15]
Lim Ng, K. (2021) The Etiology of Prostate Cancer. Prostate Cancer, Exon Publications, 17-28. https://doi.org/10.36255/exonpublications.prostatecancer.etiology.2021
[16]
Ndoye, M., Niang, L., Gandaho, K.I., Jalloh, M., Labou, I. and Gueye, S. (2014) Cancer avancé de la prostate au Sénégal. Aspects diagnostiques à l’hôpital de Grand Yoff. Progrès en Urologie, 24, 271-275. https://doi.org/10.1016/j.purol.2013.08.317
[17]
Samb, M.D. (2024) Cancers de la cavité buccale au Sénégal: Étude génétique et épidémiologique. Master’s Thesis, Université Cheikh Anta Diop de Dakar.
[18]
Hyodo, T., Kuribayashi, N., Fukumoto, C., Komiyama, Y., Shiraishi, R., Kamimura, R., et al. (2022) The Mutational Spectrum in Whole Exon of p53 in Oral Squamous Cell Carcinoma and Its Clinical Implications. Scientific Reports, 12, Article No. 21695. https://doi.org/10.1038/s41598-022-25744-8
[19]
Aboulalaa, K., Laraqui, A., Tagajdid, R., Ennibi, K. and Ennaji, M.M. (2024) Germline Mutations of TP53 Gene Can Be a Key Factor in Prostate Cancer Genesis. Exploration of Medicine, 5, 641-655. https://doi.org/10.37349/emed.2024.00246
[20]
Hwang, S.H., Baek, S.H., Lee, M.J., Kook, Y., Bae, S.J., Ahn, S.G., et al. (2024) Clinical Relevance of TP53 Mutation and Its Characteristics in Breast Cancer with Long-Term Follow-Up Date. Cancers, 16, Article 3899. https://doi.org/10.3390/cancers16233899
[21]
Sheng, S., Xu, Y., Guo, Y., Yao, L., Hu, L., Ouyang, T., et al. (2019) Prevalence and Clinical Impact of TP53 Germline Mutations in Chinese Women with Breast Cancer. International Journal of Cancer, 146, 487-495. https://doi.org/10.1002/ijc.32424
[22]
Ateenyi-Agaba, C., Weiderpass, E., Smet, A., Dong, W., Dai, M., Kahwa, B., Wabinga, H., Katongole-Mbidde, E., Franceschi, S. and Tommasino, M. (2004) Epidermodysplasia Verruciformis Human Papillomavirus Types and Carcinoma of the Conjunctiva: A Pilot Study. British Journal of Cancer, 90, 1777-1779. https://doi.org/10.1038/sj.bjc.6601743
[23]
Maurya, R.P., Kumar Bosak, S., Singh, R., Singh, V.P., Singh, S., Lundmark, P.O., et al. (2021) Analysis of Tumor Protein p53 (p53) Mutations in Eyelid Malignancy. IP International Journal of Ocular Oncology and Oculoplasty, 7, 243-249. https://doi.org/10.18231/j.ijooo.2021.051
[24]
Majhi, P.D., Sharma, A. and Jerry, D.J. (2023) Genetic Modifiers of p53: Opportunities for Breast Cancer Therapies. Oncotarget, 14, 236-241. https://doi.org/10.18632/oncotarget.28387
[25]
Hrstka, R., Coates, P.J. and Vojtesek, B. (2009) Polymorphisms in p53 and the p53 Pathway: Roles in Cancer Susceptibility and Response to Treatment. Journal of Cellular and Molecular Medicine, 13, 440-453. https://doi.org/10.1111/j.1582-4934.2008.00634.x
[26]
Murphy, M.E., Liu, S., Yao, S., Huo, D., Liu, Q., Dolfi, S.C., et al. (2017) A Functionally Significant SNP in TP53 and Breast Cancer Risk in African-American Women. npj Breast Cancer, 3, Article No. 5. https://doi.org/10.1038/s41523-017-0007-9
[27]
Diaga, S.P., Silly, T., Elmostafa, E.F., Abdoul, B.S., Demba, D.J.P., Yacouba, D., et al. (2022) Targeting Mutational Landscape of TP53 in Patients Diagnosed with Oral Cancer Living in Senegal. Journal of Cancer Genetics and Biomarkers, 1, 22-32. https://doi.org/10.14302/issn.2572-3030.jcgb-22-4121
[28]
Ochwoto, M., Oduma, C.O., Oyugi, J., Mwaengo, D., Ondigo, B.N., Kimotho, J.H., et al. (2024) Human TP53 Gene Polymorphisms among Patients with Hepatocellular Carcinoma and Chronic Hepatitis B Infection in Kenya. F1000Research, 8, Article 1364. https://doi.org/10.12688/f1000research.19416.2
[29]
Samb, M.D., Mbaye, F., Ndiaye, M.M., Fall, M., Toure, S. and Sembene, M. (2023) Involvement of TP53 Mutations in the Occurrence of Oral Cavity Cancers in Senegalese Patients. Journal of Proteomics & Bioinformatics, 16, Article ID: 1000635.
[30]
van Kempen, P.M.W., Verdam, F.J., de Poel, E., Braunius, W.W., de Weger, R.A., van Es, R.J.J., et al. (2015) TP53 Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma. Pathobiology, 82, 21-27. https://doi.org/10.1159/000369102
[31]
Malhotra, L., Singh, A., Kaur, P. and Ethayathulla, A.S. (2024) Phenotypical Mapping of TP53 Unique Missense Mutations Spectrum in Human Cancers. Journal of Biomolecular Structure and Dynamics. https://doi.org/10.1080/07391102.2024.2435060
[32]
Shahnavaz, S.A., Regezi, J.A., Bradley, G., Dubé, I.D. and Jordan, R.C.K. (2000) p53 Gene Mutations in Sequential Oral Epithelial Dysplasias and Squamous Cell Carcinomas. The Journal of Pathology, 190, 417-422. https://doi.org/10.1002/(sici)1096-9896(200003)190:4<417::aid-path544>3.3.co;2-7
[33]
Strandgren, C. and Wiman, K.G. (2024) Therapeutic Targeting of TP53 Nonsense Mutations in Cancer. Upsala Journal of Medical Sciences, 129, e10719. https://doi.org/10.48101/ujms.v129.10719
[34]
Xiong, L. and Garfinkel, A. (2022) A Common Pathway to Cancer: Oncogenic Mutations Abolish p53 Oscillations. Progress in Biophysics and Molecular Biology, 174, 28-40. https://doi.org/10.1016/j.pbiomolbio.2022.06.002
[35]
Tanaka, N., Zhao, M., Tang, L., Patel, A.A., Xi, Q., Van, H.T., et al. (2017) Gain-of-function Mutant p53 Promotes the Oncogenic Potential of Head and Neck Squamous Cell Carcinoma Cells by Targeting the Transcription Factors FOXO3a and FOXM1. Oncogene, 37, 1279-1292. https://doi.org/10.1038/s41388-017-0032-z
[36]
Balasundaram, A. and Doss, C.G.P. (2022) Unraveling the Structural Changes in the DNA-Binding Region of Tumor Protein p53 (TP53) Upon Hotspot Mutation p53 Arg248 by Comparative Computational Approach. International Journal of Molecular Sciences, 23, Article 15499. https://doi.org/10.3390/ijms232415499
