MOLECULAR CHARACTERIZATION OF THYROID CANCER IN PASHTUN ETHNIC FAMILIES OF KHYBER PAKHTUNKHWA, PAKISTAN
Main Article Content
Keywords
RET, Thyroid, cancer, Mutation, Pashtun
Abstract
Medullary thyroid carcinoma (MTC) inherits as an autosomal dominant trait with almost complete penetrance. The condition arises due to mutations in the RET proto-oncogene. Herein the present study, two Pashtun origin families, suffering from MTC, were ascertained for genetic and in Silico functional characterization. Both the families were segregating MTC disorder in autosomal dominant fashion. Whole exome analysis in family 1 and 2 found missense mutations c.C1902G: p.Cys634Trp & c.G1901A:p.Cys634Tyr respectively in the 11th exon of RET gene. In silico analysis, for both mutant RET proteins, determined drastic effects of identified mutation on protein folding pattern as well as its interaction properties. Among all report mutations of RET gene, c.C1902G: p.Cys634Trp accounts for more than 50% of all MEN-2A mutations. The current study signifies the importance of onco-genetic testing & counseling for early intervention. This research opens a new avenue for investigating the genetic landscape of MTC and encourages further exploration into the intricate genetic factors that contribute to MTC's hereditary nature.
References
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[5] Rehman AU, Lodhi S, Anwar MI. Histopathological Evaluation of 432 Cases of Goiter. APR -JUN 2009.
[6] Muzammal M, Khan MA, Mohaini M Al, Alsalman AJ, Hawaj MA Al, Farid A. In Silico Analysis of Honeybee Venom Protein Interaction with Wild Type and Mutant (A82V + P375S) Ebola Virus Spike Protein. Biologics 2022;2. https://doi.org/10.3390/biologics2010003.
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[18] Muzammal M, Firoz A, Ali HM, Farid A, Khan MA, Hakeem KR. Lumateperone Interact with S-Protein of Ebola Virus and TIM-1 of Human Cell Membrane: Insights from Computational Studies. Applied Sciences (Switzerland) 2022;12. https://doi.org/10.3390/app12178820.
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[22] Muzammal M, Ali MZ, Ahmad S, Huma S, Rizwan, Ahmad S, et al. The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly. J Pak Med Assoc 2021;71. https://doi.org/10.47391/JPMA.03-476.
[23] Fatima S, Muzammal M, Ahmad Khan M, Farid A, Kamran M, Qayum J, et al. Crispr/Cas9 Endonucleases: A New Era of Genetic Engineering. Abasyn Journal Life Sciences 2021. https://doi.org/10.34091/ajls.4.2.4.
[24] Muzammal M, Khan MA, Fatima S, Bibi A, Anum SR, Abbasi SW, et al. In silico Analysis of PRODH Mutations and their biological significance in disease etiology. Abasyn Journal Life Sciences 2022. https://doi.org/10.34091/ajls.5.1.7.
[25] Ayaz M, Muzammal M, Siraj S, Fatima S, Fatima S, Khan J, et al. Genetic basis of ß-thalassemia in families of pashtun ethnicity in Dera Ismail Khan district of Khyber Pakhtun-Khwa province, Pakistan. Expert Rev Hematol 2023;16. https://doi.org/10.1080/17474086.2023.2241639.
[26] Ahmad S, Ali MZ, Muzammal M, Khan AU, Ikram M, Muurinen M, et al. Identification of GLI1 and KIAA0825 Variants in Two Families with Postaxial Polydactyly. Genes (Basel) 2023;14. https://doi.org/10.3390/genes14040869.
[27] Muzammal M, Zubair M, Bierbaumer S, Blatterer J, Graf R, Gul A, et al. Exome sequence analysis in consanguineous Pakistani families inheriting Bardet-Biedle syndrome determined founder effect of mutation c.299delC (p.Ser100Leufs*24) in BBS9 gene. Mol Genet Genomic Med 2019;7. https://doi.org/10.1002/mgg3.834.
[28] Gul H, Shah AH, Harripaul R, Abbasi SW, Faheem M, Zubair M, et al. Homozygosity mapping coupled with whole-exome sequencing and protein modelling identified a novel missense mutation in GUCY2D in a consanguineous Pakistani family with Leber congenital amaurosis. J Genet 2021;100. https://doi.org/10.1007/s12041-021-01310-5.
[29] Muzammal M, Ali MZ, Brugger B, Blatterer J, Ahmad S, Taj S, et al. A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37. https://doi.org/10.1007/s11011-021-00832-2.
[30] Muzammal M, Di Cerbo A, Almusalami EM, Farid A, Khan MA, Ghazanfar S, et al. In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology. Genes (Basel) 2022;13. https://doi.org/10.3390/genes13040698.
[31] Ali MZ, Farid A, Ahmad S, Muzammal M, Mohaini M Al, Alsalman AJ, et al. In Silico Analysis Identified Putative Pathogenic Missense nsSNPs in Human SLITRK1 Gene. Genes (Basel) 2022;13. https://doi.org/10.3390/genes13040672.
[32] Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf) 2011;74. https://doi.org/10.1111/j.1365-2265.2010.03900.x.
[33] Pecce V, Sponziello M, Damante G, Rosignolo F, Durante C, Lamartina L, et al. A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency. PLoS Genet 2018;14. https://doi.org/10.1371/journal.pgen.1007678.
[34] Crockett DK, Piccolo SR, Ridge PG, Margraf RL, Lyon E, Williams MS, et al. Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene. PLoS One 2011;6. https://doi.org/10.1371/journal.pone.0018380.
[35] Fatima S, Malkani N, Muzammal M, Khan AA, Usama M. Stable Vesicle Production from Bacterial Total Lipid Extracts. Abasyn Journal Life Sciences 2021. https://doi.org/10.34091/ajls.4.1.1.
[36] Hussain S, Nawaz A, Hamid M, Ullah W, Khan IN, Afshan M, et al. Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein-truncating mutations of ASPM. Biotechnol Appl Biochem 2022;69. https://doi.org/10.1002/bab.2286.
[37] Gul H, Ali MZ, Khan E, Zubair M, Badar M, Khan S, et al. Ophthalmo-genetic analysis of Pakistani patients with nonsyndromic oculocutaneous albinism through whole exome sequencing. J Pak Med Assoc 2017;67.
[38] Fatima S, Kamran M, Muzammal M, Rehman A, Ullah Shah K, Mashal S, et al. Composition and Function of Saliva: A review. World J Pharm Pharm Sci 2020;9.
[39] Muzammal M, Ahmad S, Ali MZ, Fatima S, Abbas S, Khan J, et al. Whole exome sequencing coupled with in silico functional analysis identified NID1 as a novel candidate gene causing neuro-psychiatric disorder in a Pakistani family. J Natl Sci Found 2024;51. https://doi.org/10.4038/jnsfsr.v51i4.11256.
[40] Gul H, Shah AH, Harripaul R, Mikhailov A, Khan EU, Shah W, et al. Mutation Analysis of a Pakistani Oculocutaneous Albinism Family Identifies a Novel Splice Site Defect in OCA2 Gene. Pak J Zool 2022;54. https://doi.org/10.17582/journal.pjz/20200501060515.
[41] Al Mohaini M, Farid A, Muzammal M, Ghazanfar S, Dadrasnia A, Alsalman AJ, et al. Enhancing Lipase Production of Bacillus salmalaya Strain 139SI Using Different Carbon Sources and Surfactants. Appl Microbiol 2022;2. https://doi.org/10.3390/applmicrobiol2010017.
[42] Ullah A, Qureshi R, Iqbal Z, Rahman IU, Ali N, Shah M, et al. Ethnomedicinal flora of Frontier Region Tank, Fata, Pakistan. Acta Ecologica Sinica 2019;39. https://doi.org/10.1016/j.chnaes.2018.09.006.
[43] Khan KA, Khan GM, Muzammal M, Al Mohaini M, Alsalman AJ, Al Hawaj MA, et al. Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents. Molecules 2022;27. https://doi.org/10.3390/molecules27030864.
[44] Gul H, Shah AH, Harripaul R, Mikhailov A, Prajapati K, Khan E, et al. Genetic studies of multiple consanguineous Pakistani families segregating oculocutaneous albinism identified novel and reported mutations. Ann Hum Genet 2019;83. https://doi.org/10.1111/ahg.12307.
[45] Abid R, Ghazanfar S, Farid A, Sulaman SM, Idrees M, Amen RA, et al. Pharmacological Properties of 4′, 5, 7‐Trihydroxyflavone (Apigenin) and Its Impact on Cell Signaling Pathways. Molecules 2022;27. https://doi.org/10.3390/molecules27134304.
[46] Khan MA, Rafiq MA, Noor A, Hussain S, Flores J V., Rupp V, et al. Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am J Hum Genet 2012;90. https://doi.org/10.1016/j.ajhg.2012.03.023.
[47] Shahzad M, Yousaf S, Waryah YM, Gul H, Kausar T, Tariq N, et al. Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population. Sci Rep 2017;7. https://doi.org/10.1038/srep44185.
[48] Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367. https://doi.org/10.1038/367375a0.
[2] Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, Henry KA, et al. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst 2015;107. https://doi.org/10.1093/jnci/djv048.
[3] Hegedüs L. clinical practice The Thyroid Nodule. N Eng J Med 2004;351.
[4] Sushel C, Khanzada TW, Zulfikar I, Samad A. Histopathological pattern of diagnosis in patients undergoing thyroid operations. Rawal Medical Journal 2009;34.
[5] Rehman AU, Lodhi S, Anwar MI. Histopathological Evaluation of 432 Cases of Goiter. APR -JUN 2009.
[6] Muzammal M, Khan MA, Mohaini M Al, Alsalman AJ, Hawaj MA Al, Farid A. In Silico Analysis of Honeybee Venom Protein Interaction with Wild Type and Mutant (A82V + P375S) Ebola Virus Spike Protein. Biologics 2022;2. https://doi.org/10.3390/biologics2010003.
[7] Zuberi LM, Yawar A, Islam N, Jabbar A. Clinical presentation of thyroid cancer patients in Pakistan - AKUH experience. J Pak Med Assoc 2004;54.
[8] Tirrò E, Martorana F, Romano C, Vitale SR, Motta G, Di Gregorio S, et al. Molecular alterations in thyroid cancer: From bench to clinical practice. Genes (Basel) 2019;10. https://doi.org/10.3390/genes10090709.
[9] Santos AL, Oliveira V, Baptista I, Henriques I, Gomes NCM, Almeida A, et al. Wavelength dependence of biological damage induced by UV radiation on bacteria. Arch Microbiol 2013;195. https://doi.org/10.1007/s00203-012-0847-5.
[10] Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol 2015;3. https://doi.org/10.1016/S2213-8587(14)70225-6.
[11] Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: A retrospective cohort study. The Lancet 2012;380. https://doi.org/10.1016/S0140-6736(12)60815-0.
[12] de la Fouchardière C, Decaussin-Petrucci M, Berthiller J, Descotes F, Lopez J, Lifante JC, et al. Predictive factors of outcome in poorly differentiated thyroid carcinomas. Eur J Cancer 2018;92. https://doi.org/10.1016/j.ejca.2017.12.027.
[13] Randle RW, Balentine CJ, Leverson GE, Havlena JA, Sippel RS, Schneider DF, et al. Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery (United States), vol. 161, 2017. https://doi.org/10.1016/j.surg.2016.04.053.
[14] Priya SR, Dravid CS, Digumarti R, Dandekar M. Targeted therapy for medullary thyroid cancer: A review. Front Oncol 2017;7. https://doi.org/10.3389/fonc.2017.00238.
[15] Vigneri R, Malandrino P, Vigneri P. The changing epidemiology of thyroid cancer: Why is incidence increasing? Curr Opin Oncol 2015;27. https://doi.org/10.1097/CCO.0000000000000148.
[16] Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16. https://doi.org/10.1093/nar/16.3.1215.
[17] Kozakov D, Hall DR, Xia B, Porter KA, Padhorny D, Yueh C, et al. The ClusPro web server for protein-protein docking. Nat Protoc 2017;12. https://doi.org/10.1038/nprot.2016.169.
[18] Muzammal M, Firoz A, Ali HM, Farid A, Khan MA, Hakeem KR. Lumateperone Interact with S-Protein of Ebola Virus and TIM-1 of Human Cell Membrane: Insights from Computational Studies. Applied Sciences (Switzerland) 2022;12. https://doi.org/10.3390/app12178820.
[19] Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25. https://doi.org/10.1089/thy.2014.0335.
[20] Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science (1979) 1995;267. https://doi.org/10.1126/science.7824936.
[21] Bukhari U, Sadiq S, Memon J, Baiga F. Thyroid carcinoma in Pakistan: A retrospective review of 998 cases from an academic referral center. Hematology/ Oncology and Stem Cell Therapy 2009;2. https://doi.org/10.1016/S1658-3876(09)50023-4.
[22] Muzammal M, Ali MZ, Ahmad S, Huma S, Rizwan, Ahmad S, et al. The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly. J Pak Med Assoc 2021;71. https://doi.org/10.47391/JPMA.03-476.
[23] Fatima S, Muzammal M, Ahmad Khan M, Farid A, Kamran M, Qayum J, et al. Crispr/Cas9 Endonucleases: A New Era of Genetic Engineering. Abasyn Journal Life Sciences 2021. https://doi.org/10.34091/ajls.4.2.4.
[24] Muzammal M, Khan MA, Fatima S, Bibi A, Anum SR, Abbasi SW, et al. In silico Analysis of PRODH Mutations and their biological significance in disease etiology. Abasyn Journal Life Sciences 2022. https://doi.org/10.34091/ajls.5.1.7.
[25] Ayaz M, Muzammal M, Siraj S, Fatima S, Fatima S, Khan J, et al. Genetic basis of ß-thalassemia in families of pashtun ethnicity in Dera Ismail Khan district of Khyber Pakhtun-Khwa province, Pakistan. Expert Rev Hematol 2023;16. https://doi.org/10.1080/17474086.2023.2241639.
[26] Ahmad S, Ali MZ, Muzammal M, Khan AU, Ikram M, Muurinen M, et al. Identification of GLI1 and KIAA0825 Variants in Two Families with Postaxial Polydactyly. Genes (Basel) 2023;14. https://doi.org/10.3390/genes14040869.
[27] Muzammal M, Zubair M, Bierbaumer S, Blatterer J, Graf R, Gul A, et al. Exome sequence analysis in consanguineous Pakistani families inheriting Bardet-Biedle syndrome determined founder effect of mutation c.299delC (p.Ser100Leufs*24) in BBS9 gene. Mol Genet Genomic Med 2019;7. https://doi.org/10.1002/mgg3.834.
[28] Gul H, Shah AH, Harripaul R, Abbasi SW, Faheem M, Zubair M, et al. Homozygosity mapping coupled with whole-exome sequencing and protein modelling identified a novel missense mutation in GUCY2D in a consanguineous Pakistani family with Leber congenital amaurosis. J Genet 2021;100. https://doi.org/10.1007/s12041-021-01310-5.
[29] Muzammal M, Ali MZ, Brugger B, Blatterer J, Ahmad S, Taj S, et al. A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37. https://doi.org/10.1007/s11011-021-00832-2.
[30] Muzammal M, Di Cerbo A, Almusalami EM, Farid A, Khan MA, Ghazanfar S, et al. In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology. Genes (Basel) 2022;13. https://doi.org/10.3390/genes13040698.
[31] Ali MZ, Farid A, Ahmad S, Muzammal M, Mohaini M Al, Alsalman AJ, et al. In Silico Analysis Identified Putative Pathogenic Missense nsSNPs in Human SLITRK1 Gene. Genes (Basel) 2022;13. https://doi.org/10.3390/genes13040672.
[32] Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf) 2011;74. https://doi.org/10.1111/j.1365-2265.2010.03900.x.
[33] Pecce V, Sponziello M, Damante G, Rosignolo F, Durante C, Lamartina L, et al. A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency. PLoS Genet 2018;14. https://doi.org/10.1371/journal.pgen.1007678.
[34] Crockett DK, Piccolo SR, Ridge PG, Margraf RL, Lyon E, Williams MS, et al. Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene. PLoS One 2011;6. https://doi.org/10.1371/journal.pone.0018380.
[35] Fatima S, Malkani N, Muzammal M, Khan AA, Usama M. Stable Vesicle Production from Bacterial Total Lipid Extracts. Abasyn Journal Life Sciences 2021. https://doi.org/10.34091/ajls.4.1.1.
[36] Hussain S, Nawaz A, Hamid M, Ullah W, Khan IN, Afshan M, et al. Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein-truncating mutations of ASPM. Biotechnol Appl Biochem 2022;69. https://doi.org/10.1002/bab.2286.
[37] Gul H, Ali MZ, Khan E, Zubair M, Badar M, Khan S, et al. Ophthalmo-genetic analysis of Pakistani patients with nonsyndromic oculocutaneous albinism through whole exome sequencing. J Pak Med Assoc 2017;67.
[38] Fatima S, Kamran M, Muzammal M, Rehman A, Ullah Shah K, Mashal S, et al. Composition and Function of Saliva: A review. World J Pharm Pharm Sci 2020;9.
[39] Muzammal M, Ahmad S, Ali MZ, Fatima S, Abbas S, Khan J, et al. Whole exome sequencing coupled with in silico functional analysis identified NID1 as a novel candidate gene causing neuro-psychiatric disorder in a Pakistani family. J Natl Sci Found 2024;51. https://doi.org/10.4038/jnsfsr.v51i4.11256.
[40] Gul H, Shah AH, Harripaul R, Mikhailov A, Khan EU, Shah W, et al. Mutation Analysis of a Pakistani Oculocutaneous Albinism Family Identifies a Novel Splice Site Defect in OCA2 Gene. Pak J Zool 2022;54. https://doi.org/10.17582/journal.pjz/20200501060515.
[41] Al Mohaini M, Farid A, Muzammal M, Ghazanfar S, Dadrasnia A, Alsalman AJ, et al. Enhancing Lipase Production of Bacillus salmalaya Strain 139SI Using Different Carbon Sources and Surfactants. Appl Microbiol 2022;2. https://doi.org/10.3390/applmicrobiol2010017.
[42] Ullah A, Qureshi R, Iqbal Z, Rahman IU, Ali N, Shah M, et al. Ethnomedicinal flora of Frontier Region Tank, Fata, Pakistan. Acta Ecologica Sinica 2019;39. https://doi.org/10.1016/j.chnaes.2018.09.006.
[43] Khan KA, Khan GM, Muzammal M, Al Mohaini M, Alsalman AJ, Al Hawaj MA, et al. Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents. Molecules 2022;27. https://doi.org/10.3390/molecules27030864.
[44] Gul H, Shah AH, Harripaul R, Mikhailov A, Prajapati K, Khan E, et al. Genetic studies of multiple consanguineous Pakistani families segregating oculocutaneous albinism identified novel and reported mutations. Ann Hum Genet 2019;83. https://doi.org/10.1111/ahg.12307.
[45] Abid R, Ghazanfar S, Farid A, Sulaman SM, Idrees M, Amen RA, et al. Pharmacological Properties of 4′, 5, 7‐Trihydroxyflavone (Apigenin) and Its Impact on Cell Signaling Pathways. Molecules 2022;27. https://doi.org/10.3390/molecules27134304.
[46] Khan MA, Rafiq MA, Noor A, Hussain S, Flores J V., Rupp V, et al. Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am J Hum Genet 2012;90. https://doi.org/10.1016/j.ajhg.2012.03.023.
[47] Shahzad M, Yousaf S, Waryah YM, Gul H, Kausar T, Tariq N, et al. Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population. Sci Rep 2017;7. https://doi.org/10.1038/srep44185.
[48] Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367. https://doi.org/10.1038/367375a0.
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Jul 30, 2024
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Inayat ur Rehman, Muhammad Muzammal, Sami Siraj, & Jabbar Khan. (2024). MOLECULAR CHARACTERIZATION OF THYROID CANCER IN PASHTUN ETHNIC FAMILIES OF KHYBER PAKHTUNKHWA, PAKISTAN. Journal of Population Therapeutics and Clinical Pharmacology, 31(7), 1809-1820. https://doi.org/10.53555/mab52697
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Author Biographies
Inayat ur Rehman
Institute of Biological Sciences, Gomal University, 29050, Dera Ismail Khan, Pakistan
Muhammad Muzammal
Gomal Center of Biochemistry and Biotechnology, Gomal University, 29050, Dera Ismail Khan, Pakistan
Sami Siraj
Institute of Biomedical Sciences, Khyber Medical University, Peshawar, KP, Pakistan
Jabbar Khan
Institute of Biological Sciences, Gomal University, 29050, Dera Ismail Khan, Pakistan
How to Cite
Inayat ur Rehman, Muhammad Muzammal, Sami Siraj, & Jabbar Khan. (2024). MOLECULAR CHARACTERIZATION OF THYROID CANCER IN PASHTUN ETHNIC FAMILIES OF KHYBER PAKHTUNKHWA, PAKISTAN. Journal of Population Therapeutics and Clinical Pharmacology, 31(7), 1809-1820. https://doi.org/10.53555/mab52697