NOT PON1 L55M BUT ACE I/D VARIANT MIGHT BE A RISK FACTOR FOR OSCC IN THE TURKISH POPULATION
Year 2025,
Volume: 8 Issue: 1, 15 - 20, 04.03.2025
Ayşe Feyda Nursal
,
Özge Gümüşay
,
Serbülent Yiğit
,
Nilüfer Kuruca
,
Mehmet Kemal Tümer
Abstract
Objective: Oral squamous cell carcinoma (OSCC) covers more than 90% of the malignant neoplasms in the mouth. It has been shown that angiotensin-converting enzyme (ACE) and paraoxonase (PON1) gene variants were associated with several cancers. Therefore, we investigated the possible association between ACE insertion/deletion (I/D)-PON1 L55M variants and OSCC development risk in a Turkish population.
Material and Methods: A total of 155 people (104 healthy controls and 51 OSCC patients) made up the study population. These variants were genotyped using polymerase chain reaction (PCR) and/or restriction fragment length polymorphism (RFLP) assays.
Results: ACE I/D allele frequencies were significantly different between patients and controls. The ACE D allele was higher in the patient group compared to the control group, while the I allele was more prevalent in controls than patients (p˂0.0000001). When the patients and controls were examined based on the II+ID vs. DD genotype and II: ID vs. DD, a statistically significant correlation was found (p = 0.0000001 and p = 0.008691, respectively). The genotype and allele distribution of PON1 L55M did not significantly differ between the groups.
Conclusion: In conclusion, our study showed that the ACE I/D variant D allele is a risk factor for the development of OSCC in Turkey. This study contributes to more studies to confirm that ACE I/D plays a role as a genetic risk factor for OSCC.
References
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- Lee C-F, Chiang N-N, Lu Y-H, Huang Y-S, Yang J-S, Tsai S-C, et al. Benzyl isothiocyanate (BITC) triggers mitochondria-mediated apoptotic machinery in human cisplatin-resistant oral cancer CAR cells. Biomedicine 2018;8(3). google scholar
- Yaren A, Turgut S, Kursunluoglu R, Oztop I, Turgut G, Degirmencioglu S, et al. Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients with breast cancer and effects on prognostic factors. J Investig Med 2007;55(5):255-61. google scholar
- Gan L, Liu X, Wu Z, Huang M, Zhang X, Guo W. Angiotensin-converting enzyme insertion/deletion polymorphism and gastric cancer: a systematic review and meta-analysis. Int J Clin Exp Med 2015;8(4):5788-93. google scholar
- Hubert C, Houot A-M, Corvol P, Soubrier F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 1991;266(23):15377-83. google scholar
- Lin C, Yang H-Y, Wu C-C, Lee H-S, Lin Y-F, Lu K-C, et al. Angiotensin-converting enzyme insertion/deletion polymorphism contributes high risk for chronic kidney disease in Asian male with hypertension-a meta-regression analysis of 98 observational studies. PloS one 2014;9(1):e87604. google scholar
- Precourt L-P, Amre D, Denis M-C, Lavoie J-C, Delvin E, Seidman E, et al. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis 2011;214(1):20-36. google scholar
- Pan X, Huang L, Li M, Mo D, Liang Y, Liu Z, et al. The association between PON1 (Q192R and L55M) gene polymorphisms and risk of cancer: A meta-analysis based on 43 studies. Biomed Res Int 2019;2019. google scholar
- Brophy VH, Jarvik GP, Richter RJ, Rozek LS, Schellenberg GD, Furlong CE. Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype. Pharmacogenet Genomics 2000;10(5):453-60. google scholar
- Inanır A, Yigit S, Tural S, Ozturk SD, Akkanet S, Habiboğlu A. Significant association between insertion/deletion polymorphism of the angiotensin-convertig enzyme gene and ankylosing spondylitis. Mol Vis 2012;18:2107. google scholar
- Basol N, Karakus N, Savas AY, Karakus K, Kaya İ, Karaman S, et al. The evaluation of two genetic polymorphisms of paraoxonase 1 in patients with pulmonary embolism. J Clin Lab Anal 2018;32(7):e22455. google scholar
- Abram MH, van Heerden WF, Rheeder P, Girdler-Brown BV, van Zyl AW. Epidemiology of oral squamous cell carcinoma. Sadj. 2012;67(10):550-3. google scholar
- Wegman-Ostrosky T, Soto-Reyes E, Vidal-Millân S, Sânchez-Corona J. The renin-angiotensin system meets the hallmarks of cancer. J Renin Angiotensin Aldosterone Syst 2015;16(2):227-33. google scholar
- Matsushima-Otsuka S, Fujiwara-Tani R, Sasaki T, Ohmori H, Nakashima C, Kishi S, et al. Significance of intranuclear angiotensin-II type 2 receptor in oral squamous cell carcinoma. Oncotarget 2018;9(93):36561. google scholar
- de Carvalho Fraga CA, Farias LC, Jones KM, Batista de Paula AM, Guimaraes AL. Angiotensin-converting enzymes (ACE and ACE2) as potential targets for malignant epithelial neoplasia: review and bioinformatics analyses focused in oral squamous cell carcinoma. Protein Pept Lett 2017;24(9):784-92. google scholar
- Vairaktaris E, Yapijakis C, Tsigris C, Vassiliou S, Derka S, Nkenke E, et al. Association of angiotensin-converting enzyme gene insertion/ deletion polymorphism with increased risk for oral cancer. Acta Oncol 2007;46(8):1097-102. google scholar
- Xie Y, You C, Chen J. An updated meta-analysis on association between angiotensin I-converting enzyme gene insertion/deletion polymorphism and cancer risk. Tumour Biol 2014;35(7):6567-79. google scholar
- Zhang Y, He J, Deng Y, Zhang J, Li X, Xiang Z, et al. The insertion/ deletion (I/D) polymorphism in the Angiotensin-converting enzyme gene and cancer risk: a meta-analysis. BMC Med Genet 2011;12(1):1-10. google scholar
- Raba G, Zawlik I, Braun M, Paszek S, Potocka N, Skrzypa M, et al. Evaluation of the association between angiotensin converting enzyme insertion/deletion polymorphism and the risk of endometrial cancer in and characteristics of Polish women. Adv Clin Exp Med 2020;29(5):581-5. google scholar
- Chen J, Sun M, Zhou M, Lu R. Associations between I/D polymorphism in the ACE gene and lung cancer: an updated systematic review and a meta-analysis. BMC cancer 2021;21(1):1-9. google scholar
- Elabd NS, Montaser B, Gohar S, Makboul K, Elhamoly M. Association Between the ACE (I/D) Gene Polymorphism and Hepatocellular Carcinoma Risk in Egyptian HCV Patients. Int J Cancer Res 2020;4(3):159-67. google scholar
- Yigit B, Bozkurt N, Narter F, Yilmaz H, Yucebas E, Isbir T. Effects of ACE I/D polymorphism on prostate cancer risk, tumor grade and metastatis. Anticancer Res 2007;27(2):933-6. google scholar
- Chung F, Yang Y, Chen C, Lin C, Shieh T. Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers. Br J Cancer 2005;93(5):602-6. google scholar
- Cejas P, Casado E, Belda-Iniesta C, De Castro J, Espinosa E, Redondo A, et al. Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). Cancer Causes Control 2004;15(7):707-19. google scholar
- Uluocak N, Atılgan D, Parlaktaş BS, Erdemir F, Ateş Ö. A pilot study assessing the association between paraoxonase 1 gene polymorphism and prostate cancer. Turk J Urol 2017;43(3):279. google scholar
- Hashim Z, Zarina S. Assessment of paraoxonase activity and lipid peroxidation levels in diabetic and senile subjects suffering from cataract. Clin Biochem 2007;40(9-10):705-9. google scholar
- Dantoine TF, Debord J, Charmes J-P, Merle L, Marquet P, Lachatre G, et al. Decrease of serum paraoxonase activity in chronic renal failure. J Am Soc Nephrol 1998;9(11):2082-8. google scholar
- Baskol G, Karakucuk S, Oner AO, Baskol M, Kocer D, Mirza E, et al. Serum paraoxonase 1 activity and lipid peroxidation levels in patients with age-related macular degeneration. Ophthalmologica 2006;220(1):12-6. google scholar
- Raiszadeh F, Solati M, Etemadi A, Azizi F. Serum paraoxonase activity before and after treatment of thyrotoxicosis. Clin Endocrinol 2004;60(1):75-80. google scholar
- Malik UU, Siddiqui IA, Hashim Z, Zarina S. Measurement of serum paraoxonase activity and MDA concentrations in patients suffering with oral squamous cell carcinoma. Clin Chim Acta 2014;430:38-42. google scholar
- Metin ZB, Aydin S, Unur M, Cakmakoglu B, Toptas B, Hafiz G, et al. Oral squamous cell carcinoma and serum paraoxonase 1. J Laryngol Otol 2013;127(12):1208-13. google scholar
- Hu P, Ma Y, Zhang L, Ma S. PON1 L55M polymorphism might contribute to the risk of cancer. Panminerva Med 2016;59(1):107-13. google scholar
- Santana ITS, Dos Santos JNA, de Almeida VL, Ferreira WNS, Santos EM, de Almeida Freitas R, et al. Association of PON1, TNF-a and TGF-Ş gene polymorphisms with prognosis in oral and oropharyngeal squamous cell carcinoma. Acta Odontol Scand 2021;79(5):327-34. google scholar
TÜRK POPÜLASYONUNDA ACE I/D VARYANTI OSCC İÇİN BİR RİSK FAKTÖRÜ OLABİLİR FAKAT PON1 L55M RİSK FAKTÖRÜ DEĞİLDİR
Year 2025,
Volume: 8 Issue: 1, 15 - 20, 04.03.2025
Ayşe Feyda Nursal
,
Özge Gümüşay
,
Serbülent Yiğit
,
Nilüfer Kuruca
,
Mehmet Kemal Tümer
Abstract
Amaç: Oral skuamöz hücreli karsinom (OSCC), ağızdaki malign neoplazm ların %90’ından fazlasını kapsar. Anjiyotensin dönüştürücü enzim (ACE) ve paraoksonaz (PON1) gen varyantlarının birçok kanserle ilişkili olduğu gös terilmiştir. Bu nedenle, Türk popülasyonunda ACE I/D-PON1 L55M var yantları ile OSCC gelişim riski arasındaki olası ilişkiyi araştırmayı amaçladık.
Gereç ve Yöntemler: Çalışma popülasyonu toplam 155 bireyden oluşmak taydı (51 OSCC hastası ve 104 sağlıklı kontrol). ACE I/D - PON1 L55M var yantları, PCR ve RFLP analizleri kullanılarak genotiplendi.
Bulgular: ACE I/D alel frekansları hastalar ve kontroller arasında anlamlı şekilde farklılık göstermiştir. ACE D aleli, hasta grubunda kontrol grubuna kıyasla daha yüksek iken, I aleli kontrollerde hastalara kıyasla daha fazlaydı (p˂0,0000001). Hastalar ile kontroller, II+ID vs. DD genotipine (p=0,0000001) ve II: ID vs. DD’ye (p=0,008691) göre karşılaştırıldığında istatistiksel olarak anlamlı bir ilişki gözlendi. PON1 L55M genotipi veya alel dağılımı açısından hastalar ve kontroller arasında anlamlı bir fark buluna madı (p>0,05).
Sonuç: Sonuç olarak çalışmamız ACE I/D varyant D alelinin Türkiye’de OSCC gelişimi için risk faktörü olduğunu gösterdi. Bu çalışma, ACE I/D’nin OSCC için genetik bir risk faktörü olarak rol oynadığını doğrulamak amacıyla yapılacak daha fazla araştırmaya katkı sağlamaktadır.
References
- Rao SVK, Mejia G, Roberts-Thomson K, Logan R. Epidemiology of oral cancer in Asia in the past decade-an update (2000-2012). Asian Pac J Cancer Prev 2013;14(10):5567-77. google scholar
- Yang W-H, Wang S-J, Chang Y-S, Su C-M, Yang S-F, Tang C-H. Association of resistin gene polymorphisms with oral squamous cell carcinoma progression and development. Biomed Res Int 2018;14(9531315). google scholar
- Lee C-F, Chiang N-N, Lu Y-H, Huang Y-S, Yang J-S, Tsai S-C, et al. Benzyl isothiocyanate (BITC) triggers mitochondria-mediated apoptotic machinery in human cisplatin-resistant oral cancer CAR cells. Biomedicine 2018;8(3). google scholar
- Yaren A, Turgut S, Kursunluoglu R, Oztop I, Turgut G, Degirmencioglu S, et al. Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients with breast cancer and effects on prognostic factors. J Investig Med 2007;55(5):255-61. google scholar
- Gan L, Liu X, Wu Z, Huang M, Zhang X, Guo W. Angiotensin-converting enzyme insertion/deletion polymorphism and gastric cancer: a systematic review and meta-analysis. Int J Clin Exp Med 2015;8(4):5788-93. google scholar
- Hubert C, Houot A-M, Corvol P, Soubrier F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 1991;266(23):15377-83. google scholar
- Lin C, Yang H-Y, Wu C-C, Lee H-S, Lin Y-F, Lu K-C, et al. Angiotensin-converting enzyme insertion/deletion polymorphism contributes high risk for chronic kidney disease in Asian male with hypertension-a meta-regression analysis of 98 observational studies. PloS one 2014;9(1):e87604. google scholar
- Precourt L-P, Amre D, Denis M-C, Lavoie J-C, Delvin E, Seidman E, et al. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis 2011;214(1):20-36. google scholar
- Pan X, Huang L, Li M, Mo D, Liang Y, Liu Z, et al. The association between PON1 (Q192R and L55M) gene polymorphisms and risk of cancer: A meta-analysis based on 43 studies. Biomed Res Int 2019;2019. google scholar
- Brophy VH, Jarvik GP, Richter RJ, Rozek LS, Schellenberg GD, Furlong CE. Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype. Pharmacogenet Genomics 2000;10(5):453-60. google scholar
- Inanır A, Yigit S, Tural S, Ozturk SD, Akkanet S, Habiboğlu A. Significant association between insertion/deletion polymorphism of the angiotensin-convertig enzyme gene and ankylosing spondylitis. Mol Vis 2012;18:2107. google scholar
- Basol N, Karakus N, Savas AY, Karakus K, Kaya İ, Karaman S, et al. The evaluation of two genetic polymorphisms of paraoxonase 1 in patients with pulmonary embolism. J Clin Lab Anal 2018;32(7):e22455. google scholar
- Abram MH, van Heerden WF, Rheeder P, Girdler-Brown BV, van Zyl AW. Epidemiology of oral squamous cell carcinoma. Sadj. 2012;67(10):550-3. google scholar
- Wegman-Ostrosky T, Soto-Reyes E, Vidal-Millân S, Sânchez-Corona J. The renin-angiotensin system meets the hallmarks of cancer. J Renin Angiotensin Aldosterone Syst 2015;16(2):227-33. google scholar
- Matsushima-Otsuka S, Fujiwara-Tani R, Sasaki T, Ohmori H, Nakashima C, Kishi S, et al. Significance of intranuclear angiotensin-II type 2 receptor in oral squamous cell carcinoma. Oncotarget 2018;9(93):36561. google scholar
- de Carvalho Fraga CA, Farias LC, Jones KM, Batista de Paula AM, Guimaraes AL. Angiotensin-converting enzymes (ACE and ACE2) as potential targets for malignant epithelial neoplasia: review and bioinformatics analyses focused in oral squamous cell carcinoma. Protein Pept Lett 2017;24(9):784-92. google scholar
- Vairaktaris E, Yapijakis C, Tsigris C, Vassiliou S, Derka S, Nkenke E, et al. Association of angiotensin-converting enzyme gene insertion/ deletion polymorphism with increased risk for oral cancer. Acta Oncol 2007;46(8):1097-102. google scholar
- Xie Y, You C, Chen J. An updated meta-analysis on association between angiotensin I-converting enzyme gene insertion/deletion polymorphism and cancer risk. Tumour Biol 2014;35(7):6567-79. google scholar
- Zhang Y, He J, Deng Y, Zhang J, Li X, Xiang Z, et al. The insertion/ deletion (I/D) polymorphism in the Angiotensin-converting enzyme gene and cancer risk: a meta-analysis. BMC Med Genet 2011;12(1):1-10. google scholar
- Raba G, Zawlik I, Braun M, Paszek S, Potocka N, Skrzypa M, et al. Evaluation of the association between angiotensin converting enzyme insertion/deletion polymorphism and the risk of endometrial cancer in and characteristics of Polish women. Adv Clin Exp Med 2020;29(5):581-5. google scholar
- Chen J, Sun M, Zhou M, Lu R. Associations between I/D polymorphism in the ACE gene and lung cancer: an updated systematic review and a meta-analysis. BMC cancer 2021;21(1):1-9. google scholar
- Elabd NS, Montaser B, Gohar S, Makboul K, Elhamoly M. Association Between the ACE (I/D) Gene Polymorphism and Hepatocellular Carcinoma Risk in Egyptian HCV Patients. Int J Cancer Res 2020;4(3):159-67. google scholar
- Yigit B, Bozkurt N, Narter F, Yilmaz H, Yucebas E, Isbir T. Effects of ACE I/D polymorphism on prostate cancer risk, tumor grade and metastatis. Anticancer Res 2007;27(2):933-6. google scholar
- Chung F, Yang Y, Chen C, Lin C, Shieh T. Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers. Br J Cancer 2005;93(5):602-6. google scholar
- Cejas P, Casado E, Belda-Iniesta C, De Castro J, Espinosa E, Redondo A, et al. Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). Cancer Causes Control 2004;15(7):707-19. google scholar
- Uluocak N, Atılgan D, Parlaktaş BS, Erdemir F, Ateş Ö. A pilot study assessing the association between paraoxonase 1 gene polymorphism and prostate cancer. Turk J Urol 2017;43(3):279. google scholar
- Hashim Z, Zarina S. Assessment of paraoxonase activity and lipid peroxidation levels in diabetic and senile subjects suffering from cataract. Clin Biochem 2007;40(9-10):705-9. google scholar
- Dantoine TF, Debord J, Charmes J-P, Merle L, Marquet P, Lachatre G, et al. Decrease of serum paraoxonase activity in chronic renal failure. J Am Soc Nephrol 1998;9(11):2082-8. google scholar
- Baskol G, Karakucuk S, Oner AO, Baskol M, Kocer D, Mirza E, et al. Serum paraoxonase 1 activity and lipid peroxidation levels in patients with age-related macular degeneration. Ophthalmologica 2006;220(1):12-6. google scholar
- Raiszadeh F, Solati M, Etemadi A, Azizi F. Serum paraoxonase activity before and after treatment of thyrotoxicosis. Clin Endocrinol 2004;60(1):75-80. google scholar
- Malik UU, Siddiqui IA, Hashim Z, Zarina S. Measurement of serum paraoxonase activity and MDA concentrations in patients suffering with oral squamous cell carcinoma. Clin Chim Acta 2014;430:38-42. google scholar
- Metin ZB, Aydin S, Unur M, Cakmakoglu B, Toptas B, Hafiz G, et al. Oral squamous cell carcinoma and serum paraoxonase 1. J Laryngol Otol 2013;127(12):1208-13. google scholar
- Hu P, Ma Y, Zhang L, Ma S. PON1 L55M polymorphism might contribute to the risk of cancer. Panminerva Med 2016;59(1):107-13. google scholar
- Santana ITS, Dos Santos JNA, de Almeida VL, Ferreira WNS, Santos EM, de Almeida Freitas R, et al. Association of PON1, TNF-a and TGF-Ş gene polymorphisms with prognosis in oral and oropharyngeal squamous cell carcinoma. Acta Odontol Scand 2021;79(5):327-34. google scholar