Emine YAĞCI, Hikmet Melike ÖZTÜRK, Tufan ÖGE, Cansu OZBAYER, Hülyam KURT

PTEN gen polimorfizmleri, protein seviyeleri ve endometrium kanseri ilişkisi: Hastane bazlı vaka-kontrol çalışması

PTEN Gen Polimorfizmleri, Protein Seviyeleri Ve Endometrium Kanseri İlişkisi: Hastane Bazlı Vaka Kontrol Çalışması Özet Endometrium kanseri endometrium olarak isimlendirilen rahim iç zarında ortaya çıkan kanser türüdür. Endometrium kanseri Kuzey Amerika ve Avrupa bölgelerde kadınlarda meme, akciğer ve kolon kanserinden sonra 4. sıklıktadır ve kadın genital sisteminde en sık görülen kanserdir. Kromozom 10 (PTEN) üzerinde silinen fosfataz ve Tensin homologu, hem lipit hem de protein fosfataz aktivitelerine sahip olan bir 403-amino asit proteinini kodlayan, kromozom 10q23.31'de bulunan bir tümör baskılayıcı genidir. PTEN genindeki somatik mutasyonlar, insan kanserlerinde bulunan en yaygın genetik değişiklikler arasındadır. PTEN genindeki mutasyonlar PTEN enziminin tümör süpresör fonksiyonunu azaltır veya ortadan kaldırır. Verilen bilgiler eşliğinde Bu çalışmada endometrium kanserinde arttığı bildirilen PTEN ekspresyonunun ve olası azalan PTEN protein ekspresyon seviyesi nedeninin fonksiyonel PTEN polimorfizmleri (IVS4 (rs no: 3830675) ve -9 C/G) olup olmadığını ve endometrium kanseri ile PTEN gen polimorfizmleri arasındaki ilişkinin hastalık patogenezine etkisinin belirlenmesi amaçlanmıştır. 63 endometrium kanser hastası ve 63 kontrol bireye ait DNA’lar PTEN IVS4 (–/+) ve -9 C/G, genine ait 2 genetik varyant için PCR-RFLP yöntemi ile genotiplendirildi. PTEN protein seviyesi serum örneklerinden Eliza yöntemi ile belirlendi. Sonuçlarımız uygun istatistik yöntemler ile değerlendirildi. Çalışmamız sonucunda –9 C/G ve IVS4(–/+) varyantlarına ait genotip frekansları ile endometrium kanseri riski arasında istatistiksel olarak anlamlı fark tespit edilememiştir (p>0.05). PTEN serum seviyeleri kontrole göre endometrium kanserli hastalarda anlamlı oranda düşük olduğu belirlenmiştir (p<0.001). Sonuç olarak araştırmamızda etkinliğini araştırdığımız PTEN genine ait –9 C/G ve IVS4(–/+) varyantların, Türk toplumunda endometrium kanser riski ile ilişkili bulunmadı. Ancak bir tümör süpresör olan PTEN proteinin serum seviyelerinin endometriyum kanserli hastalarda azaldığı belirlendi. Anahtar kelimeler: Endometrium kanseri, PTEN, polimorfizm, IVS4(–/+), -9 C/G.

Anahtar Kelimeler:

Endometrial cancer, PTEN, polymorphism

Association of PTEN Gene Polymorphisms, Protein Levels and Endometrial Cancer: A Hospital-Based Case-Control Study

Association of PTEN Gene Polymorphisms, Protein Levels and Endometrial Cancer: A Hospital-Based Case-Control Study Emine Yagci1, Hikmet Melike Ozturk1, Tufan Oge2, Cansu Ozbayer3, Hulyam Kurt1 0000-0003-2179-1318, 0000-0002-1951-9713,0000-0002-1120-1874, 0000-0003-2433-9925 1Eskisehir Osmangazi University, Faculty of Medicine, Department of Medical Biology, Eskisehir, Turkey. 2 Eskisehir Osmangazi University, Faculty of Medicine, Department of Gynecology, Eskisehir, Turkey. 3 Kutahya Health Sciences University, Medical Faculty, Department of Medical Biology, Kutahya, Turkey. Corresponding Author: Emine Yagci, Telephone: +90 (222) 2392979/4598, e-mail adress: eminetsci@gmail.com Abstract Endometrial cancer is a type of cancer that develops in the inner lining of the uterus, called the endometrium. After breast, lung, and colon cancer, endometrial cancer is the most prevalent malignancy of the female genital system in industrialized nations like North America and Europe. Phosphatase and Tensin homolog (PTEN), deleted on chromosome 10, is a tumor suppressor gene located on chromosome 10q23.31, which encodes a 403 amino acid protein with both lipid and protein phosphatase activities. One of the most common genetic abnormalities identified in human malignancies are somatic mutations in the PTEN gene. The tumor suppressor activity of the PTEN enzyme is reduced or completely lost as a result of PTEN gene mutations. Considering this information, it is thought that PTEN gene polymorphisms may be associated with the pathogenesis of the disease. The purpose of our study is to determine the relationship between functional PTEN polymorphisms IVS4 (–/+) and -9 C/G and endometrial cancer. DNAs belonging to 63 endometrial cancer patients and 63 control individuals were genotyped by PCR-RFLP method for 2 genetic variants of PTEN IVS4 (–/+) and -9 C/G gene. The expression level of PTEN protein was measured by the Elisa method from serum samples. Our results were evaluated with appropriate statistical methods. As a result of our study, no statistically significant difference was found in the risk of endometrial cancer and genotype frequencies of –9 C/G and IVS4 (-/+) variants (p> 0.05). It was detected that the serum level of PTEN lessened significantly in patients with endometrial cancer in comparison to the control (p <0.001). As a consequence, there was no evidence that the PTEN gene variations -9 C/G and IVS4 (-/+), whose efficacy we examined in our investigation, increased the incidence of endometrial cancer in the Turkish population. However, endometrial cancer patients were shown to have lower serum levels of the tumor suppressor protein PTEN. Keywords: Endometrial cancer, PTEN, polymorphism, IVS4 and -9C/G.

Keywords:

Endometrial cancer, PTEN, polymorphism,

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1. Amant, F., Moerm an P, Neven P,[et al.]. Endometrial cancer. Lancet, 2005. 366(9484): p. 491-505.
2. Cibula, D., Onkogynekologie. 2009: Grada Publishing as.
3. Ambros, R.A., et al., Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation. Human pathology, 1995. 26(11): p. 1260-1267.
4. Ortega-Molina, A. and M. Serrano, PTEN in cancer, metabolism, and aging. Trends in Endocrinology & Metabolism, 2013. 24(4): p. 184-189.
5. Gougelet, A., et al., Estrogen receptor α and β subtype expression and transactivation capacity are differentially affected by receptor-, hsp90-and immunophilin-ligands in human breast cancer cells. The Journal of steroid biochemistry and molecular biology, 2005. 94(1-3): p. 71-81.
6. Luongo, F., et al., PTEN tumor-suppressor: the dam of stemness in cancer. Cancers, 2019. 11(8): p. 1076.
7. Álvarez-Garcia, V., et al. Mechanisms of PTEN loss in cancer: It’s all about diversity. in Seminars in Cancer Biology. 2019. Elsevier.
8. Jamaspishvili, T., et al., Clinical implications of PTEN loss in prostate cancer. Nature Reviews Urology, 2018. 15(4): p. 222-234.
9. Hollander, M.C., G.M. Blumenthal, and P.A. Dennis, PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nature Reviews Cancer, 2011. 11(4): p. 289-301.
10. Lupini, L., et al., Molecular biomarkers predicting early development of endometrial carcinoma: A pilot study. European Journal of Cancer Care, 2019. 28(6): p. e13137.
11. Reddy, P., et al., Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science, 2008. 319(5863): p. 611-613.
12. Djordjevic, B., et al., Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing. Modern pathology, 2012. 25(5): p. 699-708.
13. Ozturk, O., et al., HER2 Ile655Val and PTEN IVS4 polymorphisms in patients with breast cancer. Molecular biology reports, 2013. 40(2): p. 1813-1818.
14. Bansal, N., V. Yendluri, and R.M. Wenham, The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer control, 2009. 16(1): p. 8-13.
15. Suzuki, A., et al., High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Current biology, 1998. 8(21): p. 1169-1178.
16. Cristofano, A.D., et al., Pten is essential for embryonic development and tumour suppression. Nature genetics, 1998. 19(4): p. 348-355.
17. Wu, H., V. Goel, and F.G. Haluska, PTEN signaling pathways in melanoma. Oncogene, 2003. 22(20): p. 3113-3122.
18. Sun, L., et al., Association between PTEN Gene IVS4 polymorphism and risk of cancer: a meta-analysis. PloS one, 2014. 9(6): p. e98851.
19. Wang, Y., et al., Impact of PTEN IVS4 polymorphism (rs3830675) on cancer susceptibility: an updated meta-analysis. Cancer Genomics & Proteomics, 2015. 12(5): p. 263-269.
20. Canbay, E., et al., Increased gastric cancer risk with PTEN IVS4 polymorphism in a Turkish population. Genetic testing and molecular biomarkers, 2013. 17(3): p. 249-253.