B7-H4 Gene Variations in Postmenopausal Estrogen Receptor Positive Breast Cancer

Öz

Objective: B7-H4 gene, which has an immunosuppressive effect on T cell immunity by inhibiting T cell function, has been shown to be effective in tumor progression and poor prognosis in many types of human tumors, Increasing B7-H4 gene expression in various types of cancer, including renal cell carcinoma, ovarian cancer, gastric cancer and breast cancer, recently has led to the consideration of B7-H4 targeting in cancer treatment. Polymorphism studies of B7-H4 that may affect its expression control are very limited. Considering that polymorphisms show differences at the population level, the study of rs10754339, rs10801935 and rs3738414, which are likely to have an effect on the expression of the B7-H4 gene in different populations, may provide valuable information, especially in cancer types in which it shows high expression. For this purpose, we repeated the research, we conducted for the first time in Turkish breast cancer patients previously, in order to more clearly reveal the pathogenesis of B7-H4 gene in breast cancer. Material-Method: In our study, following DNA isolation of 201 cases, SNP analysis based on multiplex PCR and MALDI-TOF was performed.Results: Despite the increasing number of cases, as in our previous study, B7-H4 gene polymorphisms did not show statistically significant association with breast cancer. In addition, the related polymorphisms did not show a statistically significant relationship with the clinopathological data. Conclusion: Our study results have made us think that B7-H4 gene 10754339, rs10801935 and rs3738414 SNPs will not be effective in evaluating breast cancer susceptibility in the Turkish population.

Postmenopozal Östrojen Reseptör Pozitif Meme Kanserinde B7-H4 Geni Varyasyonları

Öz

Amaç: T hücre fonksiyonunu inhibe etmek suretiyle, T hücre immünitesinde immünsupresif etki gösteren B7-H4 geninin, pek çok insan tümörü çeşidinde, tümör progresyonu ve zayıf prognozda etkili olduğu yapılan çalışmalarda gösterilmiştir. Renal hücre karsinomu, over kanseri, gastrik kanser ve meme kanseri de dahil olmak üzere, çeşitli kanser türlerinde B7-H4 geni ekpresyonunun artması ve bu durumun karsinojenik etkiye sebep olması, son zamanlarda kanser tedavisinde B7-H4’ün hedef alınmasını düşündürmüştür. B7-H4’ün ekspresyon kontrolüne etki edebilecek polimorfizm çalışmaları oldukça sınırlıdır. Polimorfizmlerin popülasyon düzeyinde farklılıklar gösterdiği de göz önüne alındığında, B7-H4 geninin ekspresyonu üzerinde etkili olabileceği muhtemel olan rs10754339, rs10801935 ve rs3738414 SNP’lerinin, farklı popülasyonlarda, özellikle yüksek ekspresyon gösterdiği kanser türlerinde çalışılması değerli bilgiler sağlayabilecektir. Biz de bu amaçla, daha önce Türk popülasyonunda meme kanserinde ilk defa yaptığımız araştırmayı, meme kanserinde B7-H4 geninin patogenezini daha net ortaya koymak amacıyla daha fazla olgu grubunda gerçekleştirdik. Materyal-Metot: Çalışmamızda toplam 201 olgunun DNA izolasyonunu takiben, multipleks PCR ve MALDI-TOF temeline dayanan SNP analizi yapıldı. Bulgular: Artan olgu sayımıza rağmen bir önceki çalışmamızda olduğu gibi B7-H4 geni 10754339, rs10801935 ve rs3738414 polimorfizmleri meme kanseriyle istatistiki olarak anlamlı bir birliktelik göstermedi. Ayrıca ilgili polimorfizmler, klinopatolojik verilerle de istatistiki olarak anlamlı bir ilişki göstermedi. Sonuç: Çalışma sonuçlarımız bize, Türk popülasyonunda meme kanseri yatkınlığını değerlendirmede B7-H4 geni 10754339, rs10801935 ve rs3738414 polimorfizmlerinin etkili olmayacağını düşündürmüştür.

Anahtar Kelimeler

• Meme Kanseri
• B7-H4 Geni
• Polimorfizm

Kaynakça

1. 1. Khazaei Z, Mosavi Jarrahi A, Momenabadi V, Ghorat F, Adineh HA, Sohrabivafa M, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide stomach cancers and their relationship with the human developmentindex (HDI). World Cancer Res J. 2019;6:e1257.
2. 2. Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res. 2017;50(1):33.
3. 3. Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity. 2003;18(6):849-61.
4. 4. Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, et al. Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol. 2003;171(9):4650-4.
5. 5. Smith JB, Stashwick C, Powell DJ. B7-H4 as a potential target for immunotherapy for gynecologic cancers: a closer look. Gynecol Oncol. 2014;134(1):181-189.
6. 6. Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol. 2003;4(7):670-9.
7. 7. Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, et al. The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. Exp Cell Res. 2005;306(1):128-41.
8. 8. Podojil JR, Miller SD. Potential targeting of B7-H4 for the treatment of cancer. Immunol Rev. 2017;276(1):40-51.

9. 9. 2018-Chen X, Tao L, Yuan C, Xiu D. The prognostic value of B7-H4 in pancreatic cancer: Systematic review and meta-analysis. Medicine (Baltimore). 2018;97(12):e0088.
10. 10. MacGregor HL, Ohashi PS. Molecular pathways: evaluating the potential for B7-H4 as an immunoregulatory target. Clin Cancer Res. 2017;23:2934-41.
11. 11. Zhang X, Cai L, Zhang G, Shen Y, Huang J. B7-H4 promotes tumor growth and metastatic progression in lung cancer by impacting cell proliferation and survival. Oncotarget. 2017;8(12):18861-18871.
12. 12. Zhou L, Ruan M, Liu Y, Zhu Y, Fu D, Wu K, et al. B7H4 expression in tumor cells impairs CD8 T cell responses and tumor immunity. Cancer Immunol Immunother. 2020;69(2):163-174.
13. 13. Kim NI, Park MH, Kweon SS, Lee JS. B7-H3 and B7-H4 Expression in Breast Cancer and Their Association with Clinicopathological Variables and T Cell Infiltration. Pathobiology. 2020;87(3):179-192.
14. 14. Wang L, Heng X, Lu Y, Cai Z, Yi Q, Che F. Could B7-H4 serve as a target to activate anti-cancer immunity? Int Immunopharmacol. 2016;38:97-103.
15. 15. Zhang J, Zhang M, Jiang W, Wang L, Fu Z, Li D, et al. B7-H4 gene polymorphisms are associated with sporadic breast cancer in a Chinese Han population. BMC Cancer. 2009;9:394.
16. 16. Özgöz A, Şamlı H, Öztürk KH, Orhan B, Icduygu FM, Aktepe F, et al. An investigation of the effects of FGFR2 and B7-H4 polymorphisms in breast cancer. J Cancer Res Ther. 2013;9(3):370-5.
17. 17. Wu D, Tang R, Qi Q, Zhou X, Zhou H, Mao Y, et al. Five functional polymorphisms of B7/CD28 co-signaling molecules alter susceptibility to colorectal cancer. Cell Immunol. 2015;293(1):41-8.
18. 18. Tsai SM, Wu SH, Hou MF, Yang HH, Tsai LY. The Immune Regulator VTCN1 Gene Polymorphisms and Its Impact on Susceptibility to Breast Cancer. J Clin Lab Anal. 2015;29(5):412-8.
19. 19. Özgöz A, Şamli M, Dinçel D, Şahin A, Ince Ü, Sağlican Y, et al. Association of B7-H4 gene polymorphisms in urothelial bladder cancer. Turk J Med Sci. 2017;47(2):443-446.
20. 20. Özgöz A, İçduygu FM, Yükseltürk A, Şamlı H, Öztürk KH, Başkan Z. Low-penetrance susceptibility variants and postmenopausal oestrogen receptor positive breast cancer. J Genet. 2020;99:15.
21. 21. Türkyılmaz M, Hacıkamiloğlu E, Baran Deniz E, Boztaş G, Dündar S, Kavak Ergün A, ve ark. Türkiye kanser istatistikleri 2015, Türkiye Cumhuriyeti Sağlık Bakanlığı, Halk Sağlığı Genel Müdürlüğü, Ankara, 2018.
22. 22. Özmen V. Breast Cancer in Turkey: Clinical and Histopathological Characteristics (Analysis of 13.240 Patients). J Breast Health. 2014;10(2):98-105.
23. 23. Saad El Din G, Youness RA, Assal RA, Gad MZ. rs10754339 (A/G) in 3’UTR of B7-H4 regulated by miR-506-3p prevents breast cancer progression. 11th European Breast Cancer Conference; 21-23. March 2018; Barcelona, Spain. European Journal of Cancer 2018;92,Suppl.3:S136.