Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer

EROĞLU, ONUR; ÇİFTCİ, Evrim; Cilingir, Oguz; ARTAN, Sevilhan; DURAK ARAS, Beyhan; NURSAL, Ayşe Feyda; baydemir, canan

doi:10.5505/tjo.2019.2017

Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer

Ayşe Feyda NURSAL, (Hitit Üniversitesi, Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı, Çorum, Türkiye)

Oğuz ÇİLİNGİR, (Eskişehir Osmangazi Üniversitesi, Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı, Eskişehir, Türkiye)

Onur EROĞLU, (Bilecik Şeyh Edebali Üniversitesi, Fen Edebiyat Fakültesi, Moleküler Biyoloji ve Genetik Bölümü, Bilecik, Türkiye)

Beyhan DURAK ARAS, (Eskişehir Osmangazi Üniversitesi, Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı, Eskişehir, Türkiye)

Evrim ÇİFTCİ, (Eskişehir Osmangazi Üniversitesi, Tıp Fakültesi, Moleküler Patoloji Anabilim Dalı, Eskişehir, Türkiye)

Canan BAYDEMİR, (Kocaeli Üniversitesi, Tıp Fakültesi, Biyoistatistik ve Tıp Bilişimi Anabilim Dalı, Kocaeli, Türkiye)

Sevilhan ARTAN (Eskişehir Osmangazi Üniversitesi, Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı, Eskişehir, Türkiye)

Türk Onkoloji Dergisi

7 0

Yıl: 2020 Cilt: 35 Sayı: 1 Sayfa Aralığı: 8 - 14 Metin Dili: İngilizce DOI: 10.5505/tjo.2019.2017 İndeks Tarihi: 04-12-2020

Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer

Öz:

OBJECTIVEBreast cancer (BC) is a heterogeneous malignancy and differs widely among different patients. The aimof this study was to investigate the relationship between the HER2/TOP2A gene aberrations and promoter methylation in RASSF1A/APC genes in patients with high-risk BC.METHODSFormalin-fixed paraffin embedded (FFPE) tissue samples from primary breast tumors (n=60) were assessed. HER2/TOP2A aberrations was evaluated using FISH method. DNA was extracted from FFPEtumor tissues, and Methylation-sensitive high resolution melting (MS-HRM) analysis were performedfor RASSF1A/APC genes methylation status.RESULTSHER2 amplification and TOP2A aberration were observed in 15/60 (25%) and 18/60 (30%) cases, respectively. According to the statistical analysis, HER2 amplification was associated with higher tumorgrade (p=0.001), PR status (p=0.025), and TOP2A aberrations (p=0.004). RASSF1A and APC methylation were 58/60 (96.6%) and 26/60 (43.3%), respectively. There was a significant correlation betweenAPC methylation and TOP2A aberration. APC gene methylation was significantly more frequent intumors with TOP2A aberration (p=0.026).CONCLUSIONOur results suggested that APC gene promoter hypermethylation was associated with TOP2A geneaberrations in patients with high-risk BC. This may be significant for targeted individual therapy. Additionally, it was confirmed that there was significant association of TOP2A gene aberrations with theHER2 gene amplification seen in BC.

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1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359−86.
2. Canda T, Yavuz E, Ozdemir N, Ilvan S, Dizbay SS, Durak MG, et al. Immunohistochemical HER2 Status Evaluation in Breast Cancer Pathology Samples: A Multicenter, Parallel-Design Concordance Study. Eur J Breast Health 2018;14(3):160−5.
3. Di Cosimo S, Triulzi T, Pizzamiglio S, De Cecco L, de Azambuja E, Fumagalli D, et al. The 41-gene classifier TRAR predicts response of HER2 positive breast cancer patients in the NeoALTTO study. Eur J Cancer 2019;118:1−9.
4. Fountzilas G, Valavanis C, Kotoula V, Eleftheraki AG, Kalogeras KT, Tzaida O, et al.HER2 and TOP2A in highrisk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy. J Transl Med 2012;10:10.
5. Eltohamy MI, Badawy OM, El kinaai N, Loay I, Nassar HR, Allam RM, et al. Topoisomerase II α Gene alteration in Triple Negative Breast Cancer and Its Predictive Role for Anthracycline-Based Chemotherapy (Egyptian NCI Patients).Asian Pac J Cancer Prev 2018;19(12):3581−9.
6. Akar RO, Selvi S, Ulukaya E, Aztopal N. Key actors in cancer therapy: epigenetic modifiers. Turk J Biol 2019;43(3):155−70.
7. Vu TL, Nguyen TT, Doan VTH, Vo LTT. Methylation Profiles of BRCA1, RASSF1A and GSTP1 in Vietnamese Women with Breast Cancer Asian Pac J Cancer Prev 2018;19:1887−93.
8. Feng W, Orlandi R, Zhao N, Carcangiu ML, Tagliabue E, Xu J,et al. Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers. BMC Cancer 2010;10:378.
9. Wang B, Song H, Jiang H, Fu Y, Ding X, Zhou C. Early diagnostic potential of APC hypermethylation in esophageal cancer. Cancer Manag Res 2018;10:181−98.
10. Jönsson M, Borg A, Nilbert M, Andersson T. Involvement of adenomatous polyposis coli (APC)/betacatenin signalling in human breast cancer. Eur J Cancer 2000;36(2):242−8.
11. Beser AR, Tuzlali S, Guzey D, Dolek Guler S, Hacihanefioglu S, et al. HER-2, TOP2A and Chromosome 17 Alterations in Breast Cancer. Pathol Oncol Res 2007;13(3):180−5.
12. Sunami E, Shinozaki M, Sim MS, Nguyen SL, Vu AT, Giuliano AE, et al. Estrogen receptor and Her2/neu status effect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res 2008;10(3):R46.
13. Nami B, Maadi H, Wang Z. The Effects of Pertuzumab and Its Combination with Trastuzumab on HER2 Homodimerization and Phosphorylation. Cancers (Basel) 2019;11(3): pii: E375.
14. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al; American Society of Clinical Oncology; College of American Pathologists.Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31(31):3997−13.
15. Chen JR, Chien HP, Chen KS, Hwang CC, Chen HY, Yeh KY, et al. Amplification of HER2 and TOP2A and deletion of TOP2A genes in a series of Taiwanese breast cancer. Medicine (Baltimore) 2017;96(2):e5582.
16. Nielsen KV, Müller S, Møller S, Schønau A, Balslev E, Knoop AS, et al. Aberrations of ERBB2 and TOP2A genes in breast cancer. Mol Oncol 2010;4(2):161−8.
17. Slamon DJ, Press MF. Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers. J Natl Cancer Inst 2009;101(9):615−8.
18. Tsiambas E, Fotiades PP, Sioka C, Ragos V. HER2/Topoisomerase IIa co-amplified breast adenocarcinoma “mirror” cases with different Topoisomerase IIa expression patterns. J BUON 2017;22(2):555−6.
19. Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 2011;29(7):859−67.
20. Bhargava R, Lal P, Chen B. HER-2/neu and topoisomerase IIa gene amplification and protein expression in invasive breast carcinomas: chromogenic in situ hybridization and immunohistochemical analyses. Am J Clin Pathol 2005;123(6):889−95.
21. Beltrán-García J, Osca-Verdegal R, Mena-Mollá S, García-Giménez JL.Epigenetic IVD Tests for Personalized Precision Medicine in Cancer. Front Genet 2019;10:621.
22. Yadav P, Masroor M, Nandi K, Kaza RCM, Jain SK, Khurana N, et al. Promoter Methylation of BRCA1, DAPK1 and RASSF1A is Associated with Increased Mortality among Indian Women with Breast Cancer. Asian Pac J Cancer Prev 2018;19(2):443−8.
23. Spitzwieser M, Holzweber E, Pfeiler G, Hacker S, Cichna-Markl M. Applicability of HIN-1, MGMT and RASSF1A promoter methylation as biomarkers for detecting field cancerization in breast cancer. Breast Cancer Res 2015;17:125.
24. Jezkova E, Zubor P, Kajo K, Grendar M, Dokus K, Adamkov M, et al. Impact of RASSF1A gene methylation on the metastatic axillary nodal status in breast cancer patients. Oncol Lett 2017;14(1):758−66.
25. Liang TJ, Wang HX, Zheng YY, Cao YQ, Wu X, Zhou X, et al. APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review. Oncotarget 2017; 8(28):46468−79.
26. Li BQ, Liu PP, Zhang CH. Correlation between the methylation of APC gene promoter and colon cancer. Oncol Lett 2017;14(2):2315−9.
27. He K, Zhang L, Long X. Quantitative assessment of the association between APC promoter methylation and breast cancer. Oncotarget 2016;7(25):37920−30.
28. Jin Z, Tamura G, Tsuchiya T, Sakata K, Kashiwaba M, Osakabe M, et al. Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers. Br J Cancer 2001;85(1):69−73.
29. Shinozaki M, Hoon DS, Giuliano AE, Hansen NM, Wang HJ, Turner R, et al. Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis. Clin Cancer Res 2005;11(6):2156−62.
30. Park SY, Kwon HJ, Lee HE, Ryu HS, Kim SW, Kim JH, et al. Promoter CpG island hypermethylation during breast cancer progression. Virchows Arch 2011;458(1):73−84.
31. Sturgeon SR, Balasubramanian R, Schairer C, Muss HB, Ziegler RG, Arcaro KF. Detection of promoter methylation of tumor suppressor genes in serum DNA of breast cancer cases and benign breast disease controls. Epigenetics 2012;7(11):1258−67.
32. Zhou D, Tang W,Wang W, Pan X, An HX, Zhang Y. Association between aberrant APC promoter methylation and breast cancer pathogenesis: a meta-analysis of 35 observational studies. PeerJ 2016;4:e2203.
33. Debouki-Joudi S, Trifa F, Khabir A, Sellami-Boudawara T, Frikha M, Daoud J, et al. CpG methylation of APC promotoer 1A in sporadic and familial breast cancer patients. Cancer Biomark 2017;18(2):133−41.

APA	NURSAL A, Cilingir O, EROĞLU O, DURAK ARAS B, ÇİFTCİ E, baydemir c, ARTAN S (2020). Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. , 8 - 14. 10.5505/tjo.2019.2017
Chicago	NURSAL Ayşe Feyda,Cilingir Oguz,EROĞLU ONUR,DURAK ARAS Beyhan,ÇİFTCİ Evrim,baydemir canan,ARTAN Sevilhan Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. (2020): 8 - 14. 10.5505/tjo.2019.2017
MLA	NURSAL Ayşe Feyda,Cilingir Oguz,EROĞLU ONUR,DURAK ARAS Beyhan,ÇİFTCİ Evrim,baydemir canan,ARTAN Sevilhan Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. , 2020, ss.8 - 14. 10.5505/tjo.2019.2017
AMA	NURSAL A,Cilingir O,EROĞLU O,DURAK ARAS B,ÇİFTCİ E,baydemir c,ARTAN S Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. . 2020; 8 - 14. 10.5505/tjo.2019.2017
Vancouver	NURSAL A,Cilingir O,EROĞLU O,DURAK ARAS B,ÇİFTCİ E,baydemir c,ARTAN S Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. . 2020; 8 - 14. 10.5505/tjo.2019.2017
IEEE	NURSAL A,Cilingir O,EROĞLU O,DURAK ARAS B,ÇİFTCİ E,baydemir c,ARTAN S "Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer." , ss.8 - 14, 2020. 10.5505/tjo.2019.2017
ISNAD	NURSAL, Ayşe Feyda vd. "Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer". (2020), 8-14. https://doi.org/10.5505/tjo.2019.2017

APA	NURSAL A, Cilingir O, EROĞLU O, DURAK ARAS B, ÇİFTCİ E, baydemir c, ARTAN S (2020). Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. Türk Onkoloji Dergisi, 35(1), 8 - 14. 10.5505/tjo.2019.2017
Chicago	NURSAL Ayşe Feyda,Cilingir Oguz,EROĞLU ONUR,DURAK ARAS Beyhan,ÇİFTCİ Evrim,baydemir canan,ARTAN Sevilhan Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. Türk Onkoloji Dergisi 35, no.1 (2020): 8 - 14. 10.5505/tjo.2019.2017
MLA	NURSAL Ayşe Feyda,Cilingir Oguz,EROĞLU ONUR,DURAK ARAS Beyhan,ÇİFTCİ Evrim,baydemir canan,ARTAN Sevilhan Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. Türk Onkoloji Dergisi, vol.35, no.1, 2020, ss.8 - 14. 10.5505/tjo.2019.2017
AMA	NURSAL A,Cilingir O,EROĞLU O,DURAK ARAS B,ÇİFTCİ E,baydemir c,ARTAN S Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. Türk Onkoloji Dergisi. 2020; 35(1): 8 - 14. 10.5505/tjo.2019.2017
Vancouver	NURSAL A,Cilingir O,EROĞLU O,DURAK ARAS B,ÇİFTCİ E,baydemir c,ARTAN S Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer. Türk Onkoloji Dergisi. 2020; 35(1): 8 - 14. 10.5505/tjo.2019.2017
IEEE	NURSAL A,Cilingir O,EROĞLU O,DURAK ARAS B,ÇİFTCİ E,baydemir c,ARTAN S "Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer." Türk Onkoloji Dergisi, 35, ss.8 - 14, 2020. 10.5505/tjo.2019.2017
ISNAD	NURSAL, Ayşe Feyda vd. "Correlation of HER2/TOP2A Gene Aberrations with RASSF1A/APC Gene Methylation Status in High-Risk Breast Cancer". Türk Onkoloji Dergisi 35/1 (2020), 8-14. https://doi.org/10.5505/tjo.2019.2017