ABERRANT METHYLATION OF CANCER-RELATED GENES IN VIETNAMESE BREAST CANCER PATIENTS: ASSOCIATIONS WITH CLINICOPATHOLOGICAL FEATURES
DOI:
https://doi.org/10.15407/exp-oncology.2023.02.195Keywords:
DNA methylation, breast cancer, clinicopathological features, panel, sensitivity/specificityAbstract
Background. Epigenetic alteration is one of the most common molecular changes identified in the progression of breast cancer (BC). Aim. To study the frequency and relation between methylation of BRCA1, MLH1, MGMT, GSTP1, APC, RASSF1A, p16, WIF, and EGFR and the clinicopathological features in Vietnamese BC patients. Materials and Methods. Methylation-specific polymerase chain reaction (MS-PCR) and SPSS 20.0 software were utilized in order to identify methylated frequency as well as evaluate its relationship with the patient’s clinical features. Results. In 162 BC cases, the methylation rates of the selected genes were 53.7%, 22.8%, 38.9%, 34.6%, 29.0%, 46.3%, 20.4%, 18.5%, and 28.4% respectively. In 32 cases of benign breast diseases (BBD) – 12.5%, 15.6%, 6.3%, 3.1%, 12.5%, 21.9%, 3.1%, 15.6% and 3.1%. BC samples displayed higher BRCA1, MGMT, GSTP1, APC, RASSF1A, WIF1, and p16 methylation levels than BBD samples (p < 0.001). Hypermethylation of BRCA1, GSTP1, and RASSF1A was predominant in the invasive ductal carcinoma, while hypermethylation of BRCA1, GSTP1, RASSF1A, WIF-1, and p16 was found to significantly correlate with lymph node metastasis (p < 0.05). Hypermethylation of BRCA1, MGMT, and GSTP1 was more common in stage III (p < 0.05) than in stages I/II, whereas MLH1 methylation was predominant in stage I and APC methylation was less common in stage III (p = 0.03). In addition, methylation of RASSF1A and EGFR was more frequent in younger patients (p < 0.01) than in elder patients. Conclusion. These data suggest that a gene panel (BRCA1/MGMT/GSTP1) can be used to support the diagnosis and screening of Vietnamese patients’ BC with a sensitivity of 70%, and a specificity of 85%.
References
Francies FZ, Hull R, Khanyile R, et al. Breast cancer in low-middle income countries: Abnormality in splicing and lack of targeted treatment options. Am J Cancer Res. 2020;10(5):1568-1591.
Dworkin AM, Huang TH-M, Toland AE. Epigenetic alterations in the breast: Implications for breast cancer detection, prognosis and treatment. Semin Cancer Biol. 2009;19(3):165-171. doi: 10.1016/j.semcancer.2009.02.007
Saxena A, Dhillon VS, Shahid M, et al. GSTP1 methylation and polymorphism increase the risk of breast cancer and the effects of diet and lifestyle in breast cancer patients. Exp Therap Med. 2012;4(6):1097-1103. doi: 10.3892/ etm.2012.710
Sunami E, Shinozaki M, Sim MS, et al. Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res. 2008;10(3):R46. doi: 10.1186/bcr2098
Radpour R, Barekati Z, Kohler C, et al. Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a blood-based test in breast cancer. PloS One. 2011;6(1):e16080. doi: 10.1371/ journal.pone.0016080
Baylin SB, Belinsky SA, Herman JG. Aberrant methylation of gene promoters in cancer—Concepts, misconcepts, and promise. J Natl Cancer Inst. 2000;92(18):1460-1461. doi: 10.1093/jnci/92.18.1460
Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Gen. 1999;21(2):163-167. doi: 10.1038/5947
Toh Y, Egashira A, Yamamoto M. Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma. Gen Thorac Cardiovasc Surg. 2013;61(5):262-269. doi: 10.1007/s11748-013-0235-3
Kagohara LT, Stein-O’Brien GL, Kelley D, et al. Epigenetic regulation of gene expression in cancer: Techniques, resources and analysis. Brief Funct Genom. 2018;17(1):49-63. doi: 10.1093/bfgp/elx018
Jovanovic J, Rønneberg JA, Tost J, et al. The epigenetics of breast cancer. Mol Oncol. 2010;4(3):242-254. doi: 10.1016/j.molonc.2010.04.002
Chen KM, Stephen JK, Raju U, et al. Delineating an epigenetic continuum for initiation, transformation and progression to breast cancer. Cancers. 2011;3(2):1580-1592. doi: 10.3390/cancers3021580
Lodygin D, Hermeking H. The role of epigenetic inactivation of 14-3-3sigma in human cancer. Cell Res. 2005;15(4):237-246. doi: 10.1038/sj.cr.7290292
Michael TM, Brandes JC, Vertino PM. Cancer DNA methylation: Molecular mechanisms and clinical implica- tions. Clin Cancer Res, 2009;15(12):3927–3937. doi: 10.1158/1078-0432.CCR-08-2784
Teschendorff AE, Gao Y, Jones A, et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat Commun. 2016;7:10478. doi: 10.1038/ncomms10478
Johnson KC, Koestler DC, Fleischer T, et al. DNA methylation in ductal carcinoma in situ related with future development of invasive breast cancer. Clin Epigenetics. 2015;7:75. doi: 10.1186/s13148-015-0094-0
Zhu W, Qin W, Hewett JE, et al. Quantitative evaluation of DNA hypermethylation in malignant and benign breast tissue and fluids. Int J Cancer. 2010;126(2):474-482. doi: 10.1002/ijc.24728
Cheuk IWY, Shin VY, Kwong A. Detection of methylated circulating DNA as noninvasive biomarkers for breast cancer diagnosis. J Breast Cancer. 2017;20(1):12. doi: 10.4048/jbc.2017.20.1.12
Jiang Y, Cui L, Chen W, et al. The prognostic role of RASSF1A promoter methylation in breast cancer: A metaanalysis of published data. PloS One. 2012;7(5):e36780. doi: 10.1371/journal.pone.0036780
Zhang L, Long X. Association of BRCA1 promoter methylation with sporadic breast cancers: Evidence from 40 studies. Sci Rep. 2015;5:17869. doi: 10.1038/srep17869
Bhat A, Masood A, Wani KA, et al. Promotermethylation and gene polymorphism are two independent events in regulation of GSTP1 gene expression. Tumour Biol. 2017;39(4):1010428317697563. doi: 10.1177/1010428317697563
Cho YH, Yazici H, Wu HC, et al. Aberrant promoter hypermethylation and genomic hypomethylation in tumor, adjacent normal tissues and blood from breast cancer patients. Anticancer Res. 2010;30(7):2489-2496.
Zhou Y, Li Z, Ding Y, et al. Promoter methylation of WNT inhibitory factor-1 may be associated with the patho- genesis of multiple human tumors. J Cancer Res Ther. 2018;14:S381-S387. doi: 10.4103/0973-1482.235357
Callahan CL, Wang Y, Marian C, et al. DNAmethylation andbreasttumor clinicopathological features: The Western New York Exposures and Breast Cancer (WEB) study. Epigenetics. 2016;11(9):643-652. doi: 10.1080/15592294.2016.1192735
Ben GR, Hachana M, Ziadi S, et al. Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients. Cancer Epidem. 2012;36(2):190-197. doi: 10.1016/j.canep.2011.09.001
Birgisdottir V, Stefansson OA, Bodvarsdottir SK, et al. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res. 2006;8(4):R38. doi: 10.1186/bcr1522
Fang C, Wei XM, Zeng XT, et al. Aberrant GSTP1 promoter methylation is associated with increased risk and ad- vanced stage of breast cancer: A meta-analysis of 19 case-control studies. BMC Cancer. 2015;15:920. doi: 10.1186/ s12885-015-1926-1
Euhus DM, Bu D, Milchgrub S, et al. DNA methylation in benign breast epithelium in relation to age and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1051-1059. doi: 10.1158/1055-9965.EPI-07-2582
Van der Auwera I, Bovie C, Svensson C, et al. Quantitative methylation profiling in tumor and matched morphologically normal tissues from breast cancer patients. BMC Cancer. 2010;10(1):97. doi: 10.1186/1471-2407-10-97
Dulaimi E, Hillinck J, Ibanez de Caceres I, et al. Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res. 2004;10:6189-6193. doi: 10.1158/1078-0432.CCR-04-0597
Submitted: November 15, 2022
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