Document Type : Original Article(s)

Authors

1 Dental Research Centre, Oral Pathology Department, Dental Faculty, Hamadan University of Medical Sciences, Hamadan, Iran

2 Lecturer at Griffith University, Gold Coast, Australia

3 Pathology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Background: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and has a poor prognosis. The breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes are the key tumor suppressor genes responding in the cases of DNA damage. They repair double-strand DNA breaks to maintain gene stability. Mutations in BRCA1 and BRCA2 lead to genetic instability and develop different cancers, mainly familial breast and ovarian cancers. This study aimed to investigate the expression profiles of BRCA1 and BRCA2 genes in OSCC through the use of immunohistochemistry (IHC) technique.
Method: In this retrospective study, a total of 60 samples (20 samples of each grade) were collected from the archive of pathology department of Taleghani educational hospital, Tehran, Iran, from 2000-2017. IHC staining was performed for all tissue samples.
Results: BRCA1 immunoreactivity was positive in the cytoplasm and nuclear of 56 and 24 samples, respectively. None of the cancer cells showed nuclear BRCA2 expression; however, BRCA2 cytoplasmic staining existed in 17 cases. Chi-square test showed statistically significant differences between BRCA1 staining (P=0.001) and histological grade, and between BRCA2 expression (P=0.001) and histological grade in the research groups. Conclusion: Altered subcellular localization of BRCA1/2 and immunostaining of the cancer cells at the invasive front may indicate the critical role of BRCA1/2 in the development of OSCC. Early detection of BRCA mutation carriers by IHC has a significant impact on successful treatment.

Keywords

How to cite this article:

Irani S, Rafizadeh M. BRCA1/2 expression patterns in different grades of oral squamous cell carcinoma. Middle East J Cancer. 2020;11(4):390-8. doi: 10.30476/mejc.2020.81282.0.

1.         Irani S, Dehghan A. The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma. J Int Soc Prev Community Dent. 2018;8(2):110-117. doi: 10.4103/jispcd.JISPCD_408_17.
2.         Irani S. Pre-Cancerous Lesions in the Oral and Maxillofacial Region: A Literature Review with Special Focus on Etiopathogenesis. Iran J Pathol. 2016;11(4):303-22.
3.         Ram H, Sarkar J, Kumar H, Konwar R, Bhatt ML, Mohammad S. Oral cancer: risk factors and molecular pathogenesis. J Maxillofac Oral Surg. 2011;10(2):132-7. doi: 10.1007/s12663-011-0195-z.
4.         Irani S, Bidari-Zerehpoush F. BRCA1/2 Mutations in Salivary Pleomorphic Adenoma and Carcinoma-ex-Pleomorphic Adenoma.J Int Soc Prev Community Dent. 2017;7(Suppl 3):S155-s62. doi: 10.4103/jispcd.JISPCD_184_17.
5.         Kitami K, Kitami M, Kaku M, Wang B, Komatsu Y. BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development. PLoS Genet. 2018;14(5):e1007340. doi: 10.1371/journal.pgen.1007340.
6.         Lesnock JL, Darcy KM, Tian C, Deloia JA, Thrall MM, Zahn C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-7. doi: 10.1038/bjc.2013.70.
7.         Gumaste PV, Penn LA, Cymerman RM, Kirchhoff T, Polsky D, McLellan B. Skin cancer risk in BRCA1/2 mutation carriers. Br J Dermatol. 2015;172(6):1498-506. doi: 10.1111/bjd.13626.
8.         Chen CC, Feng W, Lim PX, Kass EM, Jasin M. Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer. Annu Rev Cancer Biol. 2018;2:313-36. doi: 10.1146/annurev-cancerbio-030617-050502.
9.         Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013;31(14):1748-57. doi: 10.1200/JCO.2012.43.1882.
10.       Cavanagh H, Rogers KM. The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. Hered Cancer Clin Pract. 2015;13(1):16. doi: 10.1186/s13053-015-0038-x.
11.       Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran. 2016;30:369.
12.       Al-Dhaheri W, Hassouna I, Karam SM. Genetic polymorphisms and protein expression of P53 and BRCA1 in preneoplastic and neoplastic rat mammary glands. Oncol Rep. 2018;39(5):2193-200. doi: 10.3892/or.2018.6284.
13.       Vora HH, Shah NG, Patel DD, Trivedi TI, Choksi TJ. BRCA1 expression in leukoplakia and carcinoma of the tongue. J Surg Oncol. 2003;83(4):232-40. doi: 10.1002/jso.10213.
14.       Loi M, Desideri I, Olmetto E, Francolini G, Greto D, Bonomo P, et al. BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management. Breast J. 2018. doi: 10.1111/tbj.13100.
15.       Hedau S, Batra M, Singh UR, Bharti AC, Ray A, Das BC. Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer. J Cancer Res Ther. 2015;11(1):158-63. doi: 10.4103/0973-1482.140985.
16.       Zhang Q, Zhang Q, Cong H, Zhang X. The ectopic expression of BRCA1 is associated with genesis, progression, and prognosis of breast cancer in young patients. Diagn Pathol. 2012;7:181. doi: 10.1186/1746-1596-7-181.
17.       Tsibulak I, Wieser V, Degasper C, Shivalingaiah G, Wenzel S, Sprung S, et al. BRCA1 and BRCA2 mRNA-expression prove to be of clinical impact in ovarian cancer. Br J Cancer. 2018;119(6):683-92. doi: 10.1038/s41416-018-0217-4.
18.       Sopik V, Phelan C, Cybulski C, Narod SA. BRCA1 and BRCA2 mutations and the risk for colorectal cancer. Clin Genet. 2015;87(5):411-8. doi: 10.1111/cge.12497.
19.       Kim KM, Moon YJ, Park SH, Park HJ, Wang SI, Park HS, et al. Individual and Combined Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predict Shorter Survival of Soft Tissue Sarcoma Patients. PLoS One. 2016;11(9):e0163193. doi: 10.1371/journal.pone.0163193.
20.       Wang GH, Zhao CM, Huang Y, Wang W, Zhang S, Wang X. BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers. Hum Pathol. 2018;71:135-44. doi: 10.1016/j.humpath.2017.10.032.
21.       Wang T, Wentz SC, Ausborn NL, Washington MK, Merchant N, Zhao Z, et al. Pattern of breast cancer susceptibility gene 1 expression is a potential prognostic biomarker in resectable pancreatic ductal adenocarcinoma. Pancreas. 2013;42(6):977-82. doi: 10.1097/MPA.0b013e318287885c.
22.       Bai F, Chan HL, Scott A, Smith MD, Fan C, Herschkowitz JI, et al. BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development. Cancer Res. 2014;74(21):6161-72. doi: 10.1158/0008-5472.CAN-14-1119.
23.       Godet I, Gilkes DM. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther. 2017;4(1). doi: 10.15761/ICST.1000228.
24.       Sharma M KM, Manjari M, Madan M, Singh T, Garg T. Immunohistochemical Characteristics of Breast Cancer Patients with the Comparative Study of BRCA1, ER, PR, BCL2, P53 and Ki-67 Immunohistochemical Markers: A Population Based Study. Ann Pathol Lab Med. 2016;3(6 (Suppl)). 10.21276/APALM.
25.       Peng L, Xu T, Long T, Zuo H. Association Between BRCA Status and P53 Status in Breast Cancer: A Meta-Analysis. Med Sci Monit. 2016;22:1939-45. doi: 10.12659/msm.896260.
26.       Osin PP, Lakhani SR. The pathology of familial breast cancer: Immunohistochemistry and molecular analysis. Breast Cancer Res. 1999;1(1):36-40. doi: 10.1186/bcr11.
27. Maroof H, Irani S, Ariana A, Vider J, Gopalan V, Lam AK. Interactions of vascular endothelial growth factor and p53 with miR-195 in thyroid carcinoma: possible therapeutic targets in aggressive thyroid cancers. Curr Cancer Drug Targets. 2019;19(7):561-70. doi: 10.2174/1568009618666180628154727.
28.       Li Y, Zhang J. Expression of mutant p53 in oral squamous cell carcinoma is correlated with the effectiveness of intra-arterial chemotherapy. Oncol Lett. 2015;10(5):2883-7. doi: 10.3892/ol.2015.3651.
29.       Sengodan SK, K HS, Nadhan R, Srinivas P. Regulation of epithelial to mesenchymal transition by BRCA1 in breast cancer. Crit Rev Oncol Hematol. 2018;123:74-82. doi: 10.1016/j.critrevonc.2018.01.008.
30.       Singla S, Singla G, Zaheer S, Rawat DS, Mandal AK. Expression of p53, epidermal growth factor receptor, c-erbB2 in oral leukoplakias and oral squamous cell carcinomas. J Cancer Res Ther. 2018;14(2):388-93. doi: 10.4103/0973-1482.191027.
31.       Marcello MA, Morari EC, Cunha LL, De Nadai Silva AC, Carraro DM, Carvalho AL, et al. P53 and expression of immunological markers may identify early stage thyroid tumors. Clin Dev Immunol. 2013;2013:846584. doi: 10.1155/2013/846584.
32.       Ko KP, Kim SJ, Huzarski T, Gronwald J, Lubinski J, Lynch HT, et al. The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers. Int J Cancer. 2018;142(11):2263-72. doi: 10.1002/ijc.31257.
33.      Zaid K1, Azar-Maalouf E, Barakat C, Chantiri M. p53 Overexpression in Oral Mucosa in Relation to Shisha Smoking in Syria and Lebanon. Asian Pac J Cancer Prev. 2018;19(7):1879-1882. doi: 10.22034/APJCP.2018.19.7.1879.
34.       Henneman L, van Miltenburg MH, Michalak EM, Braumuller TM, Jaspers JE, Drenth AP, et al. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc Natl Acad Sci U S A. 2015;112(27):8409-14. doi: 10.1073/pnas.1500223112.
35.       Rodriguez N, Maili L, Chiquet BT, Blanton SH, Hecht JT, Letra A. BRCA1 and BRCA2 gene variants and nonsyndromic cleft lip/palate. Birth Defects Res.2018;110(12):1043-8. doi: 10.1002/bdr2.1346.
36.       Kobayashi GS, Alvizi L, Sunaga DY, Francis-West P, Kuta A, Almada BV, et al. Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate. PloS one. 2013;8(6):e65677. doi: 10.1371/journal.pone.0065677.
37.       Zhu JL, Basso O, Hasle H, Winther JF, Olsen JH, Olsen J. Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark. Br J Cancer.2002;87(5):524-8. DOI: 10.1038/sj.bjc.6600488.
38.       Menezes R, Marazita ML, Goldstein McHenry T, Cooper ME, Bardi K, Brandon C, et al. AXIS inhibition protein 2, orofacial clefts and a family history of cancer. J Am Dent Assoc. 2009;140(1):80-4. doi: 10.14219/jada.archive.2009.0022.
39.       Chang S, Sharan SK. BRCA1 and microRNAs: emerging networks and potential therapeutic targets. Mol Cells. 2012;34(5):425-32. doi: 10.1007/s10059-012-0118-y.
40.       Taioli E, Ragin C, Robertson L, Linkov F, Thurman NE, Vieira AR. Cleft lip and palate in family members of cancer survivors. Cancer Invest. 2010;28(9):958-62. doi: 10.3109/07357907.2010.483510.
41.       Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, et al. Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet. 2006;43(2):138-42. doi: 10.1136/jmg.2005.031385.
42.       Vieira AR, Khaliq S, Lace B. Risk of cancer in relatives of children born with isolated cleft lip and palate. Am J Med Genet A. 2012;158a(6):1503-4. doi: 10.1002/ajmg.a.35359.
43.       Irani S, Dehghan A. Expression of Vascular Endothelial-Cadherin in Mucoepidermoid Carcinoma: Role in Cancer Development. J Int Soc Prev Community Dent. 2017;7(6):301-7. doi: 10.4103/jispcd.JISPCD_323_17.
44.       Irani S, Jafari B. Expression of Vimentin and CD44 in Mucoepidermoid Carcinoma: A Role in Tumor Growth. Indian J Dent Res. 2018; 29(3):333-340. doi: 10.4103/ijdr.IJDR_184_17.