Oral squamous cell carcinoma (OSCC), a subset of head and neck cancers, primarily originates in the epithelial tissues of the oral cavity. Despite advancements in treatment, the mortality rate for OSCC remains around 50%, underscoring the urgent need for improved prognostic markers. This review explores the role of the BRCA1 and BRCA2 genes-traditionally associated with breast and ovarian cancers-in the context of OSCC. We discuss the molecular pathways involving BRCA genes, their potential as diagnostics and prognostic biomarkers, and their implications for personalized treatment strategies, including addressing chemotherapy resistance. Furthermore, this review emphasizes the significance of genome stability in cancer progression and examines both current and emerging methodologies for detecting BRCA mutations in OSCC patients. Despite limited prevalence of BRCA mutations in OSCC compared to other cancers, their role in DNA repair and therapeutic response underscores their potential as clinical biomarkers. However, standardized, multicenter studies are still needed to validate their utility in OSCC management. A better understanding of the role of BRCA genes in OSCC could pave the way for more effective therapeutic approaches and improved patient outcomes.

Clinic of Oncology University Hospital Ostrava Ostrava Czechia

Department of Craniofacial Surgery Faculty of Medicine University of Ostrava Ostrava Czechia

Department of Experimental Biology Faculty of Science Masaryk University Brno Czechia

Department of Hematology Faculty of Medicine University of Ostrava Ostrava Czechia

Department of Hematooncology University Hospital Ostrava Ostrava Czechia

Department of Oral and Maxillofacial Surgery University Hospital Ostrava Ostrava Czechia

Health Research Centre Faculty of Medicine University of Ostrava Ostrava Czechia

Institute of Animal Physiology and Genetics Czech Academy of Sciences Brno Czechia

Institute of Molecular and Clinical Pathology and Medical Genetics Faculty of Medicine University of Ostrava Ostrava Czechia

Institute of Molecular and Clinical Pathology and Medical Genetics University Hospital Ostrava Ostrava Czechia

Zobrazit více v PubMed

Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. (2022) 233:780–6. doi: 10.1038/s41415-022-5166-x PubMed DOI PMC

WHO . International agency for research of cancer, Cancer today, Globocan 2020. (2020). Available at: https://gco.iarc.fr.

Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, et al. . Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the international head and neck cancer epidemiology consortium. JNCI J Natl Cancer Instit. (2007) 99:777–89. doi: 10.1093/jnci/djk179 PubMed DOI

Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, et al. . Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—systematic review and meta-analysis of trends by time and region. Head Neck. (2013) 35:747–55. doi: 10.1002/hed.22015 PubMed DOI

Tan Y, Wang Z, Xu M, Li B, Huang Z, Qin S, et al. . Oral squamous cell carcinomas: state of the field and emerging directions. Int J Oral Sci. (2023) 15:44. doi: 10.1038/s41368-023-00249-w PubMed DOI PMC

Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Prime. (2020) 6:92. doi: 10.1038/s41572-020-00224-3 PubMed DOI PMC

Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. (2006) 25:5864–74. doi: 10.1038/sj.onc.1209874 PubMed DOI

Li M, Yu X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell. (2013) 23:693–704. doi: 10.1016/j.ccr.2013.03.025 PubMed DOI PMC

Ashworth A. Refocusing on BRCA1. Nat Cell Biol. (2004) 6:916–7. doi: 10.1038/ncb1004-916 PubMed DOI

Clark SL, Rodriguez AM, Snyder RR, Hankins GDV, Boehning D. STRUCTURE-FUNCTION OF THE TUMOR SUPPRESSOR BRCA1. Comput Struct Biotechnol J. (2012) 1:e201204005. doi: 10.5936/csbj.201204005 PubMed DOI PMC

Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, et al. . Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet. (1996) 14:430–40. doi: 10.1038/ng1296-430 PubMed DOI

Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. (2012) 12:68–78. doi: 10.1038/nrc3181 PubMed DOI PMC

Wu S, Zhou J, Zhang K, Chen H, Luo M, Lu Y, et al. . Molecular mechanisms of PALB2 function and its role in breast cancer management. Front Oncol. (2020) 10:301. doi: 10.3389/fonc.2020.00301 PubMed DOI PMC

Le HP, Heyer WD, Liu J. Guardians of the genome: BRCA2 and its partners. Genes. (2021) 12:1229. doi: 10.3390/genes12081229 PubMed DOI PMC

Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. (2004) 95:866–71. doi: 10.1111/j.1349-7006.2004.tb02195.x PubMed DOI PMC

Kwon Y, Rösner H, Zhao W, Selemenakis P, He Z, Kawale AS, et al. . DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation. Nat Commun. (2023) 14:432. doi: 10.1038/s41467-023-36211-x PubMed DOI PMC

Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, et al. . Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. (2007) 316:1194–8. doi: 10.1126/science.1139476 PubMed DOI PMC

McCarthy-Leo C, Darwiche F, Tainsky MA. DNA repair mechanisms, protein interactions and therapeutic targeting of the MRN complex. Cancers. (2022) 14:5278. doi: 10.3390/cancers14215278 PubMed DOI PMC

Fradet-Turcotte A, Sitz J, Grapton D, Orthwein A. BRCA2 functions: from DNA repair to replication fork stabilization. Endocrine-Related Cancer. (2016) 23:T1–17. doi: 10.1530/ERC-16-0297 PubMed DOI

Li X, Heyer W-D. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. (2008) 18:99–113. doi: 10.1038/cr.2008.1 PubMed DOI PMC

Wyman C, Ristic D, Kanaar R. Homologous recombination-mediated double-strand break repair. DNA Repair. (2004) 3:827–33. doi: 10.1016/j.dnarep.2004.03.037 PubMed DOI

Ranjha L, Howard SM, Cejka P. Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes. Chromosoma. (2018) 127:187–214. doi: 10.1007/s00412-017-0658-1 PubMed DOI

Ceccaldi R, Sarangi P, D’Andrea AD. The fanconi anaemia pathway: new players and new functions. Nat Rev Mol Cell Biol. (2016) 17:337–49. doi: 10.1038/nrm.2016.48 PubMed DOI

Prime SS, Darski P, Hunter KD, Cirillo N, Parkinson EK. A review of the repair of DNA double strand breaks in the development of oral cancer. IJMS. (2024) 25:4092. doi: 10.3390/ijms25074092 PubMed DOI PMC

Oliveira-Costa JP, Oliveira LR, Zanetti JS, Silveira GGD, Buim MEC, Zucoloto S, et al. . BRCA1 and γH2AX as independent prognostic markers in oral squamous cell carcinoma. Oncoscience. (2014) 1:383–91. doi: 10.18632/oncoscience.47 PubMed DOI PMC

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

Mistry NH, Gosavi SR, Dhobley A, Mishra S, Kherde P. Expression of breast cancer gene 2 in oral squamous cell carcinoma and its correlation with the metastatic potential: A retrospective study. J Precis Oncol. (2022) 2:120–4. doi: 10.4103/jpo.jpo_25_22 DOI

Vossen DM, Verhagen CVM, Verheij M, Wessels LFA, Vens C, Van Den Brekel MWM. Comparative genomic analysis of oral versus laryngeal and pharyngeal cancer. Oral Oncol. (2018) 81:35–44. doi: 10.1016/j.oraloncology.2018.04.006 PubMed DOI

Koo K, Mouradov D, Angel CM, Iseli TA, Wiesenfeld D, McCullough MJ, et al. . Genomic signature of oral squamous cell carcinomas from non-smoking non-drinking patients. Cancers. (2021) 13:1029. doi: 10.3390/cancers13051029 PubMed DOI PMC

Biswas NK, Das C, Das S, Maitra A, Nair S, Gupta T, et al. . Lymph node metastasis in oral cancer is strongly associated with chromosomal instability and DNA repair defects. Intl J Cancer. (2019) 145:2568–79. doi: 10.1002/ijc.v145.9 PubMed DOI

Vora HH, Shah NG, Patel DD, Trivedi TI, Choksi TJ. BRCA1 expression in leukoplakia and carcinoma of the tongue. J Surg Oncol. (2003) 83:232–40. doi: 10.1002/jso.10213 PubMed DOI

Rogakou EP, Boon C, Redon C, Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo . J Cell Biol. (1999) 146:905–16. doi: 10.1083/jcb.146.5.905 PubMed DOI PMC

Santivasi WL, Wang H, Wang T, Yang Q, Mo X, Brogi E, et al. . Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer. Br J Cancer. (2015) 113:453–9. doi: 10.1038/bjc.2015.208 PubMed DOI PMC

Thorgeirsson T, Jordahl KM, Flavin R, Epstein MM, Fiorentino M, Andersson S-O, et al. . Intracellular location of BRCA2 protein expression and prostate cancer progression in the swedish watchful waiting cohort. Carcinogenesis. (2016) 37:262–8. doi: 10.1093/carcin/bgw001 PubMed DOI PMC

Wang G-H, Zhao C-M, 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 PubMed DOI

Drikos I, Nounesis G, Vorgias CE. Characterization of cancer-linked BRCA1-BRCT missense variants and their interaction with phosphoprotein targets. Proteins. (2009) 77:464–76. doi: 10.1002/prot.22460 PubMed DOI

Drikos I, Boutou E, Kastritis PL, Vorgias CE. BRCA1-BRCT mutations alter the subcellular localization of BRCA1. In Vitro. Anticancer Res. (2021) 41:2953–62. doi: 10.21873/anticanres.15077 PubMed DOI

Chen Y, Chen CF, Riley DJ, Allred DC, Chen PL, Von Hoff D, et al. . Aberrant subcellular localization of BRCA1 in breast cancer. Science. (1995) 270(5237):789–91. doi: 10.1126/science.270.5237.789 PubMed DOI

Krais JJ, Johnson N. BRCA1 mutations in cancer: Coordinating deficiencies in homologous recombination with tumorigenesis. Cancer Res. (2020) 80:4601–9. doi: 10.1158/0008-5472.CAN-20-1830 PubMed DOI PMC

Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO. Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol. (2008) 39:857–65. doi: 10.1016/j.humpath.2007.10.011 PubMed DOI

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 USA. (2015) 112:8409–14. doi: 10.1073/pnas.1500223112 PubMed DOI PMC

Farah CS, Jessri M, Bennett NC, Dalley AJ, Shearston KD, Fox SA. Exome sequencing of oral leukoplakia and oral squamous cell carcinoma implicates DNA damage repair gene defects in Malignant transformation. Oral Oncol. (2019) 96:42–50. doi: 10.1016/j.oraloncology.2019.07.005 PubMed DOI

Sparano A, Quesnelle KM, Kumar MS, Wang Y, Sylvester AJ, Feldman M, et al. . Genome-wide profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization. Laryngos. (2006) 116:735–41. doi: 10.1097/01.mlg.0000205141.54471.7f PubMed DOI

Amenábar JM, Torres-Pereira CC, Tang KD, Punyadeera C. Two enemies, one fight: An update of oral cancer in patients with Fanconi anemia. Cancer. (2019) 125:3936–46. doi: 10.1002/cncr.v125.22 PubMed DOI

Badwelan M, Muaddi H, Ahmed A, Lee KT, Tran SD. Oral squamous cell carcinoma and concomitant primary tumors, what do we know? A review of the literature. Curr Oncol. (2023) 30:3721–34. doi: 10.3390/curroncol30040283 PubMed DOI PMC

Starzyńska A, Sobocki BK, Alterio D. Current challenges in head and neck cancer management. Cancers. (2022) 14:358. doi: 10.3390/cancers14020358 PubMed DOI PMC

Armstrong N, Ryder S, Forbes C, Ross J, Quek RG. A systematic review of the international prevalence of BRCA mutation in breast cancer. CLEP. (2019) 11:543–61. doi: 10.2147/CLEP.S206949 PubMed DOI PMC

Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. (2010) 79:181–211. doi: 10.1146/annurev.biochem.052308.093131 PubMed DOI PMC

Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. (2010) 12:245–59. doi: 10.1097/GIM.0b013e3181d38f2f PubMed DOI

Loboda AP, Adonin LS, Zvereva SD, Guschin DY, Korneenko TV, Telegina AV, et al. . BRCA mutations—The achilles heel of breast, ovarian and other epithelial cancers. IJMS. (2023) 24:4982. doi: 10.3390/ijms24054982 PubMed DOI PMC

Arun B, Couch FJ, Abraham J, Tung N, Fasching PA. BRCA-mutated breast cancer: the unmet need, challenges and therapeutic benefits of genetic testing. Br J Cancer. (2024) 131:1400–14. doi: 10.1038/s41416-024-02827-z PubMed DOI PMC

Luo G, Lu Y, Jin K, Cheng H, Guo M, Liu Z, et al. . Pancreatic cancer: BRCA mutation and personalized treatment. Expert Rev Anticancer Ther. (2015) 15:1223–31. doi: 10.1586/14737140.2015.1086271 PubMed DOI

Hurník P, Režnarová J, Chyra Z, Motyka O, Putnová BM, Čermáková Z, et al. . Enhancing oral squamous cell carcinoma prediction: the prognostic power of the worst pattern of invasion and the limited impact of molecular resection margins. Front Oncol. (2023) 13:1287650. doi: 10.3389/fonc.2023.1287650 PubMed DOI PMC

Errazquin R, Carrasco E, Del Marro S, Suñol A, Peral J, Ortiz J, et al. . Early diagnosis of oral cancer and lesions in fanconi anemia patients: A prospective and longitudinal study using saliva and plasma. Cancers. (2023) 15:1871. doi: 10.3390/cancers15061871 PubMed DOI PMC

Toprani SM, Kelkar Mane V. A short review on DNA damage and repair effects in lip cancer. Hematology/Oncol Stem Cell Ther. (2021) 14:267–74. doi: 10.1016/j.hemonc.2021.01.007 PubMed DOI

Nikitakis NG, Rassidakis GZ, Tasoulas J, Gkouveris I, Kamperos G, Daskalopoulos A, et al. . Alterations in the expression of DNA damage response-related molecules in potentially preneoplastic oral epithelial lesions. Oral Surge Oral Med Oral Pathol Oral Radiol. (2018) 125:637–49. doi: 10.1016/j.oooo.2018.03.006 PubMed DOI

Kende P, Mathur Y, Varte V, Tayal S, Patyal N, Landge J. The efficacy of neoadjuvant chemotherapy as compared to upfront surgery for the management of oral squamous cell carcinoma: a systematic review and meta-analysis. Int J Oral Maxillofac Surge. (2024) 53:1–10. doi: 10.1016/j.ijom.2023.03.007 PubMed DOI

Sa P, Singh P, Panda S, Swain RK, Dash R, Sahoo SK. Reversal of cisplatin resistance in oral squamous cell carcinoma by piperlongumine loaded smart nanoparticles through inhibition of Hippo-YAP signaling pathway. Trans Res. (2024) 268:63–78. doi: 10.1016/j.trsl.2024.03.004 PubMed DOI

Cao M, Shi E, Wang H, Mao L, Wu Q, Li X, et al. . Personalized targeted therapeutic strategies against oral squamous cell carcinoma. An evidence-based review of literature. IJN. (2022) 17:4293–306. doi: 10.2147/IJN.S377816 PubMed DOI PMC

Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP. The role of BRCA1 in the cellular response to chemotherapy. JNCI J Natl Cancer Instit. (2004) 96:1659–68. doi: 10.1093/jnci/djh312 PubMed DOI

Stordal B, Davey R. A systematic review of genes involved in the inverse resistance relationship between cisplatin and paclitaxel chemotherapy: role of BRCA1. CCDT. (2009) 9:354–65. doi: 10.2174/156800909788166592 PubMed DOI

Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML, et al. . BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer. (2003) 88:1285–91. doi: 10.1038/sj.bjc.6600859 PubMed DOI PMC

Quinn JE, Kennedy RD, Mullan PB, Gilmore PM, Carty M, Johnston PG, et al. . BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. (2003) 63:6221–8. PubMed

Fan S, Liu B, Sun L, Lv X, Lin Z, Chen W, et al. . Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p–MFF axis. Oncotarget. (2015) 6:14885–904. doi: 10.18632/oncotarget.3659 PubMed DOI PMC

Wang F, Gouttia OG, Wang L, Peng A. PARP1 upregulation in recurrent oral cancer and treatment resistance. Front Cell Dev Biol. (2022) 9:804962. doi: 10.3389/fcell.2021.804962 PubMed DOI PMC

Luong KV, Wang L, Roberts BJ, Wahl JK, Peng A. Cell fate determination in cisplatin resistance and chemosensitization. Oncotarget. (2016) 7:23383–94. doi: 10.18632/oncotarget.8110 PubMed DOI PMC

Dulaney C, Marcrom S, Stanley J, Yang ES. Poly(ADP-ribose) polymerase activity and inhibition in cancer. Semin Cell Dev Biol. (2017) 63:144–53. doi: 10.1016/j.semcdb.2017.01.007 PubMed DOI

Nambiar KD, Mishra DP, Singh R. Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials. Oncol Res. (2023) 31:405–21. doi: 10.32604/or.2023.028310 PubMed DOI PMC

Chen A. PARP inhibitors: its role in treatment of cancer. Chin J Cancer. (2011) 30(7):463–71. doi: 10.5732/cjc.011.10111 PubMed DOI PMC

Moutafi M, Economopoulou P, Rimm D, Psyrri A. PARP inhibitors in head and neck cancer: Molecular mechanisms, preclinical and clinical data. Oral Oncol. (2021) 117:105292. doi: 10.1016/j.oraloncology.2021.105292 PubMed DOI

Cheng L, Sturgis EM, Eicher SA, Spitz MR, Wei Q. Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck. Cancer. (2002) 94:393–7. doi: 10.1002/cncr.10231 PubMed DOI

Chung CH, Guthrie VB, Masica DL, Tokheim C, Kang H, Richmon J, et al. . Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing. Ann Oncol. (2015) 26:1216–23. doi: 10.1093/annonc/mdv109 PubMed DOI PMC

Li C, Hu Z, Lu J, Liu Z, Wang L, El-Naggar AK, et al. . Genetic polymorphisms in DNA base-excision repair genes ADPRT, XRCC1, and APE1 and the risk of squamous cell carcinoma of the head and neck. Cancer. (2007) 110:867–75. doi: 10.1002/cncr.v110:4 PubMed DOI

Lim J, Tan DSP. Understanding resistance mechanisms and expanding the therapeutic utility of PARP inhibitors. Cancers. (2017) 9:109. doi: 10.3390/cancers9080109 PubMed DOI PMC

Gorodetska I, Kozeretska I, Dubrovska A. BRCA genes: The role in genome stability, cancer stemness and therapy resistance. J Cancer. (2019) 10:2109–27. doi: 10.7150/jca.30410 PubMed DOI PMC