Identification of Methylation Markers for the Prediction of Nodal Metastasis in Oral and Oropharyngeal Squamous Cell Carcinoma

Overview

Journal Epigenetics

Specialty Genetics

Date 2015 Jul 28

PMID 26213212

Citations 13

Authors

L J Melchers

M J A M Clausen

M F Mastik

L Slagter-Menkema

J E van der Wal

G B A Wisman

J L N Roodenburg

E Schuuring

Affiliations

Soon will be listed here.

Abstract

Hypermethylation is an important mechanism for the dynamic regulation of gene expression, necessary for metastasizing tumour cells. Our aim is to identify methylation tumour markers that have a predictive value for the presence of regional lymph node metastases in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). Significantly differentially expressed genes were retrieved from four reported microarray expression profiles comparing pN0 and pN+ head-neck tumours, and one expression array identifying functionally hypermethylated genes. Additional metastasis-associated genes were included from the literature. Thus genes were selected that influence the development of nodal metastases and might be regulated by methylation. Methylation-specific PCR (MSP) primers were designed and tested on 8 head-neck squamous cell carcinoma cell lines and technically validated on 10 formalin-fixed paraffin-embedded (FFPE) OOSCC cases. Predictive value was assessed in a clinical series of 70 FFPE OOSCC with pathologically determined nodal status. Five out of 28 methylation markers (OCLN, CDKN2A, MGMT, MLH1 and DAPK1) were frequently differentially methylated in OOSCC. Of these, MGMT methylation was associated with pN0 status (P = 0.02) and with lower immunoexpression (P = 0.02). DAPK1 methylation was associated with pN+ status (P = 0.008) but did not associate with protein expression. In conclusion, out of 28 candidate genes, two (7%) showed a predictive value for the pN status. Both genes, DAPK1 and MGMT, have predictive value for nodal metastasis in a clinical group of OOSCC. Therefore DNA methylation markers are capable of contributing to diagnosis and treatment selection in OOSCC. To efficiently identify additional new methylation markers, genome-wide methods are needed.

Citing Articles

DNA methylation biomarkers for predicting lymph node metastasis in colorectal cancer.

Sun Y, Kong D, Zhang Q, Xiang R, Lu S, Feng L Clin Transl Oncol. 2024; 27(2):439-448.

PMID: 39026026 DOI: 10.1007/s12094-024-03601-6.

Promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions are associated with tumor differentiation, nodal involvement and survival.

Rivera-Pena B, Folawiyo O, Turaga N, Rodriguez-Benitez R, Felici M, Aponte-Ortiz J Oncol Lett. 2024; 27(3):89.

PMID: 38268779 PMC: 10804364. DOI: 10.3892/ol.2024.14223.

Epigenetic methylation changes: implication as biomarkers in oral and maxillofacial area cancers.

Aghiorghiesei O, Irimie A, Braicu C, Raduly L, Nutu A, Balint E Med Pharm Rep. 2023; 96(3):310-317.

PMID: 37577021 PMC: 10419680. DOI: 10.15386/mpr-2570.

Integrative Predictive Modeling of Metastasis in Melanoma Cancer Based on MicroRNA, mRNA, and DNA Methylation Data.

Kutlay A, Aydin Son Y Front Mol Biosci. 2021; 8:637355.

PMID: 34631789 PMC: 8495312. DOI: 10.3389/fmolb.2021.637355.

High DNMT1 Is Associated With Worse Local Control in Early-Stage Laryngeal Squamous Cell Carcinoma.

Bruine de Bruin L, Clausen M, Slagter-Menkema L, de Bock G, Langendijk J, van der Vegt B Laryngoscope. 2021; 132(4):801-805.

PMID: 34427325 PMC: 9290472. DOI: 10.1002/lary.29833.

References

Perez A, Neskey D, Wen J, Pereira L, Reategui E, Goodwin W . CD44 interacts with EGFR and promotes head and neck squamous cell carcinoma initiation and progression. Oral Oncol. 2012; 49(4):306-13. PMC: 3594090. DOI: 10.1016/j.oraloncology.2012.11.009. View

Braakhuis B, Brakenhoff R, Leemans C . Gene expression profiling in head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(2):67-71. DOI: 10.1097/MOO.0b013e32833693ce. View

Puri S, Si L, Fan C, Hanna E . Aberrant promoter hypermethylation of multiple genes in head and neck squamous cell carcinoma. Am J Otolaryngol. 2005; 26(1):12-7. DOI: 10.1016/j.amjoto.2004.06.007. View

Gasche J, Goel A . Epigenetic mechanisms in oral carcinogenesis. Future Oncol. 2012; 8(11):1407-25. PMC: 3569850. DOI: 10.2217/fon.12.138. View

Weiss D, Basel T, Sachse F, Braeuninger A, Rudack C . Promoter methylation of cyclin A1 is associated with human papillomavirus 16 induced head and neck squamous cell carcinoma independently of p53 mutation. Mol Carcinog. 2011; 50(9):680-8. DOI: 10.1002/mc.20798. View

ODonnell R, Kupferman M, Wei S, Singhal S, Weber R, OMalley B . Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity. Oncogene. 2004; 24(7):1244-51. DOI: 10.1038/sj.onc.1208285. View

Jithesh P, Risk J, Schache A, Dhanda J, Lane B, Liloglou T . The epigenetic landscape of oral squamous cell carcinoma. Br J Cancer. 2013; 108(2):370-9. PMC: 3566828. DOI: 10.1038/bjc.2012.568. View

Melchers L, Mastik M, Samaniego Cameron B, van Dijk B, de Bock G, van der Laan B . Detection of HPV-associated oropharyngeal tumours in a 16-year cohort: more than meets the eye. Br J Cancer. 2015; 112(8):1349-57. PMC: 4402463. DOI: 10.1038/bjc.2015.99. View

Herman J, Graff J, Myohanen S, Nelkin B, Baylin S . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996; 93(18):9821-6. PMC: 38513. DOI: 10.1073/pnas.93.18.9821. View

10.

Arduino P, Carrozzo M, Chiecchio A, Broccoletti R, Tirone F, Borra E . Clinical and histopathologic independent prognostic factors in oral squamous cell carcinoma: a retrospective study of 334 cases. J Oral Maxillofac Surg. 2008; 66(8):1570-9. DOI: 10.1016/j.joms.2007.12.024. View

11.

Noordhuis M, Fehrmann R, Wisman G, Nijhuis E, van Zanden J, Moerland P . Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res. 2011; 17(6):1317-30. DOI: 10.1158/1078-0432.CCR-10-2320. View

12.

Sanchez-Cespedes M, Esteller M, Wu L, Yoo G, Koch W, Jen J . Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res. 2000; 60(4):892-5. View

13.

Lassen P . The role of Human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol. 2010; 95(3):371-80. DOI: 10.1016/j.radonc.2010.04.022. View

14.

Ongenaert M, Wisman G, Volders H, Koning A, Van der Zee A, Van Criekinge W . Discovery of DNA methylation markers in cervical cancer using relaxation ranking. BMC Med Genomics. 2008; 1:57. PMC: 2605750. DOI: 10.1186/1755-8794-1-57. View

15.

Rastetter M, Schagdarsurengin U, Lahtz C, Fiedler E, Marsch W, Dammann R . Frequent intra-tumoural heterogeneity of promoter hypermethylation in malignant melanoma. Histol Histopathol. 2007; 22(9):1005-15. DOI: 10.14670/HH-22.1005. View

16.

Rosas S, Koch W, da Costa Carvalho M, Wu L, Califano J, Westra W . Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res. 2001; 61(3):939-42. View

17.

Liao L, Lo W, Hsu W, Wang C, Lai M . Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck-a meta-analysis comparing different imaging modalities. BMC Cancer. 2012; 12:236. PMC: 3476985. DOI: 10.1186/1471-2407-12-236. View

18.

Kristensen L, Hansen L . PCR-based methods for detecting single-locus DNA methylation biomarkers in cancer diagnostics, prognostics, and response to treatment. Clin Chem. 2009; 55(8):1471-83. DOI: 10.1373/clinchem.2008.121962. View

19.

Ingold B, Schraml P, Heppner F, Moch H . Homogeneous MGMT immunoreactivity correlates with an unmethylated MGMT promoter status in brain metastases of various solid tumors. PLoS One. 2009; 4(3):e4775. PMC: 2652028. DOI: 10.1371/journal.pone.0004775. View

20.

Olson R, Brastianos P, Palma D . Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. J Neurooncol. 2011; 105(2):325-35. DOI: 10.1007/s11060-011-0594-5. View