Characterization of a prognostic four‑gene methylation signature associated with radiotherapy for head and neck squamous cell carcinoma

Ma,Jiabao; Li,Rui; Wang,Jie

doi:10.3892/mmr.2019.10294

Characterization of a prognostic four‑gene methylation signature associated with radiotherapy for head and neck squamous cell carcinoma

Authors:
- Jiabao Ma
- Rui Li
- Jie Wang
View Affiliations

Affiliations: Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, P.R. China
Published online on: May 24, 2019 https://doi.org/10.3892/mmr.2019.10294
Pages: 622-632
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Head and neck squamous cell carcinoma (HNSCC) remains one of the most common malignancies associated with poor prognosis. DNA methylation has emerged as an important mechanism underlying the radio‑resistance of tumors. Prognostic biomarkers based on radiotherapy‑related aberrant DNA methylation are limited. Methylation profiles of 388 patients with HNSCC were acquired from The Cancer Genome Atlas (TCGA) portal. Genes with differentially methylated CpG sites (DMGs) were screened between patients with a favorable and poor prognosis with or without radiotherapy. A weight gene co‑methylation network was constructed using a Weighted Gene Co‑expression Network Analysis (WGCNA) package. A lasso Cox‑PH model was used to identify the optimal panel of genes with the ability to predict survival in these patients. Prognostic performance of the multi‑gene methylation signature was assessed in a training set and confirmed in a validation set. A total of 976 DMGs were observed between favorable and poor prognostic samples. Four DMG‑enriched co‑methylation modules were identified. A four‑gene methylation signature was determined by the lasso Cox‑PH model that consisted of ZNF10, TMPRSS12, ERGIC2, and RNF215. The risk score based on the four‑gene signature was able to divide the training or validation set into two risk groups with significantly different overall survival. Thus, the present study revealed a radiotherapy‑related four‑gene methylation signature to predict survival outcomes of patients with HNSCC, providing candidate therapeutic targets for novel therapy against HNSCC. However, substantial validation experiments are required.

View Figures

View References

1	GBD 2015 Disease, Injury Incidence and Prevalence Collaborators: Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 388:1545–1602. 2016. View Article : Google Scholar : PubMed/NCBI
2	Leemans CR, Snijders PJF and Brakenhoff RH: The molecular landscape of head and neck cancer. Nat Rev Cancer. 18:269–282. 2018. View Article : Google Scholar : PubMed/NCBI
3	López-Verdín S, Lavalle-Carrasco J, Carreón-Burciaga RG, Serafín-Higuera N, Molina-Frechero N, González-González R and Bologna-Molina R: Molecular markers of anticancer drug resistance in head and neck squamous cell carcinoma: A literature review. Cancers (Basel). 10:E3762018. View Article : Google Scholar : PubMed/NCBI
4	Beyzadeoglu M, Selek U and Ozyigit G: Radiation Therapy for Head and Neck Cancers: A Case-Based Review. Springer; New York, NY: pp. pp2442014
5	Delpu Y, Cordelier P, Cho WC and Torrisani J: DNA methylation and cancer diagnosis. Int J Mol Sci. 14:15029–15058. 2013. View Article : Google Scholar : PubMed/NCBI
6	Klutstein M, Nejman D, Greenfield R and Cedar H: DNA methylation in cancer and aging. Cancer Res. 76:3446–3450. 2016. View Article : Google Scholar : PubMed/NCBI
7	Lechner M, Fenton T, West J, Wilson G, Feber A, Henderson S, Thirlwell C, Dibra HK, Jay A, Butcher L, et al: Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma. Genome Med. 5:152013. View Article : Google Scholar : PubMed/NCBI
8	Steinmann K, Sandner A, Schagdarsurengin U and Dammann RH: Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep. 22:1519–1526. 2009.PubMed/NCBI
9	Kostareli E, Hielscher T, Zucknick M, Baboci L, Wichmann G, Holzinger D, Mücke O, Pawlita M, Del Mistro A, Boscolo-Rizzo P, et al: Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients. Epigenetics. 11:61–73. 2016. View Article : Google Scholar : PubMed/NCBI
10	Kostareli E, Holzinger D, Bogatyrova O, Hielscher T, Wichmann G, Keck M, Lahrmann B, Grabe N, Flechtenmacher C, Schmidt CR, et al: HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. J Clin Invest. 123:2488–2501. 2013. View Article : Google Scholar : PubMed/NCBI
11	Esposti DD, Sklias A, Lima SC, Beghelli-de la Forest Divonne S, Cahais V, Fernandez-Jimenez N, Cros MP, Ecsedi S, Cuenin C, Bouaoun L, et al: Unique DNA methylation signature in HPV-positive head and neck squamous cell carcinomas. Genome Med. 9:332017. View Article : Google Scholar : PubMed/NCBI
12	Shuryak I, Hall EJ and Brenner DJ: Dose dependence of accelerated repopulation in head and neck cancer: Supporting evidence and clinical implications. Radiother Oncol. 127:20–26. 2018. View Article : Google Scholar : PubMed/NCBI
13	Zhu X, Wang Y, Tan L and Fu X: The pivotal role of DNA methylation in the radio-sensitivity of tumor radiotherapy. Cancer Med. 7:3812–3819. 2018. View Article : Google Scholar : PubMed/NCBI
14	Huang KH, Huang SF, Chen IH, Liao CT, Wang HM and Hsieh LL: Methylation of RASSF1A, RASSF2A, and HIN-1 is associated with poor outcome after radiotherapy, but not surgery, in oral squamous cell carcinoma. Clin Cancer Res. 15:4174–4180. 2009. View Article : Google Scholar : PubMed/NCBI
15	Krishnan NM, Dhas K, Nair J, Palve V, Bagwan J, Siddappa G, Suresh A, Kekatpure VD, Kuriakose MA and Panda B: A minimal DNA methylation signature in oral tongue squamous cell carcinoma links altered methylation with tumor attributes. Mol Cancer Res. 14:805–819. 2016. View Article : Google Scholar : PubMed/NCBI
16	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e472015. View Article : Google Scholar : PubMed/NCBI
17	Langfelder P and Horvath S: WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics. 9:5592008. View Article : Google Scholar : PubMed/NCBI
18	Massart R, Dymov S, Millecamps M, Suderman M, Gregoire S, Koenigs K, Alvarado S, Tajerian M, Stone LS and Szyf M: Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells. Sci Rep. 6:196152016. View Article : Google Scholar : PubMed/NCBI
19	Cao J and Zhang S: A bayesian extension of the hypergeometric test for functional enrichment analysis. Biometrics. 70:84–94. 2014. View Article : Google Scholar : PubMed/NCBI
20	Gene Ontology Consortium: Gene ontology consortium: Going forward. Nucleic Acids Res. 43:D1049–D1056. 2015. View Article : Google Scholar : PubMed/NCBI
21	Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC and Lempicki RA: DAVID Bioinformatics Resources: Expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35:W169–W175. 2007. View Article : Google Scholar : PubMed/NCBI
22	Tibshirani R: The lasso method for variable selection in the Cox model. Stat Med. 16:385–395. 1997. View Article : Google Scholar : PubMed/NCBI
23	Goel MK, Khanna P and Kishore J: Understanding survival analysis: Kaplan-Meier estimate. Int J Ayurveda Res. 1:274–278. 2010. View Article : Google Scholar : PubMed/NCBI
24	Marur S and Forastiere AA: Head and neck squamous cell carcinoma: Update on epidemiology, diagnosis, and treatment. Mayo Clin Proc. 91:386–396. 2016. View Article : Google Scholar : PubMed/NCBI
25	Marur S and Forastiere AA: Head and neck cancer: Changing epidemiology, diagnosis, and treatment. Mayo Clin Proc. 83:489–501. 2008. View Article : Google Scholar : PubMed/NCBI
26	Bøvelstad HM, Nygård S, Størvold HL, Aldrin M, Borgan Ø, Frigessi A and Lingjaerde OC: Predicting survival from microarray data-a comparative study. Bioinformatics. 23:2080–2087. 2007. View Article : Google Scholar : PubMed/NCBI
27	Goeman JJ: L1 penalized estimation in the Cox proportional hazards model. Biom J. 52:70–84. 2010.PubMed/NCBI
28	Jen J and Wang YC: Zinc finger proteins in cancer progression. J Biom Sci. 23:532016. View Article : Google Scholar
29	Chung CH, Dignam JJ, Hammond ME, Klimowicz AC, Petrillo SK, Magliocco A, Jordan R, Trotti A, Spencer S, Cooper JS, et al: Glioma-associated oncogene family zinc finger 1 expression and metastasis in patients with head and neck squamous cell carcinoma treated with radiation therapy (RTOG 9003). J Clin Oncol. 29:1326–1334. 2011. View Article : Google Scholar : PubMed/NCBI
30	Hedstrom L: Serine protease mechanism and specificity. Chem Rev. 34:4501–4524. 2003.
31	Liu M, Hu Z, Qi L, Wang J, Zhou T, Guo Y, Zeng Y, Zheng B, Wu Y, Zhang P, et al: Scanning of novel cancer/testis proteins by human testis proteomic analysis. Proteomics. 13:1200–1210. 2013. View Article : Google Scholar : PubMed/NCBI
32	Saghafinia S, Mina M, Riggi N, Hanahan D and Ciriello G: Pan-cancer landscape of aberrant DNA methylation across human tumors. Cell Rep. 25:1066–1080.e8. 2018. View Article : Google Scholar : PubMed/NCBI
33	Kwok SC, Liu X, Mangel P and Daskal I: PTX1(ERGIC2)-VP22 fusion protein upregulates interferon-beta in prostate cancer cell line PC-3. DNA Cell Biol. 25:523–529. 2006. View Article : Google Scholar : PubMed/NCBI
34	Kwok SC, Kumar S and Dai G: Characterization of a variant of ERGIC2 transcript. DNA Cell Biol. 33:73–78. 2014. View Article : Google Scholar : PubMed/NCBI
35	Takenobu M, Osaki M, Fujiwara K, Fukuhara T, Kitano H, Kugoh H and Okada F: PITX1 is a novel predictor of the response to chemotherapy in head and neck squamous cell carcinoma. Mol Clin Oncol. 5:89–94. 2016. View Article : Google Scholar : PubMed/NCBI
36	Chu P, Pardo J, Zhao H, Li CC, Pali E, Shen MM, Qu K, Yu SX, Huang BC, Yu P, et al: Systematic identification of regulatory proteins critical for T-cell activation. J Biol. 2:212003. View Article : Google Scholar : PubMed/NCBI
37	Fang S, Lorick KL, Jensen JP and Weissman AM: RING finger ubiquitin protein ligases: Implications for tumorigenesis, metastasis and for molecular targets in cancer. Semin Cancer Biol. 13:5–14. 2003. View Article : Google Scholar : PubMed/NCBI
38	Yang L, Zhou B, Li X, Lu Z, Li W, Huo X and Miao Z: RNF125 is a ubiquitin-protein ligase that promotes p53 degradation. Cell Physiol Biochem. 35:237–245. 2015. View Article : Google Scholar : PubMed/NCBI
39	Khan AQ, Siveen KS, Prabhu KS, Kuttikrishnan S, Akhtar S, Shaar A, Raza A, Mraiche F, Dermime S and Uddin S: Curcumin-mediated degradation of s-phase kinase protein 2 induces cytotoxic effects in human papillomavirus-positive and negative squamous carcinoma cells. Front Onco. 8:3992018. View Article : Google Scholar