Methylation of PCDH17 and NEFH as prognostic biomarker for nonmetastatic RCC: A cohort study.
Journal
Medicine
ISSN: 1536-5964
Titre abrégé: Medicine (Baltimore)
Pays: United States
ID NLM: 2985248R
Informations de publication
Date de publication:
15 Jul 2022
15 Jul 2022
Historique:
entrez:
15
7
2022
pubmed:
16
7
2022
medline:
20
7
2022
Statut:
epublish
Résumé
DNA methylation makes up a main part of the molecular mechanism of cancer evolution and has shown promising results in the prognosis of renal cell cancer (RCC). In this study, we investigated the possible association of promoter methylation of PCDH17, NEFH, RASSF1A, and FHIT, genes with the prognosis of nonmetastatic RCC patients. Cancerous and normal adjacent tissues from surgical specimens of 41 patients with long follow-up were treated for DNA isolation and bisulfite conversion. The gene promoter methylation was determined with quantitative methylation-specific PCR (qMSP). Wilcoxon signed-rank test was used for paired methylation comparisons, while univariate linear regression and Mann-Whitney test were applied for associating methylation status with clinical and disease characteristics. Cox regression proportional hazards models and Kaplan-Meier plots were used for survival analyses in reference to methylation status. Paired comparisons showed tissue-specific hypermethylation for PCDH17 (P < .001), NEFH (P < .001), RASSF1A (P = .032), while a positive association of methylation in normal tissues with age was demonstrated for PCDH17 (P < .001), RASSF1A (P < .001), FHIT (P < .001). PCDH17 was more methylated in cases with clear cell RCC (P = .015) and high-grade tumor (P = .013), while NEFH methylation was higher in locally advanced cases (P = .032). PCDH17 hypermethylation in cancerous and normal tissues was linked to shorter disease-specific survival (DSS, P = .026, P = .004), disease-free survival (DFS, P = .004, P = .019) while NEFH hypermethylation in cancerous tissues was related to shorter DSS (P = .032). Increased methylation difference of NEFH was also associated with shorter DSS (P = .041) and DFS (P = .020), while the corresponding parameter for PCDH17 was associated with poor DFS (P = .014). Kaplan-Meier curves for hypermethylation in cancer tissues demonstrated different clinical courses for PCDH17 (P = .017), NEFH (P = .023) regarding DSS, and PCDH17 (P = .001) regarding DFS. Our study not only highlights the prognostic value of promoter methylation of PCDH17 and NEFH in cancer tissues but also is the first report of the prognostic value of methylation alterations in normal tissues. Our findings are the first report of the prognostic value of methylation alterations in normal tissues, which can contribute to improved assessment of recurrence risk.
Identifiants
pubmed: 35838992
doi: 10.1097/MD.0000000000029599
pii: 00005792-202207150-00005
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e29599Informations de copyright
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
Déclaration de conflit d'intérêts
The authors have no funding and conflicts of interest to disclose.
Références
Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018;103:356–87.
Tahbaz R, Schmid M, Merseburger AS. Prevention of kidney cancer incidence and recurrence: lifestyle, medication and nutrition. Curr Opin Urol. 2018;28:62–79.
Sun M, Shariat SF, Cheng C, et al. Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol. 2011;60:644–61.
Joosten SC, Smits KM, Aarts MJ, et al. Epigenetics in renal cell cancer: mechanisms and clinical applications. Nat Rev Urol. 2018;15:430–51.
Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol. 2016;8:a019505.
Lommen K, Vaes N, Aarts MJ, et al. Diagnostic DNA methylation biomarkers for renal cell carcinoma: a systematic review. Eur Urol Oncol. 2021;4:215–226.
Joosten SC, Deckers IAG, Aarts MJ, et al. Prognostic DNA methylation markers for renal cell carcinoma: a systematic review. Epigenomics. 2017;9:1243–57.
Peters I, Merseburger AS, Tezval H, et al. The prognostic value of DNA methylation markers in renal cell cancer: a systematic review. Kidney Cancer. 2020;4:3–13.
Dubois F, Bergot E, Zalcman G, et al. RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis—an updated review. Cell Death Dis. 2019;10:928.
Raos D, Ulamec M, Katusic Bojanac A, et al. Epigenetically inactivated RASSF1A as a tumor biomarker. Bosn J Basic Med Sci. 2020;21:386–97.
Zhuang Q, Chen Z, Shen J, et al. RASSF1A promoter methylation correlates development, progression, and poor cancer-specific survival of renal cell carcinoma: trial sequential analysis. Onco Targets Ther. 2018;12:119–34.
Ure I, Konac E, Alp E, et al. Transcriptomic expression levels of the VHL, TIMP-3, and RASSF1A genes in renal tumors. Eur Rev Med Pharmacol Sci. 2019;23:9313–20.
Kawai Y, Sakano S, Suehiro Y, et al. Methylation level of the <em>RASSF1A</em> promoter is an independent prognostic factor for clear-cell renal cell carcinoma. Ann Oncol. 2010;21:1612–7.
Klacz J, Wierzbicki PM, Wronska A, et al. Decreased expression of RASSF1A tumor suppressor gene is associated with worse prognosis in clear cell renal cell carcinoma. Int J Oncol. 2016;48:55–66.
Waters C, Saldivar JC, Hosseini SA, et al. The FHIT gene product: tumor suppressor and genome@ caretake’. Cell Mol Life Sci. 2014;71:4577–87.
Joannes A, Grelet S, Duca L, et al. Fhit regulates EMT targets through an EGFR/Src/ERK/Slug signaling axis in human bronchial cells. Mol Cancer Res. 2014;12:775–83.
Zöchbauer-Müller S, Fong KM, Maitra A, et al. 5′ CpG Island methylation of the <em>FHIT</em> gene is correlated with loss of gene expression in Lung and breast cancer. Cancer Res. 2001;61:3581–5.
Tanaka H, Shimada Y, Harada H, et al. Methylation of the 5′ CpG Island of the <em>FHIT</em> gene is closely associated with transcriptional inactivation in esophageal squamous cell carcinomas. Cancer Res. 1998;58:3429–34.
Costa VL, Henrique R, Ribeiro FR, et al. Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors. BMC Cancer. 2007;7:133.
Kvasha S, Gordiyuk V, Kondratov A, et al. Hypermethylation of the 5′CpG island of the FHIT gene in clear cell renal carcinomas. Cancer Lett. 2008;265:250–7.
Alholle A, Brini AT, Gharanei S, et al. Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma. Epigenetics. 2013;8:1198–204.
Calmon MF, Jeschke J, Zhang W, et al. Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer. Epigenetics. 2015;10:622–32.
Kim MS, Chang X, LeBron C, et al. Neurofilament heavy polypeptide regulates the Akt-β-Catenin pathway in human esophageal squamous cell carcinoma. PLoS One. 2010;5:e9003.
Dubrowinskaja N, Gebauer K, Peters I, et al. Neurofilament Heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response. Cancer Med. 2014;3:300–9.
van Vlodrop IJH, Joosten SC, De Meyer T, et al. A four-gene promoter methylation marker panel consisting of <em>GREM1, NEURL, LAD1,</em> and <em>NEFH</em> predicts survival of clear cell renal cell cancer patients. Clin Cancer Res. 2017;23:2006.
Dutra TTB, Bezerra TMM, Luna ECM, et al. Do protocadherins show prognostic value in the carcinogenesis of human malignant neoplasms? Systematic review and meta-analysis. Asian Pac J Cancer Prev. 2020;21:3677–88.
Yin X, Xiang T, Mu J, et al. Protocadherin 17 functions as a tumor suppressor suppressing Wnt/β-catenin signaling and cell metastasis and is frequently methylated in breast cancer. Oncotarget. 2016;7:51720–32.
Dang Z, Shangguan J, Zhang C, et al. Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma. Tumor Biol. 2016;37:2527–35.
Liu S, Lin H, Wang D, et al. PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death. Signal Transduct Target Ther. 2019;4:53–53.
Wang X-B, Lin Y-L, Li Z-G, et al. Ma J-G. Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma. J Int Med Res. 2014;42:292–9.
Lin Y-L, Xie P-G, Wang L. Ma J-G. Aberrant methylation of protocadherin 17 and its clinical significance in patients with prostate cancer after radical prostatectomy. Med Sci Monit. 2014;20:1376–82.
Costa VL, Henrique R, Danielsen SA, et al. TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics. 2011;6:1120–30.
Lin Y-L, Gui S-L, Guo H, et al. Protocadherin17 promoter methylation is a potential predictive biomarker in clear cell renal cell carcinoma. Med Sci Monit. 2015;21:2870–6.
Lin Y-L, Wang Y-P, Li H-Z, et al. Aberrant promoter methylation of PCDH17 (Protocadherin 17) in serum and its clinical significance in renal cell carcinoma. Med Sci Monit. 2017;23:3318–23.
Brait M, Begum S, Carvalho AL, et al. Aberrant promoter methylation of multiple genes during pathogenesis of bladder cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:2786–94.
Wang Y, Yu Y, Ye R, et al. An epigenetic biomarker combination of PCDH17 and POU4F2 detects bladder cancer accurately by methylation analyses of urine sediment DNA in Han Chinese. Oncotarget. 2016;7:2754–64.
Harden SV, Tokumaru Y, Westra WH, et al. Gene promoter hypermethylation in tumors and lymph nodes of stage I Lung cancer patients. Clin Cancer Res. 2003;9:1370.
Moribe T, Iizuka N, Miura T, et al. Methylation of multiple genes as molecular markers for diagnosis of a small, well-differentiated hepatocellular carcinoma. Int J Cancer. 2009;125:388–97.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25:402–8.
Partin Alan W, Van Neste L, Klein Eric A, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol. 2014;192:1081–7.
Møller M, Strand SH, Mundbjerg K, et al. Heterogeneous patterns of DNA methylation-based field effects in histologically normal prostate tissue from cancer patients. Sci Rep. 2017;7:40636.
Gao Y, Widschwendter M, Teschendorff AE. DNA methylation patterns in normal tissue correlate more strongly with breast cancer status than copy-number variants. EBioMedicine. 2018;31:243–52.
Lucarelli G, Loizzo D, Franzin R, et al. Metabolomic insights into pathophysiological mechanisms and biomarker discovery in clear cell renal cell carcinoma. Expert Rev Mol Diagn. 2019;19:397–407.
Ragone R, Sallustio F, Piccinonna S, et al. Renal cell carcinoma: a study through NMR-based metabolomics combined with transcriptomics. Diseases. 2016;4:7.
Bianchi C, Meregalli C, Bombelli S, et al. The glucose and lipid metabolism reprogramming is gradedependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation. Oncotarget. 2017;8:113502–15.
Lucarelli G, Rutigliano M, Sallustio F, et al. Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma. Aging (Albany NY). 2018;10:3957–85.
Dabral S, Muecke C, Valasarajan C, et al. A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension. Nat Commun. 2019;10:2130.
Druck T, Cheung DG, Park D, et al. Fhit–Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells. Cell Death Dis. 2019;10:147.
Di Lorenzo G, De Placido S, Pagliuca M, et al. The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review. Expert Opin Biol Ther. 2016;16:1387–401.
Bersanelli M, Gnetti L, Azzoni C, et al. Loss of heterozygosity of key tumor suppressor genes in advanced renal cancer patients treated with nivolumab. Immunotherapy. 2018;10:743–52.
Leveridge MJ, Finelli A, Kachura JR, et al. Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol. 2011;60:578–84.
Chopra S, Liu J, Alemozaffar M, et al. Improving needle biopsy accuracy in small renal mass using tumor-specific DNA methylation markers. Oncotarget. 2017;8:5439–48.
Sun M, Becker A, Tian Z, et al. Management of localized kidney cancer: calculating cancer-specific mortality and competing risks of death for surgery and nonsurgical management. Eur Urol. 2014;65:235–41.
Dabestani S, Beisland C, Stewart GD, et al. Long-term outcomes of follow-up for initially localised clear cell renal cell carcinoma: RECUR database analysis. Eur Urol Focus. 2019;5:857–66.
Sun M, Vetterlein M, Harshman LC, et al. Risk assessment in small renal masses: a review article. Urol Clin N Am. 2017;44:189–202.
Andersson-Evelönn E, Vidman L, Källberg D, et al. Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma. J Transl Med. 2020;18:435.
El Khoury LY, Fu S, Hlady RA, et al. Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer. Clin Epigenetics. 2021;13:12.
Ridyard DG, Buller DM, Ristau BT. The current state of adjuvant therapy following surgery for high-risk renal cell carcinoma. Eur Urol Focus. 2019;5:935–8.
Sun M, Marconi L, Eisen T, et al. Adjuvant vascular endothelial growth factor–targeted therapy in renal cell carcinoma: a systematic review and pooled analysis. Eur Urol. 2018;74:611–20.
Kim SP, Crispen PL, Thompson RH, et al. Assessment of the pathologic inclusion criteria from contemporary adjuvant clinical trials for predicting disease progression after nephrectomy for renal cell carcinoma. Cancer. 2012;118:4412–20.
Williams C, Pontén F, Moberg C, et al. A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am J Pathol. 1999;155:1467–71.
Lehmann U, Kreipe H. Real-time PCR-based assay for quantitative determination of methylation status. Methods Mol Biol (Clifton, N.J.). 2004;287:207–18.