Identification of Epigenetically Regulated Genes That Predict Patient Outcome in Neuroblastoma

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2011 Feb 15

PMID 21314941

Citations 43

Authors

Helena Caren

Anna Djos

Maria Nethander

Rose-Marie Sjoberg

Per Kogner

Camilla Enstrom

Staffan Nilsson

Tommy Martinsson

Affiliations

Soon will be listed here.

Abstract

Background: Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes.

Methods: In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA). Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation.

Results: We present eight genes (KRT19, PRKCDBP, SCNN1A, POU2F2, TGFBI, COL1A2, DHRS3 and DUSP23) that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes SCNN1A (p < 0.001), PRKCDBP (p < 0.001) and KRT19 (p < 0.01). Among these, the mRNA expression of KRT19 and PRKCDBP was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for KRT19 and fold change -2.4, p = 0.04 for PRKCDBP).

Conclusions: In our study, a low methylation frequency of SCNN1A, PRKCDBP and KRT19 is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas.

Citing Articles

Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research.

Sharma R, Yadav J, Bhat S, Musayev A, Myrzagulova S, Sharma D Mol Neurobiol. 2025; .

PMID: 39804528 DOI: 10.1007/s12035-024-04680-w.

A multi-omics approach for biomarker discovery in neuroblastoma: a network-based framework.

Hussein R, Abou-Shanab A, Badr E NPJ Syst Biol Appl. 2024; 10(1):52.

PMID: 38760476 PMC: 11101461. DOI: 10.1038/s41540-024-00371-3.

Evaluation of circulating tumor DNA by electropherogram analysis and methylome profiling in high-risk neuroblastomas.

Trinidad E, Juan-Ribelles A, Pisano G, Castel V, Canete A, Gut M Front Oncol. 2023; 13:1037342.

PMID: 37251933 PMC: 10213460. DOI: 10.3389/fonc.2023.1037342.

Liquidhope: methylome and genomic profiling from very limited quantities of plasma-derived DNA.

Trinidad E, Vidal E, Coronado E, Esteve-Codina A, Castel V, Canete A Brief Bioinform. 2023; 24(1).

PMID: 36611239 PMC: 9851319. DOI: 10.1093/bib/bbac575.

A Selective Histone Deacetylase Inhibitor Induces Autophagy and Cell Death via SCNN1A Downregulation in Glioblastoma Cells.

Chang H, Chang Y, Tsai B, Chen L, Chang A, Chuang J Cancers (Basel). 2022; 14(18).

PMID: 36139696 PMC: 9496778. DOI: 10.3390/cancers14184537.

References

Becker J, Erdlenbruch B, Noskova I, Schramm A, Aumailley M, Schorderet D . Keratoepithelin suppresses the progression of experimental human neuroblastomas. Cancer Res. 2006; 66(10):5314-21. DOI: 10.1158/0008-5472.CAN-05-3049. View

Sengupta P, Smith E, Kim K, Murnane M, Smith B . DNA hypermethylation near the transcription start site of collagen alpha2(I) gene occurs in both cancer cell lines and primary colorectal cancers. Cancer Res. 2003; 63(8):1789-97. View

Han W, Cauchi S, Herman J, Spivack S . DNA methylation mapping by tag-modified bisulfite genomic sequencing. Anal Biochem. 2006; 355(1):50-61. DOI: 10.1016/j.ab.2006.05.010. View

Astuti D, Agathanggelou A, Honorio S, Dallol A, Martinsson T, Kogner P . RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene. 2001; 20(51):7573-7. DOI: 10.1038/sj.onc.1204968. View

Martinsson T, Sjoberg R, Hedborg F, Kogner P . Homozygous deletion of the neurofibromatosis-1 gene in the tumor of a patient with neuroblastoma. Cancer Genet Cytogenet. 1997; 95(2):183-9. DOI: 10.1016/s0165-4608(96)00259-2. View

Haeseleer F, Huang J, Lebioda L, SAARI J, Palczewski K . Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal. J Biol Chem. 1998; 273(34):21790-9. DOI: 10.1074/jbc.273.34.21790. View

Wu Q, Li Y, Gu S, Li N, Zheng D, Li D . Molecular cloning and characterization of a novel dual-specificity phosphatase 23 gene from human fetal brain. Int J Biochem Cell Biol. 2004; 36(8):1542-53. DOI: 10.1016/j.biocel.2003.12.014. View

Thompson P, Maris J, Hogarty M, Seeger R, Reynolds C, Brodeur G . Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. Cancer Res. 2001; 61(2):679-86. View

Zochbauer-Muller S, Fong K, Geradts J, Xu X, Seidl S, End-Pfutzenreuter A . Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. Oncogene. 2005; 24(41):6249-55. DOI: 10.1038/sj.onc.1208775. View

10.

Banelli B, Gelvi I, Di Vinci A, Scaruffi P, Casciano I, Allemanni G . Distinct CpG methylation profiles characterize different clinical groups of neuroblastic tumors. Oncogene. 2005; 24(36):5619-28. DOI: 10.1038/sj.onc.1208722. View

11.

Dahlman T, Lammerts E, Bergstrom D, Franzen A, Westermark K, Heldin N . Collagen type I expression in experimental anaplastic thyroid carcinoma: regulation and relevance for tumorigenicity. Int J Cancer. 2002; 98(2):186-92. DOI: 10.1002/ijc.10181. View

12.

Caren H, Erichsen J, Olsson L, Enerback C, Sjoberg R, Abrahamsson J . High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors: four cases of homozygous deletions of the CDKN2A gene. BMC Genomics. 2008; 9:353. PMC: 2527340. DOI: 10.1186/1471-2164-9-353. View

13.

Caren H, Ejeskar K, Fransson S, Hesson L, Latif F, Sjoberg R . A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation. Mol Cancer. 2005; 4(1):10. PMC: 554762. DOI: 10.1186/1476-4598-4-10. View

14.

Kamei N, Hiyama K, Yamaoka H, Kamimatsuse A, Onitake Y, Sueda T . Evaluation of genes identified by microarray analysis in favorable neuroblastoma. Pediatr Surg Int. 2009; 25(11):931-7. DOI: 10.1007/s00383-009-2448-1. View

15.

Caren H, Fransson S, Ejeskar K, Kogner P, Martinsson T . Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours. Br J Cancer. 2007; 97(10):1416-24. PMC: 2360241. DOI: 10.1038/sj.bjc.6604032. View

16.

Origone P, Defferrari R, Mazzocco K, Cunsolo C, De Bernardi B, Tonini G . Homozygous inactivation of NF1 gene in a patient with familial NF1 and disseminated neuroblastoma. Am J Med Genet A. 2003; 118A(4):309-13. DOI: 10.1002/ajmg.a.10167. View

17.

Takai D, Jones P . Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A. 2002; 99(6):3740-5. PMC: 122594. DOI: 10.1073/pnas.052410099. View

18.

Xu X, Wu L, DU F, Davis A, Peyton M, Tomizawa Y . Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers. Cancer Res. 2001; 61(21):7943-9. View

19.

Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T . Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas. Cancer Res. 2006; 66(12):6080-6. DOI: 10.1158/0008-5472.CAN-06-0157. View

20.

Tusnady G, Simon I, Varadi A, Aranyi T . BiSearch: primer-design and search tool for PCR on bisulfite-treated genomes. Nucleic Acids Res. 2005; 33(1):e9. PMC: 546182. DOI: 10.1093/nar/gni012. View