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Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer
- Source :
- EPIGENETICS, 10(10), 970-980. Landes Bioscience, Epigenetics, 10(10), 970-980. Landes Bioscience, Lando, M, Fjeldbo, C S, Wilting, S M, Snoek, B C, Aarnes, E K, Forsberg, M F, Kristensen, G B, Steenbergen, R D M & Lyng, H 2015, ' Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer ', Epigenetics, vol. 10, no. 10, pp. 970-980 . https://doi.org/10.1080/15592294.2015.1085140
- Publication Year :
- 2015
-
Abstract
- Loss of 3p11-p14 is a frequent event in epithelial cancer and a candidate prognostic biomarker in cervical cancer. In addition to loss, promoter methylation can participate in gene silencing and promote tumor aggressiveness. We have performed a complete mapping of promoter methylation at 3p11-p14 in two independent cohorts of cervical cancer patients (n = 149, n = 121), using Illumina 450K methylation arrays. The aim was to investigate whether hyperm-ethylation was frequent and could contribute to gene silencing and disease aggressiveness either alone or combined with loss. By comparing the methylation level of individual CpG sites with corresponding data of normal cervical tissue, 26 out of 41 genes were found to be hypermethylated in both cohorts. The frequency of patients with hypermethylation of these genes was found to be higher at tumor stages of 3 and 4 than in stage 1 tumors. Seventeen of the 26 genes were transcriptionally downregulated in cancer compared to normal tissue, whereof 6 genes showed a significant correlation between methylation and expression. Integrated analysis of methylation, gene dosage, and expression of the 26 hypermethylated genes identified 3 regulation patterns encompassing 8 hypermethylated genes; a methylation driven pattern (C3orf14, GPR27, ZNF717), a gene dosage driven pattern (THOC7, PSMD6), and a combined methylation and gene dosage driven pattern (FHIT, ADAMTS9, LRIG1). In survival analysis, patients with both hypermethylation and loss of LRIG1 had a worse outcome compared to those harboring only hypermethylation or none of the events. C3orf14 emerged as a novel methylation regulated suppressor gene, for which knockdown was found to promote invasive growth in human papilloma virus (HPV)-transformed keratinocytes. In conclusion, hypermethylation at 3p11-p14 is common in cervical cancer and may exert a selection pressure during carcinogenesis alone or combined with loss. Information on both events could lead to improved prognostic markers.
- Subjects :
- Adult
Cancer Research
Carcinogenesis
Tumor suppressor genes
Uterine Cervical Neoplasms
Kaplan-Meier Estimate
Biology
medicine.disease_cause
Gene dosage
Disease-Free Survival
Epigenesis, Genetic
FHIT
medicine
Humans
Gene silencing
Gene Silencing
Promoter Regions, Genetic
Molecular Biology
Aged
3p
Cancer
Methylation
DNA Methylation
Middle Aged
medicine.disease
Promoter methylation
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
CpG site
DNA methylation
Cancer research
Cervical cancer
CpG Islands
Female
Chromosomes, Human, Pair 3
Chromosomal loss
Gene expression
Chromosome Deletion
Integrative genomic profiling
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 15592294
- Database :
- OpenAIRE
- Journal :
- EPIGENETICS, 10(10), 970-980. Landes Bioscience, Epigenetics, 10(10), 970-980. Landes Bioscience, Lando, M, Fjeldbo, C S, Wilting, S M, Snoek, B C, Aarnes, E K, Forsberg, M F, Kristensen, G B, Steenbergen, R D M & Lyng, H 2015, ' Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer ', Epigenetics, vol. 10, no. 10, pp. 970-980 . https://doi.org/10.1080/15592294.2015.1085140
- Accession number :
- edsair.doi.dedup.....54e718632f5e601e9ee6ca23927c2d2f