Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma

Naoimh Herlihy, Mehmet Dogrusöz, T. Huibertus Van Essen, J. William Harbour, Pieter A. Van Der Velden, Marja C J A Van Eggermond, Geert W. Haasnoot, Peter J. Van Den Elsen, Martine J. Jager

Research output: Contribution to journalArticle

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Abstract

PURPOSE. Monosomy 3 (M3) or the presence of a specific RNA expression profile, known as class 2, is strongly associated with death from uveal melanoma (UM). Given the important role of epigenetic processes in cancer development and progression, we compared the transcriptional profiles of a selection of epigenetic regulators between primary UM with a good and a bad prognosis. METHODS. Transcriptional levels of 59 epigenetic regulator genes were measured by quantitative PCR (qPCR) in 20 UM, 12 with monosomy of chromosome 3 (M3) and 8 with disomy of chromosome 3 (D3). Validation was performed in an independent cohort. Expression levels were compared to clinicopathological characteristics, including class type. Bisulfite sequencing was used to evaluate the role of DNA methylation in gene silencing. RESULTS. In the first set of tumors, general downregulation of transcription of the genes encoding epigenetic regulatory enzymes was seen in association with M3. The 10 genes with the highest differential expression between M3 and D3 were selected and were analyzed in a second set of tumors. In the validation set, significantly lower levels of KAT2B (P ¼ 0.008), HDAC11 (P ¼ 0.009), KMT1C (P ¼ 0.05), KDM4B (P ¼ 0.003), KDM6B (P ¼ 0.04), and BMI- 1 (P ¼ 0.001) transcripts were found in tumors with M3/class2. Methylation of C-phosphate- G (CpG) residues was not observed on the putative regulatory regions of KAT2B, KDM4B, or KDM6B. CONCLUSIONS. Expression levels of a number of histone-modifying genes and polycomb family members are significantly lower in uveal melanoma with monosomy 3/class 2, supporting a general dysregulation of epigenetic modifiers in UM with a bad prognosis.

Original languageEnglish (US)
Pages (from-to)1447-1458
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number3
DOIs
StatePublished - 2015

Fingerprint

Monosomy
Epigenomics
Gene Expression
Chromosomes, Human, Pair 3
Neoplasms
Genetic Epigenesis
Genes
Nucleic Acid Regulatory Sequences
Gene Silencing
DNA Methylation
Regulator Genes
Uveal melanoma
Histones
Methylation
Down-Regulation
Phosphates
RNA
Polymerase Chain Reaction
Enzymes

Keywords

  • Epigenetics
  • Gene expression
  • Melanoma
  • Oncology
  • Uvea

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Herlihy, N., Dogrusöz, M., Van Essen, T. H., William Harbour, J., Van Der Velden, P. A., Van Eggermond, M. C. J. A., ... Jager, M. J. (2015). Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma. Investigative Ophthalmology and Visual Science, 56(3), 1447-1458. https://doi.org/10.1167/iovs.14-15250

Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma. / Herlihy, Naoimh; Dogrusöz, Mehmet; Van Essen, T. Huibertus; William Harbour, J.; Van Der Velden, Pieter A.; Van Eggermond, Marja C J A; Haasnoot, Geert W.; Van Den Elsen, Peter J.; Jager, Martine J.

In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 3, 2015, p. 1447-1458.

Research output: Contribution to journalArticle

Herlihy, N, Dogrusöz, M, Van Essen, TH, William Harbour, J, Van Der Velden, PA, Van Eggermond, MCJA, Haasnoot, GW, Van Den Elsen, PJ & Jager, MJ 2015, 'Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma', Investigative Ophthalmology and Visual Science, vol. 56, no. 3, pp. 1447-1458. https://doi.org/10.1167/iovs.14-15250
Herlihy, Naoimh ; Dogrusöz, Mehmet ; Van Essen, T. Huibertus ; William Harbour, J. ; Van Der Velden, Pieter A. ; Van Eggermond, Marja C J A ; Haasnoot, Geert W. ; Van Den Elsen, Peter J. ; Jager, Martine J. / Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma. In: Investigative Ophthalmology and Visual Science. 2015 ; Vol. 56, No. 3. pp. 1447-1458.
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abstract = "PURPOSE. Monosomy 3 (M3) or the presence of a specific RNA expression profile, known as class 2, is strongly associated with death from uveal melanoma (UM). Given the important role of epigenetic processes in cancer development and progression, we compared the transcriptional profiles of a selection of epigenetic regulators between primary UM with a good and a bad prognosis. METHODS. Transcriptional levels of 59 epigenetic regulator genes were measured by quantitative PCR (qPCR) in 20 UM, 12 with monosomy of chromosome 3 (M3) and 8 with disomy of chromosome 3 (D3). Validation was performed in an independent cohort. Expression levels were compared to clinicopathological characteristics, including class type. Bisulfite sequencing was used to evaluate the role of DNA methylation in gene silencing. RESULTS. In the first set of tumors, general downregulation of transcription of the genes encoding epigenetic regulatory enzymes was seen in association with M3. The 10 genes with the highest differential expression between M3 and D3 were selected and were analyzed in a second set of tumors. In the validation set, significantly lower levels of KAT2B (P ¼ 0.008), HDAC11 (P ¼ 0.009), KMT1C (P ¼ 0.05), KDM4B (P ¼ 0.003), KDM6B (P ¼ 0.04), and BMI- 1 (P ¼ 0.001) transcripts were found in tumors with M3/class2. Methylation of C-phosphate- G (CpG) residues was not observed on the putative regulatory regions of KAT2B, KDM4B, or KDM6B. CONCLUSIONS. Expression levels of a number of histone-modifying genes and polycomb family members are significantly lower in uveal melanoma with monosomy 3/class 2, supporting a general dysregulation of epigenetic modifiers in UM with a bad prognosis.",
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AU - Herlihy, Naoimh

AU - Dogrusöz, Mehmet

AU - Van Essen, T. Huibertus

AU - William Harbour, J.

AU - Van Der Velden, Pieter A.

AU - Van Eggermond, Marja C J A

AU - Haasnoot, Geert W.

AU - Van Den Elsen, Peter J.

AU - Jager, Martine J.

PY - 2015

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N2 - PURPOSE. Monosomy 3 (M3) or the presence of a specific RNA expression profile, known as class 2, is strongly associated with death from uveal melanoma (UM). Given the important role of epigenetic processes in cancer development and progression, we compared the transcriptional profiles of a selection of epigenetic regulators between primary UM with a good and a bad prognosis. METHODS. Transcriptional levels of 59 epigenetic regulator genes were measured by quantitative PCR (qPCR) in 20 UM, 12 with monosomy of chromosome 3 (M3) and 8 with disomy of chromosome 3 (D3). Validation was performed in an independent cohort. Expression levels were compared to clinicopathological characteristics, including class type. Bisulfite sequencing was used to evaluate the role of DNA methylation in gene silencing. RESULTS. In the first set of tumors, general downregulation of transcription of the genes encoding epigenetic regulatory enzymes was seen in association with M3. The 10 genes with the highest differential expression between M3 and D3 were selected and were analyzed in a second set of tumors. In the validation set, significantly lower levels of KAT2B (P ¼ 0.008), HDAC11 (P ¼ 0.009), KMT1C (P ¼ 0.05), KDM4B (P ¼ 0.003), KDM6B (P ¼ 0.04), and BMI- 1 (P ¼ 0.001) transcripts were found in tumors with M3/class2. Methylation of C-phosphate- G (CpG) residues was not observed on the putative regulatory regions of KAT2B, KDM4B, or KDM6B. CONCLUSIONS. Expression levels of a number of histone-modifying genes and polycomb family members are significantly lower in uveal melanoma with monosomy 3/class 2, supporting a general dysregulation of epigenetic modifiers in UM with a bad prognosis.

AB - PURPOSE. Monosomy 3 (M3) or the presence of a specific RNA expression profile, known as class 2, is strongly associated with death from uveal melanoma (UM). Given the important role of epigenetic processes in cancer development and progression, we compared the transcriptional profiles of a selection of epigenetic regulators between primary UM with a good and a bad prognosis. METHODS. Transcriptional levels of 59 epigenetic regulator genes were measured by quantitative PCR (qPCR) in 20 UM, 12 with monosomy of chromosome 3 (M3) and 8 with disomy of chromosome 3 (D3). Validation was performed in an independent cohort. Expression levels were compared to clinicopathological characteristics, including class type. Bisulfite sequencing was used to evaluate the role of DNA methylation in gene silencing. RESULTS. In the first set of tumors, general downregulation of transcription of the genes encoding epigenetic regulatory enzymes was seen in association with M3. The 10 genes with the highest differential expression between M3 and D3 were selected and were analyzed in a second set of tumors. In the validation set, significantly lower levels of KAT2B (P ¼ 0.008), HDAC11 (P ¼ 0.009), KMT1C (P ¼ 0.05), KDM4B (P ¼ 0.003), KDM6B (P ¼ 0.04), and BMI- 1 (P ¼ 0.001) transcripts were found in tumors with M3/class2. Methylation of C-phosphate- G (CpG) residues was not observed on the putative regulatory regions of KAT2B, KDM4B, or KDM6B. CONCLUSIONS. Expression levels of a number of histone-modifying genes and polycomb family members are significantly lower in uveal melanoma with monosomy 3/class 2, supporting a general dysregulation of epigenetic modifiers in UM with a bad prognosis.

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