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Targeted DNA Methylation Analysis by Next-generation Sequencing
Published on: February 24, 2015
Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across
Jonathan J Lee1, Lynette M Sholl1, Neal I Lindeman1
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, EBRC Suite 401, Boston, MA 02115 USA.
Background:
Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution.
Results:
Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples.
Conclusions:
Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma.
Insights
Somatic mutations in epigenetic regulators are common in melanoma, with over 90% of patients having at least one. These mutations, particularly in DNA demethylation and histone modification genes, are linked to melanoma development and UV exposure.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Genomic sequencing advances understanding of cancer mutations.
- Melanoma is a genetically diverse cancer known for treatment resistance.
- Epigenetic mechanisms are increasingly recognized in melanoma pathogenesis.
Purpose of the Study:
- To determine the frequency and types of mutations in epigenetic regulators in treatment-naïve melanoma.
- To analyze the role of epigenetic regulators in melanoma development.
Main Methods:
- Targeted next-generation sequencing of 275 cancer genes in 38 melanoma samples.
- Analysis of mutations in 41 epigenetic regulator genes.
- Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma dataset.
Main Results:
- 22.3% of all non-silent mutations occurred in epigenetic regulators.
- 92.1% of melanoma samples had at least one mutation in an epigenetic regulator.
- UVB-signature mutations were more frequent in epigenetic genes (e.g., MLL2, MECOM) than non-epigenetic genes.
Conclusions:
- High prevalence of somatic mutations in epigenetic regulators in melanoma.
- Epigenetic mechanisms, especially involving MECOM and MLL2, are implicated in melanoma pathobiology.
- Findings highlight the role of epigenetic dysregulation in melanoma development and UV-induced mutations.
