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Lee JJ, Sholl LM, Lindeman NI, et al. Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas. Clin Epigenetics. 2015;7:59doi: 10.1186/s13148-015-0091-3.
Lee, J. J., Sholl, L. M., Lindeman, N. I., Granter, S. R., Laga, A. C., Shivdasani, P., Chin, G., Luke, J. J., Ott, P. A., Hodi, F. S., Mihm, M. C., Lin, J. Y., Werchniak, A. E., Haynes, H. A., Bailey, N., Liu, R., Murphy, G. F., & Lian, C. G. (2015). Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas. Clinical epigenetics, 759. https://doi.org/10.1186/s13148-015-0091-3
Lee, Jonathan J, et al. "Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas." Clinical epigenetics vol. 7 (2015): 59. doi: https://doi.org/10.1186/s13148-015-0091-3
Lee JJ, Sholl LM, Lindeman NI, Granter SR, Laga AC, Shivdasani P, Chin G, Luke JJ, Ott PA, Hodi FS, Mihm MC, Lin JY, Werchniak AE, Haynes HA, Bailey N, Liu R, Murphy GF, Lian CG. Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas. Clin Epigenetics. 2015 Jun 09;7:59. doi: 10.1186/s13148-015-0091-3. eCollection 2015. PMID: 26221190; PMCID: PMC4517542.
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Clin Epigenetics. 2015 Jun 09;7:59. doi: 10.1186/s13148-015-0091-3. eCollection 2015.

Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas.

Clinical epigenetics

Jonathan J Lee, Lynette M Sholl, Neal I Lindeman, Scott R Granter, Alvaro C Laga, Priyanka Shivdasani, Gary Chin, Jason J Luke, Patrick A Ott, F Stephen Hodi, Martin C Mihm, Jennifer Y Lin, Andrew E Werchniak, Harley A Haynes, Nancy Bailey, Robert Liu, George F Murphy, Christine G Lian

Affiliations

  1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, EBRC Suite 401, Boston, MA 02115 USA.
  2. Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02215-5450 USA.

PMID: 26221190 PMCID: PMC4517542 DOI: 10.1186/s13148-015-0091-3

Abstract

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.

Keywords: 5-hydroxymethylcytosine; DNA demethylation; Epigenetics; Isocitrate dehydrogenase 2 (IDH2); MECOM (MDS1 and EV1 complex locus); MLL2; Melanoma; Next-generation sequencing (NGS); Ten-eleven translocation (TET)

References

  1. Cancer. 2002 Jun 15;94(12):3192-209 - PubMed
  2. Blood. 2008 Apr 15;111(8):4329-37 - PubMed
  3. Nat Rev Clin Oncol. 2013 Oct;10(10):588-98 - PubMed
  4. PLoS One. 2013;8(2):e56308 - PubMed
  5. Science. 2011 Sep 2;333(6047):1229-30 - PubMed
  6. Science. 2011 Sep 2;333(6047):1303-7 - PubMed
  7. J Clin Oncol. 2013 Jan 1;31(1):95-103 - PubMed
  8. N Engl J Med. 2012 Jul 12;367 (2):107-14 - PubMed
  9. Nature. 2014 Oct 9;514(7521):247-51 - PubMed
  10. Elife. 2013 Jun 25;2:e00747 - PubMed
  11. Nature. 2002 Jun 27;417(6892):949-54 - PubMed
  12. J Natl Cancer Inst. 2014 Feb;106(2):djt435 - PubMed
  13. Ann Oncol. 2014 May;25(5):959-67 - PubMed
  14. Nat Commun. 2015 Jan 22;6:6051 - PubMed
  15. Nat Genet. 2003 Jan;33(1):19-20 - PubMed
  16. EMBO Rep. 2011 Dec 23;13(1):28-35 - PubMed
  17. Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17603-8 - PubMed
  18. Carcinogenesis. 2014 Sep;35(9):2097-101 - PubMed
  19. Oncogene. 2013 May 9;32(19):2373-9 - PubMed
  20. Nat Genet. 2014 Oct;46(10):1097-102 - PubMed
  21. Ann Oncol. 2014 May;25(5):917-8 - PubMed
  22. Sci Rep. 2014 Aug 12;4:6036 - PubMed
  23. J Natl Cancer Inst. 2010 Jul 7;102(13):932-41 - PubMed
  24. Cancer Res. 2014 Mar 15;74(6):1814-21 - PubMed
  25. Cancer Sci. 2012 Aug;103(8):1371-7 - PubMed
  26. Oncogene. 2003 May 19;22(20):3081-6 - PubMed
  27. N Engl J Med. 2010 Aug 19;363(8):711-23 - PubMed
  28. Science. 2011 Sep 2;333(6047):1300-3 - PubMed
  29. Cell. 2012 Jul 20;150(2):251-63 - PubMed
  30. Sci Signal. 2013 Apr 02;6(269):pl1 - PubMed
  31. Pigment Cell Melanoma Res. 2010 Dec;23(6):741-5 - PubMed
  32. Genes Dev. 2006 Aug 15;20(16):2149-82 - PubMed
  33. N Engl J Med. 2015 Jan 22;372(4):320-30 - PubMed
  34. Mod Pathol. 2015 Feb;28(2):218-29 - PubMed
  35. PLoS One. 2012;7(5):e38156 - PubMed
  36. Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):E2885-94 - PubMed
  37. N Engl J Med. 2011 Jun 30;364(26):2507-16 - PubMed
  38. Mol Cell. 2007 Jan 12;25(1):15-30 - PubMed
  39. J Dermatol Sci. 2014 Feb;73(2):161-3 - PubMed
  40. N Engl J Med. 2009 Feb 19;360(8):765-73 - PubMed
  41. Oncotarget. 2011 Aug;2(8):627-37 - PubMed
  42. J Natl Cancer Inst. 2014 May 28;106(6):dju112 - PubMed
  43. Science. 2014 Nov 21;346(6212):945-9 - PubMed
  44. JAMA Dermatol. 2015 Jan;151(1):51-8 - PubMed
  45. Science. 2013 Feb 22;339(6122):957-9 - PubMed
  46. Lab Invest. 2014 Aug;94(8):822-38 - PubMed
  47. Cancer Discov. 2012 May;2(5):401-4 - PubMed
  48. PLoS One. 2014 Nov 13;9(11):e111153 - PubMed
  49. Cancer Discov. 2014 Jan;4(1):94-109 - PubMed
  50. Nat Genet. 2014 May;46(5):482-6 - PubMed
  51. Epigenetics. 2010 May 16;5(4):352-63 - PubMed
  52. Lupus. 2014 May;23(6):568-76 - PubMed
  53. J Clin Pathol. 2014 Sep;67(9):772-6 - PubMed
  54. Pigment Cell Melanoma Res. 2008 Oct;21(5):509-16 - PubMed
  55. Genes Dev. 2013 Apr 15;27(8):836-52 - PubMed
  56. Cell. 2012 Sep 14;150(6):1135-46 - PubMed
  57. Pigment Cell Melanoma Res. 2014 Jul;27(4):653-63 - PubMed
  58. Hematol Oncol Clin North Am. 2014 Jun;28(3):437-53 - PubMed
  59. Nat Commun. 2014 Apr 08;5:3630 - PubMed
  60. Cancer Cell. 2014 Nov 10;26(5):603-4 - PubMed
  61. Br J Cancer. 2004 Jul 19;91(2):355-8 - PubMed
  62. N Engl J Med. 2012 Nov;367 (18):1694-703 - PubMed
  63. J Natl Cancer Inst. 2014 Feb;106(2):djt443 - PubMed
  64. Protein Cell. 2014 Apr;5(4):265-96 - PubMed

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