DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

E. B. Conemans; L. Lodewijk; C. B. Moelans; G. J. A. Offerhaus; C. R. C. Pieterman; F. H. Morsink; O. M. Dekkers; W. W. de Herder; A. R. Hermus; A. N. van der Horst-Schrivers; M. L. Drent; P. H. Bisschop; B. Havekes; L. A. A. Brosens; K. M. A. Dreijerink; I. H. M. Borel Rinkes; H. Th M. Timmers; G. D. Valk; M. R. Vriens

doi:10.1530/EJE-18-0195

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

E. B. Conemans, L. Lodewijk, C. B. Moelans, G. J. A. Offerhaus, C. R. C. Pieterman, F. H. Morsink, O. M. Dekkers, W. W. de Herder, A. R. Hermus, A. N. van der Horst-Schrivers, M. L. Drent, P. H. Bisschop, B. Havekes, L. A. A. Brosens, K. M. A. Dreijerink, I. H. M. Borel Rinkes, H. Th M. Timmers, G. D. Valk, M. R. Vriens^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Objective: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. Design and methods: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN 1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. Results: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876. P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002), In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. Conclusion: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Original language	English
Pages (from-to)	153-160
Number of pages	8
Journal	European Journal of Endocrinology
Volume	179
Issue number	3
DOIs	https://doi.org/10.1530/EJE-18-0195
Publication status	Published - 1 Sept 2018

Keywords

PROMOTER HYPERMETHYLATION
CANCER
MENIN
EXPRESSION
GENES
HEREDITARY
PATHOLOGY
MUTATION
PATHWAY
MGMT

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10.1530/EJE-18-0195

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Conemans, E. B., Lodewijk, L., Moelans, C. B., Offerhaus, G. J. A., Pieterman, C. R. C., Morsink, F. H., Dekkers, O. M., de Herder, W. W., Hermus, A. R., van der Horst-Schrivers, A. N., Drent, M. L., Bisschop, P. H., Havekes, B., Brosens, L. A. A., Dreijerink, K. M. A., Rinkes, I. H. M. B., Timmers, H. T. M., Valk, G. D., & Vriens, M. R. (2018). DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment. European Journal of Endocrinology, 179(3), 153-160. https://doi.org/10.1530/EJE-18-0195

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title = "DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment",

abstract = "Objective: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. Design and methods: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN 1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. Results: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876. P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002), In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. Conclusion: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.",

keywords = "PROMOTER HYPERMETHYLATION, CANCER, MENIN, EXPRESSION, GENES, HEREDITARY, PATHOLOGY, MUTATION, PATHWAY, MGMT",

author = "Conemans, {E. B.} and L. Lodewijk and Moelans, {C. B.} and Offerhaus, {G. J. A.} and Pieterman, {C. R. C.} and Morsink, {F. H.} and Dekkers, {O. M.} and {de Herder}, {W. W.} and Hermus, {A. R.} and {van der Horst-Schrivers}, {A. N.} and Drent, {M. L.} and Bisschop, {P. H.} and B. Havekes and Brosens, {L. A. A.} and Dreijerink, {K. M. A.} and Rinkes, {I. H. M. Borel} and Timmers, {H. Th M.} and Valk, {G. D.} and Vriens, {M. R.}",

year = "2018",

month = sep,

day = "1",

doi = "10.1530/EJE-18-0195",

language = "English",

volume = "179",

pages = "153--160",

journal = "European Journal of Endocrinology",

issn = "0804-4643",

publisher = "BioScientifica Ltd.",

number = "3",

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Conemans, EB, Lodewijk, L, Moelans, CB, Offerhaus, GJA, Pieterman, CRC, Morsink, FH, Dekkers, OM, de Herder, WW, Hermus, AR, van der Horst-Schrivers, AN, Drent, ML, Bisschop, PH, Havekes, B, Brosens, LAA, Dreijerink, KMA, Rinkes, IHMB, Timmers, HTM, Valk, GD & Vriens, MR 2018, 'DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment', European Journal of Endocrinology, vol. 179, no. 3, pp. 153-160. https://doi.org/10.1530/EJE-18-0195

TY - JOUR

T1 - DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

AU - Conemans, E. B.

AU - Lodewijk, L.

AU - Moelans, C. B.

AU - Offerhaus, G. J. A.

AU - Pieterman, C. R. C.

AU - Morsink, F. H.

AU - Dekkers, O. M.

AU - de Herder, W. W.

AU - Hermus, A. R.

AU - van der Horst-Schrivers, A. N.

AU - Drent, M. L.

AU - Bisschop, P. H.

AU - Havekes, B.

AU - Brosens, L. A. A.

AU - Dreijerink, K. M. A.

AU - Rinkes, I. H. M. Borel

AU - Timmers, H. Th M.

AU - Valk, G. D.

AU - Vriens, M. R.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Objective: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. Design and methods: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN 1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. Results: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876. P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002), In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. Conclusion: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

AB - Objective: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. Design and methods: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN 1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. Results: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876. P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002), In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. Conclusion: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

KW - PROMOTER HYPERMETHYLATION

KW - CANCER

KW - MENIN

KW - EXPRESSION

KW - GENES

KW - HEREDITARY

KW - PATHOLOGY

KW - MUTATION

KW - PATHWAY

KW - MGMT

U2 - 10.1530/EJE-18-0195

DO - 10.1530/EJE-18-0195

M3 - Article

C2 - 29903750

SN - 0804-4643

VL - 179

SP - 153

EP - 160

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

IS - 3

ER -