<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis
DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered t...
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doaj-7d010980eb41452c8517d4135ef1c33c2020-11-25T03:20:14ZengMDPI AGCancers2072-66942020-06-01121461146110.3390/cancers12061461<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different PrognosisGitta Boons0Timon Vandamme1Joe Ibrahim2Geert Roeyen3Ann Driessen4Dieter Peeters5Ben Lawrence6Cristin Print7Marc Peeters8Guy Van Camp9Ken Op de Beeck10Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, BelgiumCenter for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, BelgiumCenter for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, BelgiumDepartment of Hepatobiliary, Endocrine and Transplantation Surgery, Antwerp University Hospital, 2650 Edegem, BelgiumDepartment of Pathology, Antwerp University Hospital and University of Antwerp, 2650 Edegem, BelgiumHistopathology, Imaging and Quantification Unit, HistoGeneX, 2610 Antwerp, BelgiumDiscipline of Oncology, Faculty of Medicine and Health Sciences, University of Auckland, Auckland 1023, New ZealandMaurice Wilkins Centre Hosted by the University of Auckland, Auckland 1023, New ZealandCenter for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, BelgiumCenter for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, BelgiumCenter for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, BelgiumDNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the <i>PDX1</i> region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the <i>PDX1</i> methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], <i>p</i> = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the <i>PDX1</i> methylation status for the subtyping of PNENs and its prognostic importance.https://www.mdpi.com/2072-6694/12/6/1461pancreatic neuroendocrine neoplasmsDNA methylationPDX1subtypescell-of-originprognosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gitta Boons Timon Vandamme Joe Ibrahim Geert Roeyen Ann Driessen Dieter Peeters Ben Lawrence Cristin Print Marc Peeters Guy Van Camp Ken Op de Beeck |
spellingShingle |
Gitta Boons Timon Vandamme Joe Ibrahim Geert Roeyen Ann Driessen Dieter Peeters Ben Lawrence Cristin Print Marc Peeters Guy Van Camp Ken Op de Beeck <i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis Cancers pancreatic neuroendocrine neoplasms DNA methylation PDX1 subtypes cell-of-origin prognosis |
author_facet |
Gitta Boons Timon Vandamme Joe Ibrahim Geert Roeyen Ann Driessen Dieter Peeters Ben Lawrence Cristin Print Marc Peeters Guy Van Camp Ken Op de Beeck |
author_sort |
Gitta Boons |
title |
<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis |
title_short |
<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis |
title_full |
<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis |
title_fullStr |
<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis |
title_full_unstemmed |
<i>PDX1</i> DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis |
title_sort |
<i>pdx1</i> dna methylation distinguishes two subtypes of pancreatic neuroendocrine neoplasms with a different prognosis |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-06-01 |
description |
DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the <i>PDX1</i> region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the <i>PDX1</i> methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], <i>p</i> = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the <i>PDX1</i> methylation status for the subtyping of PNENs and its prognostic importance. |
topic |
pancreatic neuroendocrine neoplasms DNA methylation PDX1 subtypes cell-of-origin prognosis |
url |
https://www.mdpi.com/2072-6694/12/6/1461 |
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