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open access

Vol 74, No 1 (2023)
Original paper
Submitted: 2022-12-16
Accepted: 2022-12-17
Published online: 2023-02-02
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Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas

Anna Skalniak1, Małgorzata Trofimiuk-Müldner1, Agata Jabrocka-Hybel1, Justyna Totoń-Żurańska2, Paweł Wołkow2, Alicja Hubalewska-Dydejczyk1
DOI: 10.5603/EP.a2023.0009
·
Pubmed: 36847722
·
Endokrynol Pol 2023;74(1):31-46.
Affiliations
  1. Chair and Department of Endocrinology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
  2. Center for Medical Genomics — OMICRON, Jagiellonian University Medical College, Krakow, Poland

open access

Vol 74, No 1 (2023)
Original Paper
Submitted: 2022-12-16
Accepted: 2022-12-17
Published online: 2023-02-02

Abstract

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a monogenic disease caused by inactivating variants in the MEN1 gene. Although the reason for its development is well-known, disease phenotypes are unpredictable and differ even among carriers of the same pathogenic driver mutation. Genetic, epigenetic, and environmental factors may play a role in driving the individual phenotype. Those factors, however, still mostly remain unidentified. In our work, we focused on the inherited genetic background in pancreatic neuroendocrine neoplasms (pNENs) in MEN1 patients, and the pancreatic tumour subgroup with insulinoma.

Material and methods: Whole exome sequencing was performed in MEN1 patients. The symptoms of interest were pancreatic neuroendocrine tumours in one analysis and insulinoma in the second. The study included families as well as unrelated cases. Genes with variants that are not neutral to the encoded gene product were defined in symptom-positive patients as compared to symptom-negative controls. The interpretation of the results was based on functional annotations and pathways shared between all patients with the given symptom in the course of MEN1.

Results: Whole-exome screening of family members and unrelated patients with and without pNENs revealed a number of pathways that are common for all the analysed cases with pNENs. Those included pathways crucial for morphogenesis and development, proper insulin signalling, and structural cellular organization. An additional analysis of insulinoma pNEN patients revealed additional pathways engaged in glucose and lipid homeostasis, and several non-canonical insulin-regulating mechanisms.

Conclusions: Our results show the existence of pathways that are identified in a non-literature-predefined manner, which might have a modifying function in MEN1, differentiating the specific clinical outcomes. Those results, although preliminary, provide evidence of the reasonableness of performing large-scale studies addressing the genetic background of MEN1 patients in determining their individual outcomes.

Abstract

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a monogenic disease caused by inactivating variants in the MEN1 gene. Although the reason for its development is well-known, disease phenotypes are unpredictable and differ even among carriers of the same pathogenic driver mutation. Genetic, epigenetic, and environmental factors may play a role in driving the individual phenotype. Those factors, however, still mostly remain unidentified. In our work, we focused on the inherited genetic background in pancreatic neuroendocrine neoplasms (pNENs) in MEN1 patients, and the pancreatic tumour subgroup with insulinoma.

Material and methods: Whole exome sequencing was performed in MEN1 patients. The symptoms of interest were pancreatic neuroendocrine tumours in one analysis and insulinoma in the second. The study included families as well as unrelated cases. Genes with variants that are not neutral to the encoded gene product were defined in symptom-positive patients as compared to symptom-negative controls. The interpretation of the results was based on functional annotations and pathways shared between all patients with the given symptom in the course of MEN1.

Results: Whole-exome screening of family members and unrelated patients with and without pNENs revealed a number of pathways that are common for all the analysed cases with pNENs. Those included pathways crucial for morphogenesis and development, proper insulin signalling, and structural cellular organization. An additional analysis of insulinoma pNEN patients revealed additional pathways engaged in glucose and lipid homeostasis, and several non-canonical insulin-regulating mechanisms.

Conclusions: Our results show the existence of pathways that are identified in a non-literature-predefined manner, which might have a modifying function in MEN1, differentiating the specific clinical outcomes. Those results, although preliminary, provide evidence of the reasonableness of performing large-scale studies addressing the genetic background of MEN1 patients in determining their individual outcomes.

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Keywords

multiple endocrine neoplasia type 1; neuroendocrine tumours; pancreatic neoplasms; insulinoma; modifier; genetic background; exome sequencing

About this article
Title

Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas

Journal

Endokrynologia Polska

Issue

Vol 74, No 1 (2023)

Article type

Original paper

Pages

31-46

Published online

2023-02-02

Page views

2907

Article views/downloads

530

DOI

10.5603/EP.a2023.0009

Pubmed

36847722

Bibliographic record

Endokrynol Pol 2023;74(1):31-46.

Keywords

multiple endocrine neoplasia type 1
neuroendocrine tumours
pancreatic neoplasms
insulinoma
modifier
genetic background
exome sequencing

Authors

Anna Skalniak
Małgorzata Trofimiuk-Müldner
Agata Jabrocka-Hybel
Justyna Totoń-Żurańska
Paweł Wołkow
Alicja Hubalewska-Dydejczyk

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