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A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors

The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequen...

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Autores principales: Dumanski, Jan P, Rasi, Chiara, Björklund, Peyman, Davies, Hanna, Ali, Abir S, Grönberg, Malin, Welin, Staffan, Sorbye, Halfdan, Grønbæk, Henning, Cunningham, Janet L, Forsberg, Lars A, Lind, Lars, Ingelsson, Erik, Stålberg, Peter, Hellman, Per, Tiensuu Janson, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527373/
https://www.ncbi.nlm.nih.gov/pubmed/28634180
http://dx.doi.org/10.1530/ERC-17-0196
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author Dumanski, Jan P
Rasi, Chiara
Björklund, Peyman
Davies, Hanna
Ali, Abir S
Grönberg, Malin
Welin, Staffan
Sorbye, Halfdan
Grønbæk, Henning
Cunningham, Janet L
Forsberg, Lars A
Lind, Lars
Ingelsson, Erik
Stålberg, Peter
Hellman, Per
Tiensuu Janson, Eva
author_facet Dumanski, Jan P
Rasi, Chiara
Björklund, Peyman
Davies, Hanna
Ali, Abir S
Grönberg, Malin
Welin, Staffan
Sorbye, Halfdan
Grønbæk, Henning
Cunningham, Janet L
Forsberg, Lars A
Lind, Lars
Ingelsson, Erik
Stålberg, Peter
Hellman, Per
Tiensuu Janson, Eva
author_sort Dumanski, Jan P
collection PubMed
description The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56–14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.
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spelling pubmed-55273732017-07-31 A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors Dumanski, Jan P Rasi, Chiara Björklund, Peyman Davies, Hanna Ali, Abir S Grönberg, Malin Welin, Staffan Sorbye, Halfdan Grønbæk, Henning Cunningham, Janet L Forsberg, Lars A Lind, Lars Ingelsson, Erik Stålberg, Peter Hellman, Per Tiensuu Janson, Eva Endocr Relat Cancer Research The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56–14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs. Bioscientifica Ltd 2017-06-20 /pmc/articles/PMC5527373/ /pubmed/28634180 http://dx.doi.org/10.1530/ERC-17-0196 Text en © 2017 The authors http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Dumanski, Jan P
Rasi, Chiara
Björklund, Peyman
Davies, Hanna
Ali, Abir S
Grönberg, Malin
Welin, Staffan
Sorbye, Halfdan
Grønbæk, Henning
Cunningham, Janet L
Forsberg, Lars A
Lind, Lars
Ingelsson, Erik
Stålberg, Peter
Hellman, Per
Tiensuu Janson, Eva
A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
title A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
title_full A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
title_fullStr A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
title_full_unstemmed A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
title_short A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
title_sort mutyh germline mutation is associated with small intestinal neuroendocrine tumors
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527373/
https://www.ncbi.nlm.nih.gov/pubmed/28634180
http://dx.doi.org/10.1530/ERC-17-0196
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