Cargando…
Somatic mutations in intracranial arteriovenous malformations
BACKGROUND: Intracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938308/ https://www.ncbi.nlm.nih.gov/pubmed/31891627 http://dx.doi.org/10.1371/journal.pone.0226852 |
_version_ | 1783484011946967040 |
---|---|
author | Goss, Jeremy A. Huang, August Y. Smith, Edward Konczyk, Dennis J. Smits, Patrick J. Sudduth, Christopher L. Stapleton, Christopher Patel, Aman Alexandrescu, Sanda Warman, Matthew L. Greene, Arin K. |
author_facet | Goss, Jeremy A. Huang, August Y. Smith, Edward Konczyk, Dennis J. Smits, Patrick J. Sudduth, Christopher L. Stapleton, Christopher Patel, Aman Alexandrescu, Sanda Warman, Matthew L. Greene, Arin K. |
author_sort | Goss, Jeremy A. |
collection | PubMed |
description | BACKGROUND: Intracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with brain AVM and to determine if any genotype-phenotype associations exist. METHODS: Human brain AVM specimens (n = 16) were collected during a clinically-indicated procedure and subjected to multiplex targeted sequencing using molecular inversion probe (MIP-seq) for mutations in KRAS, BRAF, HRAS, NRAS, and MAP2K1. Endothelial cells (ECs) were separated from non-ECs by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations and to screen for mutations that may have been missed by MIP-seq. Patient and AVM characteristics were recorded. RESULTS: We detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting symptom, AVM location, or AVM size between patients with a confirmed mutation and those without. Nor did we observe differences in these features between patients with KRAS or BRAF mutations. However, two patients with BRAF mutations presented at an older age than other study participants. CONCLUSIONS: Somatic mutations in KRAS and, less commonly in BRAF, are found in many but not all intracranial AVM samples. Currently, there are no obvious genotype-phenotype correlations that can be used to predict whether a somatic mutation will be detected and, if so, which gene will be mutated. |
format | Online Article Text |
id | pubmed-6938308 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-69383082020-01-07 Somatic mutations in intracranial arteriovenous malformations Goss, Jeremy A. Huang, August Y. Smith, Edward Konczyk, Dennis J. Smits, Patrick J. Sudduth, Christopher L. Stapleton, Christopher Patel, Aman Alexandrescu, Sanda Warman, Matthew L. Greene, Arin K. PLoS One Research Article BACKGROUND: Intracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with brain AVM and to determine if any genotype-phenotype associations exist. METHODS: Human brain AVM specimens (n = 16) were collected during a clinically-indicated procedure and subjected to multiplex targeted sequencing using molecular inversion probe (MIP-seq) for mutations in KRAS, BRAF, HRAS, NRAS, and MAP2K1. Endothelial cells (ECs) were separated from non-ECs by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations and to screen for mutations that may have been missed by MIP-seq. Patient and AVM characteristics were recorded. RESULTS: We detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting symptom, AVM location, or AVM size between patients with a confirmed mutation and those without. Nor did we observe differences in these features between patients with KRAS or BRAF mutations. However, two patients with BRAF mutations presented at an older age than other study participants. CONCLUSIONS: Somatic mutations in KRAS and, less commonly in BRAF, are found in many but not all intracranial AVM samples. Currently, there are no obvious genotype-phenotype correlations that can be used to predict whether a somatic mutation will be detected and, if so, which gene will be mutated. Public Library of Science 2019-12-31 /pmc/articles/PMC6938308/ /pubmed/31891627 http://dx.doi.org/10.1371/journal.pone.0226852 Text en © 2019 Goss et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Goss, Jeremy A. Huang, August Y. Smith, Edward Konczyk, Dennis J. Smits, Patrick J. Sudduth, Christopher L. Stapleton, Christopher Patel, Aman Alexandrescu, Sanda Warman, Matthew L. Greene, Arin K. Somatic mutations in intracranial arteriovenous malformations |
title | Somatic mutations in intracranial arteriovenous malformations |
title_full | Somatic mutations in intracranial arteriovenous malformations |
title_fullStr | Somatic mutations in intracranial arteriovenous malformations |
title_full_unstemmed | Somatic mutations in intracranial arteriovenous malformations |
title_short | Somatic mutations in intracranial arteriovenous malformations |
title_sort | somatic mutations in intracranial arteriovenous malformations |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938308/ https://www.ncbi.nlm.nih.gov/pubmed/31891627 http://dx.doi.org/10.1371/journal.pone.0226852 |
work_keys_str_mv | AT gossjeremya somaticmutationsinintracranialarteriovenousmalformations AT huangaugusty somaticmutationsinintracranialarteriovenousmalformations AT smithedward somaticmutationsinintracranialarteriovenousmalformations AT konczykdennisj somaticmutationsinintracranialarteriovenousmalformations AT smitspatrickj somaticmutationsinintracranialarteriovenousmalformations AT sudduthchristopherl somaticmutationsinintracranialarteriovenousmalformations AT stapletonchristopher somaticmutationsinintracranialarteriovenousmalformations AT patelaman somaticmutationsinintracranialarteriovenousmalformations AT alexandrescusanda somaticmutationsinintracranialarteriovenousmalformations AT warmanmatthewl somaticmutationsinintracranialarteriovenousmalformations AT greenearink somaticmutationsinintracranialarteriovenousmalformations |