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Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma

Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53...

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Autores principales: Nordfors, Kristiina, Haapasalo, Joonas, Afyounian, Ebrahim, Tuominen, Joonas, Annala, Matti, Häyrynen, Sergei, Karhu, Ritva, Helén, Pauli, Lohi, Olli, Nykter, Matti, Haapasalo, Hannu, Granberg, Kirsi J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880256/
https://www.ncbi.nlm.nih.gov/pubmed/29602769
http://dx.doi.org/10.1101/mcs.a002246
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author Nordfors, Kristiina
Haapasalo, Joonas
Afyounian, Ebrahim
Tuominen, Joonas
Annala, Matti
Häyrynen, Sergei
Karhu, Ritva
Helén, Pauli
Lohi, Olli
Nykter, Matti
Haapasalo, Hannu
Granberg, Kirsi J.
author_facet Nordfors, Kristiina
Haapasalo, Joonas
Afyounian, Ebrahim
Tuominen, Joonas
Annala, Matti
Häyrynen, Sergei
Karhu, Ritva
Helén, Pauli
Lohi, Olli
Nykter, Matti
Haapasalo, Hannu
Granberg, Kirsi J.
author_sort Nordfors, Kristiina
collection PubMed
description Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with the loss of ATRX protein expression. In the astrocytoma case, R132C missense mutation was found in the known hotspot site in isocitrate dehydrogenase 1 (IDH1) and LOH was detected in TP53. The mother carried few other somatic alterations, suggesting that the IDH1 mutation and LOH in TP53 were sufficient to drive tumor development. The genome in the AT/RT tumor was atypically aneuploid: Most chromosomes had experienced copy-neutral LOH or whole-chromosome gains. Only Chromosome 18 had normal diploid status. INI1/hSNF5/SMARCB1 was homozygously deleted in the AT/RT tumor. This report provides further information about tumor development in a predisposed genetic background and describes two special Li–Fraumeni cases with a familial brain tumor.
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spelling pubmed-58802562018-04-13 Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma Nordfors, Kristiina Haapasalo, Joonas Afyounian, Ebrahim Tuominen, Joonas Annala, Matti Häyrynen, Sergei Karhu, Ritva Helén, Pauli Lohi, Olli Nykter, Matti Haapasalo, Hannu Granberg, Kirsi J. Cold Spring Harb Mol Case Stud Research Article Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with the loss of ATRX protein expression. In the astrocytoma case, R132C missense mutation was found in the known hotspot site in isocitrate dehydrogenase 1 (IDH1) and LOH was detected in TP53. The mother carried few other somatic alterations, suggesting that the IDH1 mutation and LOH in TP53 were sufficient to drive tumor development. The genome in the AT/RT tumor was atypically aneuploid: Most chromosomes had experienced copy-neutral LOH or whole-chromosome gains. Only Chromosome 18 had normal diploid status. INI1/hSNF5/SMARCB1 was homozygously deleted in the AT/RT tumor. This report provides further information about tumor development in a predisposed genetic background and describes two special Li–Fraumeni cases with a familial brain tumor. Cold Spring Harbor Laboratory Press 2018-04 /pmc/articles/PMC5880256/ /pubmed/29602769 http://dx.doi.org/10.1101/mcs.a002246 Text en © 2018 Nordfors et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Article
Nordfors, Kristiina
Haapasalo, Joonas
Afyounian, Ebrahim
Tuominen, Joonas
Annala, Matti
Häyrynen, Sergei
Karhu, Ritva
Helén, Pauli
Lohi, Olli
Nykter, Matti
Haapasalo, Hannu
Granberg, Kirsi J.
Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
title Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
title_full Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
title_fullStr Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
title_full_unstemmed Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
title_short Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma
title_sort whole-exome sequencing identifies germline mutation in tp53 and atrx in a child with genomically aberrant at/rt and her mother with anaplastic astrocytoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880256/
https://www.ncbi.nlm.nih.gov/pubmed/29602769
http://dx.doi.org/10.1101/mcs.a002246
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