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Am J Pathol. 2014 Sep;184(9):2374-81. doi: 10.1016/j.ajpath.2014.05.017. Epub 2014 Jul 18.

TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors.

Author information

1
Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France; Translational Epidemiology Research Branch, National Cancer Center, Goyang, Republic of Korea.
2
Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France.
3
Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
4
Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University Frankfurt, Frankfurt/Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Medical Faculty, University of Zürich, Zürich, Switzerland.
6
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
7
Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France. Electronic address: ohgaki@iarc.fr.

Abstract

Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53 germline mutation who developed peripheral schwannomas also carried the MSH4 germline mutation, and in addition, a germline mutation of the LATS1 gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1 gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4 mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53 and LATS1 germline mutations.

PMID:
25041856
DOI:
10.1016/j.ajpath.2014.05.017
[Indexed for MEDLINE]

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