Coexistence of schwannomatosis and glioblastoma in two families

https://doi.org/10.1016/j.ejmg.2019.103680Get rights and content

Abstract

Schwannomatosis is a rare affection predisposing to multiple peripheral neurologic tumors development. Approximatively, one third of patients with schwannomatosis are carriers of a germline mutation in LZTR1 (Leucin Zipper Transcription Regulator 1). Tumorigenesis in schwannomatosis responds to a somatic 5-hit/3-step mechanism resulting in a loss of function (LOF) of LZTR1 and the contiguous genes of locus 22q11.2q12.2. Effectively, LZTR1 is mapped on 22q11.2 and centromeric to SMARCB1 also implicated in the determinism of schwannomatosis and NF2, responsible for neurofibromatosis type 2. On a somatic point of view, LZTR1 mutations are known to drive with a significant frequency glioblastoma (GB) development. We report here two families in which segregate both multiple schwannomas and GB. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. Her father, having unremarkable medical history deceased from an apparently isolated GB at age 59. In the second family, LZTR1-related schwannomatosis was diagnosed in the index case at age 70 after multiple schwannomas surgeries. Her elder sister had no neurological medical history before occurrence of a lethal GB at age 78. Molecular analysis of GB sample from both affected relatives showed the presence of the familial mutation. These observations hypothesize a potential link between schwannomatosis and the GB development.

Introduction

Schwannomatosis (OMIM #162091) is a rare predisposition to develop multiple peripheral schwannomas. The diagnosis is based on clinical examination and molecular analysis (Table 1). Although mutations in SMARCB1 were first described (Hulsebos et al., 2007), loss of function (LOF) mutations in LZTR1 were recently incriminated (Piotrowski et al., 2014; Paganini et al., 2015). Germline SMARCB1 mutations account for 48% of familial and 9.8% of sporadic cases and germline LZTR1 mutations are found in approximately 38% of familial and 22–30% of sporadic SMARCB1-negative cases (Kehrer-Sawatzki et al., 2017). Tumorigenesis in schwannomatosis responds to a somatic 5-hit/3-step mechanism resulting in a loss of function (LOF) of LZTR1 and of the contiguous genes of locus 22q11.2q12.2, SMARCB1 and NF2, implicated in neurofibromatosis type 2.

Moreover, somatic mutations and biallelic inactivation of LZTR1 are identified in 22% of sporadic GB, LZTR1 loss driving immortalization and proliferation of cells, and acting thus as a classical tumor suppressor gene (Frattini et al., 2013).

We describe two non-related families in which germline LZTR1 mutations were found in a proband displaying schwannomatosis. In each family, the LZTR1 mutations was also identified at a somatic level in an isolated glioblastoma of a relative.

Section snippets

Patients and samples

Blood samples were obtained from index cases after accurate information and signed consent in accordance with law of bioethics n°2004-800 of 06.08.2004, revised 7. July 2011. DNA was isolated from peripheral blood leucocytes using standard procedures. Genetic analysis of tumor samples was assessed after information and consent of living relatives. DNA extraction of GB samples conserved in paraffin block (FFPE, formalin-fixed, paraffin-embedded tissue) was performed with the Maxwell® 16 FFPE

Family 1

The proband was a 43-year-old woman referred to our genetic department after surgery of a lumbar schwannoma. She suffered from atypical left sciatica for several years. Medullar MRI showed a schwannoma at L2 level. Her personal history was marked by removal of a schwannoma in her left arm at age 18. Her father (Fig. 1), after uneventful medical history, presented at age 59 a mild progressive right hemiparesia associated with one right facial motor partial seizure that led to discover a left

Discussion

LZTR1 is a tumor suppressor gene. LZTR1 is highly conserved throughout evolution and contains two functional domains with a kelch-BTB-BACK-BTB-BACK motive. The BTB domains of the protein interact with the cullin 3 (CUL3)-RING ubiquitin ligase (CRL3) complex, a multi-subunit RING-class E3 ligase involved in protein mono- and poly-ubiquitination (Frattini et al., 2013; Zimmerman et al., 2010). It has been recently shown that LZTR1 binds substrates including RAS via the tandemly repeated Kelch

Acknowledgments

We thank the patients and their families.

We thank the Biological Resources Center, Tumorothèque, Hôpital Cochin, Paris, France for DNA extraction from FFPE samples.

References (14)

There are more references available in the full text version of this article.

Cited by (8)

View all citing articles on Scopus
1

Both authors contributed equally to this work.

View full text