Coexistence of schwannomatosis and glioblastoma in two families
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.
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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.
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Both authors contributed equally to this work.