Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis.
Neuro-Oncology. 2018-02-02; 20(7): 917-929
DOI: 10.1093/neuonc/noy009
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1. Neuro Oncol. 2018 Jun 18;20(7):917-929. doi: 10.1093/neuonc/noy009.
Targeted next-generation sequencing for differential diagnosis of
neurofibromatosis type 2, schwannomatosis, and meningiomatosis.
Louvrier C(1), Pasmant E(1)(2), Briand-Suleau A(1)(2), Cohen J(1), Nitschké P(3),
Nectoux J(1), Orhant L(1), Zordan C(4), Goizet C(2)(5), Goutagny S(6), Lallemand
D(2), Vidaud M(1)(2), Vidaud D(1)(2), Kalamarides M(7), Parfait B(1)(2).
Author information:
(1)Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Assistance
Publique-Hôpitaux de Paris, Paris, France.
(2)Université Paris Descartes-Sorbonne, Paris Cité, Faculté de Pharmacie de
Paris, Paris, France.
(3)Bioinformatic Platform, INSERM UMR 1163, Université Paris Descartes-Sorbonne,
Paris Cité, Imagine Institute, Paris, France.
(4)Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux, Bordeaux,
France.
(5)Laboratoire MRGM, INSERM U1211, Université Bordeaux, Bordeaux, France.
(6)Service de Neurochirurgie, Hôpital Beaujon, Assistance Publique-Hôpitaux de
Paris, Clichy, France.
(7)Service de Neurochirurgie, Hôpital Pitié Salpêtrière, Assistance
Publique-Hôpitaux de Paris, Paris, France.
Background: Clinical overlap between neurofibromatosis type 2 (NF2),
schwannomatosis, and meningiomatosis can make clinical diagnosis difficult.
Hence, molecular investigation of germline and tumor tissues may improve the
diagnosis.
Methods: We present the targeted next-generation sequencing (NGS) of NF2,
SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon-based
approach. We analyzed blood DNA from a cohort of 196 patients, including patients
with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no
clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when
available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27
NF2-negative meningiomatosis patients were also evaluated.
Results: A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1
variants were identified in 5/40 (12.5%) and 13/40 (∼32%) patients in the
schwannomatosis cohort. Potentially pathogenic variants were found in 12/65
(18.5%) patients with no clearly established diagnosis. A LZTR1 variant was
identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A
SMARCE1 variant was found in 3/39 (∼8%) meningiomatosis patients. No SUFU variant
was found in the cohort. NGS was an effective and sensitive method to detect
mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we
identified a 4-hit mechanism resulting in the complete NF2 loss-of-function
combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from
NF2 patients.
Conclusions: Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a
key element in the differential diagnosis of NF2, schwannomatosis, and
meningiomatosis. The targeted NGS strategy is suitable for the identification of
NF2 mosaicism in blood and for the investigation of tumors from these patients.
DOI: 10.1093/neuonc/noy009
PMCID: PMC6007397
PMID: 29409008 [Indexed for MEDLINE]