Editors’ Pick in May 2025

Clinical and genetic overview of neurofibromatosis type 2 (NF2) [3]

NF2 is a life-threatening disorder which manifests various symptoms according to the patient’s age and location of central nervous system tumors. It is characterized by bilateral vestibular schwannomas (VS), meningioma, non-VS and spinal ependymomas. It is caused by the pathogenic variant of the NF2 tumor suppressor gene on chromosome 22q12 (OMIM 101000). The term “NF2” is now updated as “NF2-related schwannomatosis” according to the new criteria updated in 2022 [4]. “Schwannomatosis (SWN)” became an umbrella term for conditions that predispose to schwannomas.

The diagnostic criteria for NF2 have been regularly revised to distinguish NF2 from other neurofibromatosis syndromes; neurofibromatosis type 1 (NF1) and SWN. The most widely used criteria were the revised Manchester criteria published in 2019, however, it was still difficult for clinicians to separate NF2 from other SWN with these criteria because of the overlapping clinical features, such as development of both VS and meningiomas. An international panel of experts have updated the diagnostic criteria of NF2 in 2022 and revised the terminology to “NF2-related schwannomatosis”. Incorporation of genetic criteria to supplement clinical criteria has been made to help standardize the diagnosis process.

The NF2 gene was identified in 1993 revealing 17 exons on chromosome 22q12 which encoded for a protein called merlin (moesin-ezrin-radixin-like protein) or schwannomin. Merlin is a protein product similar to the ERM (ezrin, radixin, moesin) protein family members and regulates cell proliferation and functions in cell-to-cell adhesion and transmembrane signaling.

The first step of genetics testing for NF2 and SWN is done for pathogenic variants in NF2, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) and leucine zipper-like transcription regulator 1 (LZTR1) are tested from unaffected tissues such as blood or saliva. Results with heterozygous pathogenic variants in each gene with clinical features are classified as full NF2-, SMARCB1-, or LZTR1-related SWN. Mosaic NF2-, SMARCB1-, or LZTR1-related SWN will be diagnosed when the pathogenic variants in each gene exhibit a variant allele fraction clearly less than 50% with clinical features.

This article describes the overview of NF2, revised diagnostic criteria and genetic basis. It is helpful in providing updated information on terminology, diagnosis and involved genes and their clinical significance.

Germline variants in pediatric cancer : based on oncogenic pathways [2]

Determining the pathogenicity of a certain germline variant is a dynamic process due to the growing and updated evidence in large genome databases. The majority of pathogenic germline variants (PGVs) causing cancer predisposing syndromes show an autosomal dominant inheritance pattern and involve mutations in tumor suppressor genes. A study investigating 871 PGVs revealed that 659 were found in 66 tumor suppressor genes, while 33 were found in five proto-oncogenes [1].

The role of PGVs in key oncogenic pathways, including RTK/RAS/MAPK, PI3K/AKT, WNT, and Hedgehog signaling, highlighting their associations with specific cancer predisposition syndromes and neurosurgical implications was reviewed. Germline variants in proto-oncogenes such as PTPN11, KRAS, and HRAS are associated with RASopathies, including Noonan and Costello syndromes, which show variable cancer risks.

Emerging evidence suggests that approximately 8.5–20% of pediatric cancer patients harbor PGVs, with a substantial proportion occurring de novo. Routine germline screening for pediatric cancer patients is increasingly recommended, as many PGVs lack family history. Due to the rarity of pediatric cancers and the need for personalized precision medicine, efforts to build comprehensive pediatric genome databases of tumor and germline data are actively ongoing on a nationwide basis in many countries. STREAM (Solid Tumor REsearch And Magic) was established in Korea 2023. It includes 1) integrated genomic analysis: whole-genome, transcriptome, and methylome sequencing of tumor tissue along with matched germline sequencing, 2) high-throughput drug screening, and 3) multidisciplinary discussion at molecular tumor-board. The purpose of this program is to build a personalized, precision medicine platform that will enhance the diagnosis and treatment of pediatric solid tumor patients. With the expanding use of next generation sequencing and continuous updates to genome databases, the identification and clinical application of PGVs in cancer genomics are becoming increasingly important. Given the substantial proportion of de novo variants, paired germline sequencing should be adopted. The role of worldwide working groups is critical in advancing pediatric cancer research to establish sufficient genome database.

This article is significant in that it well explains the significance of PGV in pediatric tumors, the clinical significance of well-known genetic pathways, and the need for worldwide collaboration.