Neuro-Oncology Shanghai Jiaotong University Professor Wu Hao's team discovered a new mechanism for the development and development of auditory nerve tumors in NF2 patients

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iNature neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease, which is mainly manifested by bilateral auditory nerve tumors.
The onset age is early.
Disabling symptoms such as bilateral deafness may appear in adolescents, and the quality of life is poor.
Lack of effective treatment
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The biallelic inactivation of NF2 based on the "twice hit" theory is the main cause of acoustic neuroma tumor formation in NF2 patients
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However, the molecular mechanism of the "second hit" of NF2 tumors is still unclear
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On December 16, 2021, the internationally renowned academic journal Neuro-Oncology (IF=12) published online the "Origins of biallelic inactivation of NF2 in Neurofibromatosis Type 2" from the team of Professor Wu Hao, the Ninth People's Hospital of Shanghai Jiaotong University School of Medicine
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In this study, comprehensive genomic analysis was performed on tumor samples and paired blood samples of NF2 patients, and the correlation analysis between gene phenotype and clinical phenotype was performed, and the neurofibromatosis type 2 NF2 biallelic loss was calculated through deep learning methods.
The process of living, verified the "second hit theory" of NF2, proposed for the first time that the biallelic inactivation of NF2 was driven by neutral evolution, and determined the effect of the "first hit" of pre-existing NF2 alleles The mechanism that determines its clinical phenotype provides theoretical guidance for the clinical treatment decision of this rare disease
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Neurofibromatosis type 2 (neurofibromatosis type Ⅱ, NF2) is an autosomal dominant tumor syndrome
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The pathogenic gene is the NF2 gene (MIM: #101000), which is located on chromosome 22q12.
2.
The protein merlin encoded by the NF2 gene is a tumor suppressor protein
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Its characteristic manifestation is multiple non-invasive nerve sheath tumors derived from neural crest cells, and the common typical feature is bilateral acoustic neuromas
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Some affected individuals may further develop other cranial nerve and peripheral nerve sheath tumors, and some patients may also develop symptoms that cause eye dysfunction (such as lens opacity) and retinal hamartoma
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Any treatment method for NF2 disease or the disease itself will expose the patient to life-threatening complications and the risk of severe central system dysfunction.
Because of the complexity and diversity of its pathogenesis and clinical phenotype, there is no system yet.
Sexual treatment strategies and no cure
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The usual treatment strategy is follow-up observation and symptomatic treatment, which is especially reflected in newly diagnosed patients
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And this passive treatment strategy may cause patients to miss the narrow window of time to preserve and/or rebuild hearing
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Through family linkage and tumor detection, the NF2 gene is the only gene found to be related to NF2, and the gene is inherited in an autosomal dominant manner
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Evidence from molecular genetic studies shows that biallelic inactivation of NF2 based on the "second hit" theory is the main cause of acoustic neuroma tumor formation in NF2 patients
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However, the molecular mechanism of the "second hit" of NF2 tumors is still unclear
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Professor Wu Hao’s team found in the previous study that the occurrence and development of acoustic neuroma may be related to NF2 gene mutations (respectively published in EBioMedicine 2018, Genet Med 2014).
Similar clinical characteristics can be found in the same NF2 family, such as tumor distribution and growth.
Speed, etc.
, and its severity is enhanced in the offspring, such as the age of onset; and NF2 has huge differences in different families
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The study also found that patients with different NF2 mutations have significantly different clinical characteristics
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These results indicate that NF2 genotype may be one of the important reasons that affect the clinical biological characteristics of tumors, and genetic research may play a role in predicting the development and outcome of the disease, and provide a theoretical basis for clinical diagnosis and treatment strategies
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In order to further study the mechanism of NF2 gene "two hits" in the process of tumorigenesis, comprehensive genomic analysis was performed on tumor samples and paired blood samples of NF2 patients through targeted capture, and their genotypes and clinical phenotypes were analyzed.
Relevance analysis
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The results of the study indicate that the "first hit" of NF2 may be related to certain clinical phenotypes: for example, the variant allele frequency (VAF) of NF2 may be linearly negatively correlated with the incubation period of the disease/age of onset; and the null mutation (Null Mutation) Hypomorphic mutations often show an earlier age of onset
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Atypical NF2 patients may be associated with germline mutations in homologous recombination repair (HRR) related genes.
As for NF2 genes, they are low-abundance chimeric mutations rather than germline mutations, indicating that this clinical subtype is actually other cancers The performance of susceptible syndrome should be treated from different perspectives
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In addition, the researchers calculated the relative time of the occurrence of clones and found that there were independent "second hits" in the same patient, and the times of their clones were all random, indicating that the "second hit" events were not caused by pre-existing events.
The mutation (ie, the "first hit") selected; and the relative occurrence time of the "second hit" in the clone exists in the first 10%
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Therefore, biallelic inactivation of NF2 occurs through neutral evolution
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Professor Wu Hao, Professor Wang Zhaoyan, and Associate Professor Jiang Gu from the Ninth People’s Hospital of Shanghai Jiaotong University School of Medicine are the corresponding authors of the paper; Dr.
Xue Lu, Dr.
He Weiwei, and Dr.
Zhang Yi are the co-first authors
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Professor Wu Hao’s team has long been committed to clinical diagnosis and treatment strategies for acoustic neuroma and tumor growth mechanism research, and has won the second prize of the National Science and Technology Progress Award
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This research has opened up new research directions for neurofibromatosis type 2 gene clinical phenotype correlation analysis, tumor prediction model construction, and NF2 gene therapy
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Reference message: https://academic.
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