Recurrent Tumor-Specific Alternately Processed Transcripts as a Source of Neoantigens for NF1-associated Malignant Peripheral Nerve Sheath Tumor Immunoprevention

复发性肿瘤特异性交替加工转录本作为 NF1 相关恶性周围神经鞘肿瘤免疫预防的新抗原来源

• 批准号: 10488079
• 负责人: DAVID ANDREW LARGAESPADA
• 金额: $ 60.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488079
• 关键词: Alleles; Amino Acid Sequence; Benign; CDKN2A gene; Cause of Death; Cell Line; Chimera organism; Code; Codon Nucleotides; Dangerousness; Data; Development; Drug usage; Excision; Exons; Frameshift Mutation; Genes; Genetic Transcription; Grant; Human; Immune Targeting; Immune response; Immune system; Immunization; Immunoprecipitation; Immunoprevention; Introns; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Mus; Mutation; NF1 gene; Neoplasm Metastasis; Nerve; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; Patients; Peptide Vaccines; Peptides; Peripheral Nerve Sheath Neoplasm; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plexiform Neurofibroma; Predisposition; Preventative vaccination; Prevention; Preventive vaccine; Process; Production; Public Health; RNA Splicing; Radiation therapy; Recurrence; Recurrent tumor; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Schwann Cells; Site; Soft tissue sarcoma; Source; Surgical margins; Survival Rate; Syndrome; Terminator Codon; Transcript; Translating; Tumor Cell Line; Tumor Tissue; Vaccinee; Vaccines; Variant; cancer predisposition; chemoradiation; chemotherapy; dermal neurofibroma; design; lifetime risk; loss of function mutation; mouse model; neoantigens; neurofibroma; novel; premalignant; premature; prevent; prophylactic; transcriptome; transcriptome sequencing; tumor

Abstract/Summary Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant tumor predisposition syndrome that is caused by loss-of-function mutations of NF1 gene encoding neurofibromin. Among patients with NF1, loss of the non-mutant allele of NF1 in a rare Schwann cell or precursor, along with other ill-defined factors, leads to benign dermal or plexiform neurofibromas. The main cause of death among NF1 patients is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that most likely develops from plexiform neurofibroma, in particular the so-called “atypical” plexiform neurofibroma. Approximately half of MPNSTs are NF1-associated, and NF1 patients have 10-15% lifetime risk of developing this terrible cancer. MPNSTs metastasize early and are often resistant to radiotherapy and chemotherapy. The main treatment for MPNSTs is surgical resection but, despite radical excision with wide surgical margins, followed by chemoradiation, 5-year survival rates are poor due to metastases as well as local recurrence. NF1 patients could greatly benefit from prophylactic vaccination that would prevent the malignant transformation of benign plexiform neurofibromas into “atypical” plexiform neurofibromas and to MPNSTs. We aim to determine if the mutations that govern the development of “atypical” plexiform neurofibroma (NF1 loss followed by CDKN2A loss) and MPSNT (NF1, CDKN2A, and SUZ12 loss) lead to the expression of recurrent alternately processed transcripts, such as transcriptionally-induced chimeras, that could express neoantigens and be used as targets for prophylactic vaccines. Such transcripts can be translated to produce novel peptides downstream of frameshift mutations caused by coding exon read-through into introns, mis-splicing from a coding exon to a non-canonical splice acceptors or splice acceptors in other genes. In most cases, a premature termination codon (PTC) will be rapidly encountered by the ribosome translating such transcripts. Therefore, we furthermore hypothesize that these alternately processed transcripts can express what we call “cryptic” neoantigens when treated with drugs that suppress utilization of premature codons such as Ataluren or gentamycin. In such a way, we could administer a prophylactic vaccine and induce conditionally active immune response that would eliminate nascent tumors only when drug treatment is used.

抽象/总结