Frameshift Peptides of Children With NF1
Condition: Neurofibromatosis Type 1
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
Study type: Observational

Summary: 
      The objective of this study is to determine if children and young adults with
      Neurofibromatosis Type 1 (NF1) and either Low Grade Gliomas (LGGs) or Plexiform Neurofibromas
      (PNs) have a specific frameshift peptide protein profile and whether a disease specific
      vaccine created to address these frameshift mutations and variants can be developed. Three
      study populations will be analyzed; patients with NF1 and active LGGs, NF1 and active PNs,
      and NF1 and no evidence of active LGGs or PNs. Participation involves a onetime blood draw.
    

Detailed description: 
      I. Objective and Specific Aims

      A. Objectives:

      To determine if children and young adults with NF1 and either Low Grade Gliomas (LGGs) or
      Plexiform Neurofibromas (PNs) have a specific frameshift peptide protein profile and whether
      a disease specific vaccine created to address these frameshift mutations and variants can be
      developed.

      B. Primary Aims:

        1. Determine the frameshift peptide profile of children and young adults with NF1 and
           active LGGs, NF1 and active PNs, and NF1 and no evidence of active LGGs or PNs.

        2. Determine if the frameshift peptide profiles of children and young adults with NF1 in
           each of the populations of interest differ.

        3. Determine if specific frameshift peptide profiles can be used to create a disease
           specific vaccine for children and young adults with NF1 and either LGGs or PNs.

      C. Secondary Aims:

        1. To assess the impact of age, gender, family history of NF, disease state (stable,
           progressive, or responding), and treatment on the frameshift peptide profiles of
           children and young adults with NF1 and active LGGs or PNs.

        2. To assess the impact of NF1 mutation type on the frameshift peptide profiles found.

      II. Background

      A. Neurofibromatosis Type 1

      Neurofibromatosis Type I (NF1) is a genetic disorder that affects 1 in 3000 individuals
      caused by a germline heterozygous mutation of the NF1 gene located on chromosome 17.
      Inherited as an autosomal dominant gene, the mutation is 100% penetrant and is manifested by
      multiple complications, many of which can significantly inhibit an individual's ability to
      function in daily life and, in some cases, may be life threatening (Viskochil et al., 1990,
      Wallace et al., 1990). To date, only a variable association has been made between the type of
      mutation present and the phenotype of the affected individual. Some manifestations of NF1,
      such as café au lait spots and dermal fibromas, are extremely common while others, although
      less frequent, may cause severe neurologic or other organ dysfunction (Ferner et al., 2007).
      Two of the most common NF1-related manifestations are plexiform neurofibromas and gliomas,
      especially gliomas affecting the visual system. Treatment for both is currently suboptimal,
      however new molecularly targeted and immunologic approaches hold the promise of improved
      outcomes (Khatua et al., 2018).

      Gliomas may develop as early as infancy with an initial peak in diagnosis between the ages of
      3 and 5 years (Schmandt & Packer, 2000, Khatua et al., 2018). At the time of clinical
      detection, there is often significant tumor associated morbidity frequently resulting in
      irreversible visual impairment, which may worsen as these tumors of the optic nerve and
      chiasm progress. Therapies are currently available to slow or stop the growth of these
      lesions; however, these therapies often do not halt visual loss, rarely result in visual
      improvement, and may only be of transient benefit. Gliomas may also arise in different areas
      of the brain, especially in the brain stem later in childhood and into early adulthood. When
      these tumors become active in adolescents or young adults, they may mutate into more
      aggressive anaplastic pilocytic astrocytomas and become resistant to therapy. These more
      aggressive gliomas are a potential cause of death in patients with NF1.

      Plexiform neurofibromas may occur in up to 60% of NF1 patients with the potential to result
      in severe disfigurement and neurologic compromise by compression of the spinal cord or
      peripheral nerves (Packer et al., 2018). Depending on location, plexiform neurofibromas may
      also result in severe respiratory compromise or urologic dysfunction. Although believed to be
      congenital manifestations, many may not become evident or symptomatic until later in life.
      Between 6-13% of plexiform neurofibromas will mutate into malignant peripheral nerve sheath
      lesions, which typically respond poorly to current therapeutic options and can result in
      death.

      Patients with NF1 have a shortened life expectancy compared to those without due, in part, to
      the devastating plexiform neurofibromas, malignant peripheral nerve sheath tumors, and
      gliomas they develop (Packer et al., 2018). A clinically important question in NF1 patients
      is whether the diagnosis and treatment of incipient tumors will result in better outcomes and
      decrease the likelihood of malignant progression of those tumors. Recent advances in imaging
      and image processing have improved the precision and detail of visualization of the growing
      tumor mass, however, it would be ideal to develop a blood test capable of indicating the
      status of these NF1 children. Early interventions with better treatments may prove more
      effective and less harmful to the patient than more aggressive treatments needed at a later
      stage of disease. Furthermore, treatment by immunotherapeutic approaches, especially the
      development of a vaccine to prevent the occurrence or progression of gliomas and plexiform
      neurofibromas, is a potentially function saving and lifesaving intervention.

      III. Methods

      Each enrolled participant will undergo a one-time blood draw, collecting up to 10ml. Study
      sites will also obtain basic demographic and clinical information.
    

Intervention name(s): Frameshift Array blood sample test
Intervention type(s): Genetic
Intervention description(s): Patient blood test samples will be collected and evaluated for frameshift peptide mutations.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        There will be a total of 60 patients enrolled in the study. Cohort 1 will consist of 20
        subjects with NF1 and active LGG. Cohort 2 will consist of 20 subjects with NF1 and active
        PN. Cohort 3 will consist of 20 subjects with NF1 and no active LGG or active PN.
      
Biospecimen description: 
      A frameshift peptide profile will be determined from patient blood samples