Page 14 - Molecular features of low-grade developmental brain tumours

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CHAPTER 1
domain of RAF can interact with MEK resulting in phosphorylation of MEK1 and/or MEK2, which subsequently activates ERK1 and ERK2 48,49. Upon activation ERK1/2 translocate to the nucleus where they can regulate transcription of genes involved in cell proliferation, differentiation, survival and apoptosis 50. Moreover, the ERK/MAPK pathway is known to be involved in brain development 51,52. Therefore, it is not surprising that dysregulation of the ERK/MAPK pathway can lead to the occurrence and progression of LEATs and pLGGs.
Treatment and diagnosis of LEATs and pLGGs
Currently the treatment of choice for LEATs and pLGGs is gross total surgical resection 53. However, in cases where total resection is not possible, or cases with recurrence or malignant transformation, additional radiation or chemotherapy is needed, which can negatively affect survival rates and the quality of life of patients 33,54-59. Therefore, a better understanding of the molecular profile of these tumours could help to improve the postsurgical treatment regimen 33,58,59. Over the past decades, the development of sequencing techniques has transformed the landscape of molecular biology especially at the levels of transcriptomics and genomics. Molecular stratification of pLGGs and LEATs has led to novel diagnostic strategies and trials with more specific inhibitors, such as MEK and mTOR inhibitors 60-62. Clinical trials with such inhibitors seem promising for the treatment of pLGGs and LEATs with BRAF mutation or other alterations of the ERK/MAPK pathway including GGs (for review see 63). However, despite the advances, response to treatment with these inhibitors can be variable and the clinical implications of these molecular markers are not always clear 64-66. Moreover, response to treatment with these inhibitors can be variable depending on the genetic mutations emphasizing the risk of trials without a good molecular characterization. Furthermore, although some histological entities are enriched for molecular events, they are not always mutually exclusive. Therefore, more comprehensive analyses of low grade gliomas, including LEATs and pLGGs, using novel sequencing techniques in combination with conventional methods are needed to identify novel targets for therapy and to further improve treatment and diagnosis.
Tuberous sclerosis complex
TSC is a neurocutaneous disorder caused by mutations in either the TSC1 or TSC2 gene, resulting in dysregulation of the mTOR pathway, which demonstrates a direct link between a genetic mutation and brain pathology 67-71. Clinically, TSC is associated with epilepsy, autism and intellectual disability. About 90% of individuals with TSC exhibit TSC- Associated Neuropsychiatric Disorders (TANDs) which includes behavioral, psychiatric, intellectual, neuropsychological, and psychosocial issues 72-75. In addition to the neurological manifestations, TSC can also cause dermatologic manifestations (facial angiofibromas), renal angiomyolipomas, pulmonary lymphangioleiomyomatosis and cardiac rhabdomyoma 71,76,77.
Neuropathological examination of TSC brain specimens reveals three major lesions: subependymal nodules (SENs), SEGAs and cortical tubers (Figure 3) 26,78-82. Cortical tubers are lesions that are predominantly found in frontal and temporal regions and can extend into the white matter. They show cortical dyslamination and consist of dysmorphic neurons