Subependymal giant cell astrocytomas in Tuberous Sclerosis Complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations

Abstract

Subependymal giant cell astrocytomas (SEGAs) are rare, low-grade glioneuronal brain tumors that occur almost exclusively in patients with tuberous sclerosis complex (TSC). Though histologically benign, SEGAs can lead to serious neurological complications, including hydrocephalus, intractable seizures and death. Previous studies in a limited number of SEGAs have provided evidence for a biallelic two-hit inactivation of either TSC1 or TSC2, resulting in constitutive activation of the mechanistic target of rapamycin complex 1 pathway. The activating BRAF V600E mutation is a common genetic alteration in low grade gliomas and glioneuronal tumors, and has been reported in SEGAs as well. In the present study, we assessed the prevalence of the BRAF V600E mutation in a large cohort of TSC related SEGAs (n=58 patients including 56 with clinical TSC) and found no evidence of either BRAF V600E or other mutations in BRAF. To confirm that these SEGAs fit the classic model of two hit TSC1 or TSC2 inactivation, we also performed massively parallel sequencing of these loci. Nineteen (19) of 34 (56%) samples had mutations in TSC2, 10 (29%) had mutations in TSC1, while 5 (15%) had no mutation identified in TSC1/TSC2. The majority of these samples had loss of heterozygosity in the same gene in which the mutation was identified. These results significantly extend previous studies, and in agreement with the Knudson two hit mechanism indicate that biallelic alterations in TSC2 and less commonly, TSC1 are consistently seen in SEGAs.

Genetics, genomics, and genotype–phenotype correlations of TSC: Insights for clinical practice

“…A second somatic event is required for hamartoma formation. In accordance with this model, loss of heterozygosity and small changes on the second allele have been found in renal angiomyolipomas, some cells in cortical tubers and subependymal giant cell astrocytomas (SEGAs) (Au, Hebert, Roach, & Northrup, 1999;Bongaarts et al, 2017). Recently, several studies demonstrated that biallelic loss (either second-hit point mutations or copy-neutral LOH) of TSC1/TSC2 is the primary driver event for angiomyolipoma development, and somatic mutations in other known cancer-associated genes are very rare (Giannikou et al, 2016).…”

“…In accordance with this model, loss of heterozygosity and small changes on the second allele have been found in renal angiomyolipomas, some cells in cortical tubers and subependymal giant cell astrocytomas (SEGAs) (Au, Hebert, Roach, & Northrup, 1999;Bongaarts et al, 2017). Germline pathogenic variants in TSC1 or TSC2 alone are not sufficient to cause the tumors.…”

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

“…It is intriguing that mutant pericytes that likely give rise to the TSC-associated renal angiomyolipoma (Siroky et al 2014) could also be involved in TSC renal cystogenesis. Pericytes that have lost TSC gene function may be responsible for altered blood brain barrier function giving rise to the tensor weighted imaging findings in TSC (Jurkiewicz et al 2007;Arulrajah et al 2009;Ertan et al 2010) and may participate in inducing subependymal giant cell astrocytoma formation, a TSC tumor also sometimes identified without loss of heterozygosity (Parry et al 2000;Bongaarts et al 2017;Roux et al 2017), possibly through this extracellular vesicle mechanism. The expansion of A-intercalated cell as well as potential role for extracellular vesicles in many aspects of TSC renal cystic disease manifestation offers new therapeutic opportunities for intervention in this disease.…”

Subependymal giant cell astrocytoma harboring a PRRC2B‐ALK fusion: A case report

“…12 Furthermore, some patients developed only one TSC-associated manifestation, that is, sporadic SEGA or sporadic lymphangiomyomatosis. 4,13,14 Somatic TSC1/TSC2 variants were detected in some but not all of these cases.…”

“…Martin et al reported that somatic or germline TSC1/TSC2 variants were not detected in two out of 66 patients with TSC when using whole‐exome sequencing, single‐nucleotide polymorphism arrays, and targeted deep sequencing . Furthermore, some patients developed only one TSC‐associated manifestation, that is, sporadic SEGA or sporadic lymphangiomyomatosis . Somatic TSC1/TSC2 variants were detected in some but not all of these cases.…”