Page 50 - Molecular features of low-grade developmental brain tumours

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Case (#)
Gene
Nucleotide change
MAF (%)
Mutation type
Protein change
Summary
CHAPTER 2
27 TSC2
28 TSC2
29 TSC2
30 TSC2
31 TSC2
32 TSC2
33 TSC2
c.5168C>A c.3599G>C c.1372C>T
c.1831C>T c.3814+1G>C c.412G>T
34 57 32
15 47
51
Nonsense p.S1723* Missense p.R1200P Nonsense p.R458*
Missense p.R611W
Yes point+CN-LOH Yes point+CN-LOH Yes point+CN-LOH
No 2 points No point no LOH
Splice Nonsense
p.V1272_splice p.E138*
TSC2 CN-LOH, no point
TSC2 CN-LOH, no point
Table 3B. Summary of results for BRAF mutational analysis by MPS in 31 SEGA samples.
34 TSC2
NMI = No Mutation Identified, MAF = mutant allele frequency, CN-LOH = Copy neutral loss of
heterozygosity, point = point mutation or small insertion or deletion.
Yes Yes Yes
TSC2 CN-LOH, no point
25 BRAF 8 BRAF
c.82G>T 100 c.31G>A 56
Missense Missense
p.G28C p.G11S
Novel per cBio, not seen in ExAC
Seen once in an hepato- biliary cancer (cBio), not seen in ExAC
48
while the remaining BRAFV600E positive samples were either TSC negative or defined as possible TSC 23,26. Altogether, these results suggest that SEGAs derived from patients with TSC, are negative for the BRAFV600E mutation 18,21,23,26,32.
Additionally, our results indicate that TSC1/TSC2 alterations, including CN-LOH, are nearly universally present in SEGAs, consistent with TSC1/TSC2 molecular findings seen in other TSC-related tumours e.g. renal angiomyolipomas (AMLs) and lymphangioleiomyomatosis (LAM) 40. TSC2 LOH has also been reported in sporadic renal and hepatic AMLs as well as sporadic perivascular epithelioid cell tumours. Conversely, TSC1 mutation and LOH is rare in angiomyolipoma and perivascular epithelioid cell tumours 40,59. In contrast TSC1 mutations and LOH were relatively common in this series, seen in 10 of 34 (29%) and 9 of 34 (26%), respectively 40,59-61. Regarding the 5 SEGA cases in which no definite small mutation was identified, there are several possible causes. First the DNA quality of many SEGA samples was poor, limiting the sensitivity of the MPS analysis. In particular large genomic deletions may have been missed in this analysis, and are relatively common in TSC2 40.
Consequently, the mechanism of MAPK/ERK and AKT pathway activation in SEGAs is uncertain, and further investigation is required 27-31.