The development of GBM – A single case study


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Astrid Wendler1,Sarah Field1,Juliane Perner1,Simon Tavaré1,Colin Watts1
1Cambridge University

Abstract

Background

Glioblastoma multiforme (GBM) is the most malignant form of astrocytoma and the most common primary brain cancer in adults. GBMs are characterized by diffuse infiltration of the surrounding brain tissue, strong vascularization, necrosis and high proliferation. The median survival in the untreated general patient population is around four months. Even under optimal treatment the median rate increases to only 14 to 16 months with a 2.5-year survival around 8%. The standard therapy is resection, radiation and treatment with Temozolomide (TMZ).

Method

We performed WGS and RNAseq on three spatially distinct samples of the treatment naïve primary tumour and three samples each of two consecutive recurrences.

Results

The DNA analysis showed only one shared mutation in all of the 9 samples; a mutation in EGFR (G598V), and it appears that subsequent tumours developed from an original clone bearing this mutation.  We also observed a massive increase in mutations from the first to the second recurrence showing predominantly C>T/A>G transitions. This patern of C>T hypermutation is typical of TMZ. However, the fact that the hypermutation did not appear until the second recurrence raises questions about the mechanism of hypermutation. The therapeutic apoptotic action of TMZ relies on the function of the mismatch repair (MMR) pathway. In the third recurrence we observed disruptive mutations at MSH2, 5 and 6 all of which are crucial to the MMR. The pattern of mutations at these genes varied between the samples taken from the second recurrence, however, all three samples showed hypermutation.

Conclusion

This suggests that the hypermutation observed after TMZ treatment only occurs if the MMR is damaged, but that this damage does not need to be at a specific locus.