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. 2019 Aug 30;11(9):1279.
doi: 10.3390/cancers11091279.

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Valeria Barresi  1 , Michele Simbolo  2 , Andrea Mafficini  3 , Maria Liliana Piredda  2 , Maria Caffo  4 , Salvatore Massimiliano Cardali  4 , Antonino Germanò  4 , Sara Cingarlini  5 , Claudio Ghimenton  6 , Aldo Scarpa  2   3   6
Affiliations

Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Valeria Barresi et al. Cancers (Basel). .

Abstract

Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18-54 years for which limited data are available.

Methods: Sixteen IDH-wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel.

Results: Eight (50%) IDH-wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs (p = 0.04).

Conclusions: We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy.

Keywords: IDH wild-type; POLE; giant cells; glioblastoma; mismatch repair; tumour mutation load.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Histopathological aspects of ultra-mutated GBMs. Both cases 5 GL (a) and 12 GL (b) featured neoplastic giant cells bi- or multinucleated, which were uniformly dispersed throughout the tumour (a,b: original magnification, 200×).
Figure 2
Figure 2
Genomic landscape of 16 IDH-wt glioblastomas. The matrix shows 36 genes that were altered at sequencing analysis; molecular alterations are annotated as illustrated in the panel below. Samples are ordered according to tumour mutational load (TML) from higher to lower values. The mutational spectrum is characterized by prevalent T > C and C > T transitions with low to absent contributions of T > A, T > G, C > G, and C > A transversions. The proportion of C > T over T > C increased in parallel with the increase of TML. Case 12 GL also showed a significant proportion of C > A transversions.
Figure 3
Figure 3
Chromosomal asset of 16 IDH-wt glioblastomas. The panel summarizes copy number variation (CNV) in whole chromosomes. Consensus of chromosome CNV is represented in red for copy gain events and in blue for loss events.
Figure 4
Figure 4
Mutational signatures of 16 IDH-wt glioblastomas. The signatures of somatic mutations (mutational spectrum) of individual tumours were obtained considering six major mutation classes: C > T; C > A; C > G; T > A; T > C; T > G. On top are the two ultra-mutated samples with indications of tumour mutational load (TML) and the peculiar molecular alterations. The mutational signature of case 12 GL shows a predominance of C > T over T > C transitions, and four peaks of C > A transversions in the trinucleotide contexts CCT, TCT, GCT, and ACT; this latter mutational pattern corresponds to signature SBS14 in the Catalogue Of Somatic Mutations In Cancer (COSMIC) version 3, and is associated to tumours with concurrent impairment of DNA mismatch repair and POLE proofreading functions (https://cancer.sanger.ac.uk/cosmic/signatures/SBS/) [25]. On the horizontal axis, the reference base with 5′ (left) and 3′ (right) bases are shown. On the vertical axis, the number of mutations is shown.
Figure 5
Figure 5
Immunohistochemical analysis of mutated mismatch repair genes in cases 5 GL (a–d) and 12 GL (e–h). Case 5 GL shows loss of MSH2 expression (b) and positive staining for MLH1, MSH6 and PMS2 (a,c,d) (original magnification, 200×). Case 12 GL shows loss of MSH6 expression (g) and positive staining for MLH1, MSH2, and PMS2 (original magnification, 200×) (e,f,h).
Figure 5
Figure 5
Immunohistochemical analysis of mutated mismatch repair genes in cases 5 GL (a–d) and 12 GL (e–h). Case 5 GL shows loss of MSH2 expression (b) and positive staining for MLH1, MSH6 and PMS2 (a,c,d) (original magnification, 200×). Case 12 GL shows loss of MSH6 expression (g) and positive staining for MLH1, MSH2, and PMS2 (original magnification, 200×) (e,f,h).
Figure 6
Figure 6
Impact of tumour mutational load on clinical outcome. Overall survival analysis showing that TML > 200 mutations/Mb was associated with better prognosis in IDH wild-type GBMs (p-value = 0.036).
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