Genetic, epigenetic and immunologic profiling of MMR-deficient relapsed glioblastoma

Stefano Indraccolo, Giuseppe Lombardi, Matteo Fassan, Lorenza Pasqualini, Silvia Giunco, Raffaella Marcato, Alessandra Gasparini, Cinzia Candiotto, Silvia Nalio, Pasquale Fiduccia, Giuseppe Nicolò Fanelli, Ardi Pambuku, Alessandro Della Puppa, Domenico D'Avella, Laura Bonaldi, Marina P Gardiman, Roberta Bertorelle, Anita De Rossi, Vittorina Zagonel

Research output: Contribution to journalArticlepeer-review


PURPOSE: In-depth characterization of recurrent glioblastoma (rGBM) might contribute to a better understanding of the mechanisms behind tumor progression and enable rGBM treatment with targeted drugs.

EXPERIMENTAL DESIGN: In this study, GBM samples were collected at diagnosis and recurrence from adult patients treated with Stupp protocol. Expression of mismatch repair (MMR) proteins was evaluated by IHC, followed by whole exome sequencing (WES) of tumor samples showing loss of MSH6 reactivity. Established genetic, epigenetic and immunologic markers were assessed by standard methods and correlated with loss of MMR proteins and patient survival.

RESULTS: Expression of MMR proteins was partially or completely lost in 25.9% rGBM samples. Specifically, 12 samples showed partial or total MSH6 expression reduction. Conversely, 96.4% of GBM samples at diagnosis expressed MMR markers. WES disclosed lack of variants in MMR genes in primary samples, whereas two MSH6 negative rGBM samples shared a c.3438+1G>A* splicing MSH6 variant with a potential loss of function effect. MSH6 negative rGBM specimens had high tumor mutational burden (TMB), but no microsatellite instability. In contrast, GBM samples with partial loss of MMR proteins disclosed low TMB. MMR-deficient rGBM showed significant telomere shortening and MGMT methylation and are characterized by highly heterogeneous MHC class I expression.

CONCLUSIONS: Multi-level profiling of MMR-deficient rGBM uncovered hypermutated genotype uncoupled from enriched expression of immune-related markers. Assessment of MHC class I expression and TMB should be included in protocols aiming to identify rGBM patients potentially eligible for treatment with drugs targeting immune checkpoint inhibitors.

Original languageEnglish
JournalClinical Cancer Research
Publication statusE-pub ahead of print - Dec 4 2018


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