Mismatch Repair Deficiency and Lynch Syndrome Among Adult Patients With Glioma

• DOI: 10.1200/po.22.00525
• Publication Date: 2023-06-01T20:01:00Z
• Authors: Patrick R. Benusi...; Fikret Elder; Mehdi Touat; Alexandre Perrier; Marc Sanson; Chrystelle Colas; Lea Guerrini-Rous...; Duy Thanh Tran; Nesrine Trabelsi; Catherine Carpentier; Yannick Marie; Clovis Adam; Michèle Bernier; Dominique Cazals-...; Karima Mokhtari; Suzanne Tran; Bertrand Mathon; Laurent Capelle; Marion Dhooge; Ahmed Idbaih; Agusti Alentorn; Caroline Houillier; Caroline Dehais; Khe Hoang-Xuan; Stefania Cuzzubbo; Antoine Carpentier; Alex Duval; Florence Coulet; Franck Bielle
• Keywords: Adult; [SDV.CAN] Life Sciences [q-bio]/Cancer; Neoplastic Syndromes, Hereditary; [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Humans; Glioma; [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics; Middle Aged; Glioblastoma; Colorectal Neoplasms, Hereditary Nonpolyposis; 3. Good health

PURPOSE The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention. METHODS Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period. RESULTS Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant. ATRX (n = 5) and TP53 (n = 8) PV were common. There was no TERT promoter PV or EGFR amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in MSH2 (n = 3) and MLH1 (n = 1). One additional patient had PMS2-associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group. CONCLUSION Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.