Genetic Characteristics of Mismatch Repair-deficient Glioblastoma

Abstract

Mismatch repair (MMR) gene deficiency is rarely observed in gliomas, a constitutional defect is associated with tumorigenesis in Lynch syndrome, and an acquired defect is associated with hypermutation after temozolomide treatment. However, the meaning of MMR gene deficiency in gliomas is unclear. Two cases of MMR-deficient glioblastomas are reported, and mutational status of oncogenes was compared between primary and recurrent tumor samples in a glioblastoma patient with Lynch syndrome. Additionally, the characteristics of MMR-deficient glioblastomas were analyzed using public glioma datasets to determine the meaning of MMR deficiency in gliomas. Case 1 was a glioblastoma patient with Lynch syndrome, and treatment with pembrolizumab for the recurrent tumor was temporarily effective for a short period. Comparison of mutational changes between primary and recurrent tumor samples showed many additional mutated genes associated with multiple signaling pathways in the recurrent tumor. Tumor recurrence and chemoresistance could be associated with intratumoral heterogeneity and accelerated tumor progression due to defects of multiple signaling pathways. Case 2 was a glioblastoma patient with acquired MMR gene deficiency, and she died of rapid progression of bone marrow metastases. This rare clinical course was considered to be associated with gene expression changes and heterogeneity that resulted from MMR gene deficiency. Two cases of MMR gene-deficient glioblastomas were presented, and their genetic characteristics suggested that their clinical courses could be associated with MMR gene deficiency.

Keywords: Lynch syndrome; bone marrow; glioma; mismatch repair; pembrolizumab.

Fig. 1. (A) The family tree for Case 1. The squares and circles indicate male and female, respectively. P indicates proband, and filled circles indicate affected. * indicates the patients evaluated by genetic examination. E+ and E- indicate positive and negative for genetic examination of Lynch syndrome, respectively. CRC, GC, BC, EnC, and GBM indicate colorectal cancer, gastric cancer, breast cancer, endometrial cancer, and glioblastoma. (B–G) Serial changes of the glioblastoma on gadolinium-enhanced T1-weighted MRI. (B) Preoperative image of the primary tumor before the first surgery; (C) preoperative image of the recurrent tumor before the second surgery; (D) postoperative image of the second surgery; (E) the image before treatment with pembrolizumab; (F) the image after two cycles of pembrolizumab treatment. (G) The image after three cycles of pembrolizumab treatment. (H) Time course of treatment for case 1. The base point of the time line is the date of the first surgery. 1st surgery: tumor resection for primary glioblastoma; RT+TMZ: extended local irradiation concomitant with temozolomide therapy; 2nd surgery: tumor resection for recurrent glioblastoma; PD: progressive disease. (I) IHC for the MMR proteins; MSH2, MSH6, MLH1, and PMS2. (J) Changes of mutated genes and tumor mutation burden compared between primary and recurrent tumors. Mutated genes observed in the primary tumor were associated with a signaling pathway, the p53 pathway, and the RB pathway, but mutated genes added in the recurrent tumor were associated with multiple signaling pathways. IHC: immunohistochemistry, MRI: magnetic resonance imaging.

Fig. 2. (A) Time course of treatment for case 2. The base point of the time line is the date of the first surgery. 1st surgery: tumor resection for primary glioblastoma; RT+TMZ: extended local irradiation concomitant with temozolomide therapy; 2nd surgery: tumor resection for recurrent glioblastoma; Bone marrow meta: the date bone marrow biopsy was performed. (B–D) Serial changes of the glioblastoma on gadolinium-enhanced T1-weighted MRI. (B) Preoperative image of the primary tumor before the first surgery; (C) preoperative image of the recurrent tumor before the second surgery; (D) the image on the date bone marrow biopsy was performed. (E) IHC of the primary tumor for the MMR proteins. (F) Pathological findings of the bone marrow. Hematoxylin–eosin staining and immunostaining for GFAP, synaptophysin, and OLG2 are presented. (G) Immunohistochemistry of the bone marrow for the MMR proteins. IHC: immunohistochemistry, MRI: magnetic resonance imaging.

Fig. 3. Kaplan–Meier curves of overall survival in the IDH wild type (A) and IDH mutant gliomas (B) comparing between the MMR gene mutant group and the MMR gene wild-type group are presented. There is no difference between the MMR mutant group and the MMR wild-type group, both in IDH wild-type gliomas and in IDH mutant gliomas (p = 0.4 in IDH wild type, p = 0.2 in IDH mutant). MMR: mismatch repair, MMR mt: MMR gene mutant group, MMR wt: MMR gene wild-type group.