PMC8769403_01
(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.
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F1
She had been treated for ascending colon cancer, and she and her family had been diagnosed with Lynch syndrome by genetic screening (Fig. 1A). Magnetic resonance imaging (MRI) showed a ring-enhancing lesion in the left parietal lobe accompanied by peritumoral edema (Fig. 1B). IDH wild type (Fig. 1H). Immunohistochemical examination showed loss of MSH2 expression, TP53 mutation, and an MIB-1 index of 47%. MSH6 expression was partially lost accompanied with loss of MSH2 expression (Fig. 1I). Local irradiation of 34 Gy concomitant with temozolomide was performed as adjuvant therapy (Fig. 1H). After 10 cycles of maintenance temozolomide therapy, her motor aphasia worsened, and tumor progression was observed on MRI 11 months after the surgery (Fig. 1C). A second resection was performed for recurrence of glioblastoma (Fig. 1D). Pembrolizumab was given as the second-line chemotherapy because of MSI detected in the tumor (Fig. 1E). Partial response was observed on MRI after two cycles of pembrolizumab (Fig. 1F), but the tumor showed progression after three cycles (Fig. 1G). In contrast, most of the additional mutated genes in the recurrent tumor belonged to signaling pathways (PI3K, NF1, KIT, NOTCH, ERBB, FGFR, and SMAD) (Fig. 1J).
PMC8769403_02
(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.
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F2
MRI showed a ring-enhancing lesion in the right parietal lobe, and gross total resection of the tumor was performed (Fig. 2A and 2B). MLH1 expression (Fig. 2E). After two cycles of maintenance temozolomide therapy, tumor progression was observed on MRI 5.3 months after surgery (Fig. 2C). The tumor cells were positive for GFAP, synaptophysin, and OLIG2, indicating that they were metastases of glioblastoma (Fig. 2F). These tumor cells also showed loss of MLH1 and PMS2 expression (Fig. 2G). Intracranial tumor progression was not observed at this point (Fig. 2D), but she died of progression of pancytopenia 8.6 months after the first surgery.
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.
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F3
Overall survival of the MMR mutant glioma patients was no different from that of the MMR wild-type glioma patients, both in IDH mutant and IDH wild-type gliomas (p = 0.4 in IDH wild type, Fig. 3A, p = 0.2 in IDH mutant, Fig. 3B, Log-rank test).