Establishment and molecular profiling of a PDX model of a metachronous brain tumor in a patient with constitutional mismatch repair deficiency with biallelic MSH6 variant

Background: Constitutional mismatch repair deficiency (CMMRD) is a rare disorder resulting from biallelic germline pathogenic variants in mismatch repair genes. This study described the molecular profile of two metachronous brain tumors and a patient-derived xenograft (PDX) from a Brazilian child with CMMRD. Methods: After PDX development, methylation array, whole exome sequencing, and NanoString techniques were applied to describe the genetic landscape of CMMRD. Results: A 6½-year-old girl was diagnosed with Sonic Hedgehog (SHH)-activated medulloblastoma and somatic TP53-mutant. After surgery and radiochemotherapy, she remained free of disease progression. At 10 years and 3 months, she developed a diffuse pediatric-type high-grade glioma (dpHGG). The child had a family history of cancer, and subsequent investigation revealed a biallelic germline variant on MSH6 (c.3556+1G>A) with the absence of protein expression in both normal and tumor tissue. A PDX model of the dpHGG was developed. The methylation profile confirmed the diagnosis of both brain tumors and PDX, refining the classification of dpHGG, Rtk1 subtype, subclass A, with an actionable alteration on Platelet-derived growth factor receptor A (PDGFRA). Exome analysis showed high tumor mutational burden, with 3019, 540, and 1049 pathogenic variants in the medulloblastoma, dpHGG, and PDX, respectively. Only the medulloblastoma exhibited microsatellite instability. The CD24, CD47, and CD276 immune checkpoints had elevated messenger RNA levels, yet no programmed death ligand 1 expression was observed in CMMRD-derived tumors. Conclusion: We report an extensive molecular profile of a CMMRD patient, and the developed PDX model can be applied to explore new therapeutic approaches for CMMRD-associated brain tumors.