DOI: 10.1002/ame2.70069
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
Daniel Antunes Moreno1
Bruna Minniti Mançano2
Mirella Baroni1
Eric Allison Philot1
Felipe Antonio de Oliveira Garcia1
Murilo Bonatelli3
Flávia Escremim de Paula3
Iara Viana Vidigal Santana4
Gustavo Ramos Teixeira5
Mauricio Yamanari6
Luciane Sussuchi da Silva1
André Escremim de Paula3
Augusto Perazzolo Antoniazzi7
Adrian Willig8
Xiaobin Xing8
Zhenyu Xu8
Lucas Lourenço2
Carlos Almeida Junior2
Silvia Aparecida Teixeira1
Rui Manuel Reis9
1.Molecular Oncology Research Center,Barretos Cancer2.Department of Pediatric Oncology,Barretos Cancer H3.Department of Molecular Diagnosis,Barretos Cancer 4.Department of Pathology,Barretos Cancer Hospital,B5.Department of Pathology,Barretos Cancer Hospital,B6.Department of Radiotherapy,Barretos Cancer Hospita7.Department of Oncogenetics,Barretos Cancer Hospita8.SOPHIA Genetics,Rolle,Switzerland9.Molecular Oncology Research Center,Barretos Cancer
摘要：Background:Constitutional mismatch repair deficiency(CMMRD)is a rare disor-der 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 61/2-year-old girl was diagnosed with Sonic Hedgehog(SHH)-activated me-dulloblastoma and somatic TP53-mutant.After surgery and radiochemotherapy,she re-mained free of disease progression.At 10years 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 path-ogenic variants in the medulloblastoma,dpHGG,and PDX,respectively.Only the me-dulloblastoma 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.
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论文发表日期：2025-11-30
在线出版日期：2026-01-09（本平台首次上网日期，不代表文献的发表时间）
页数：12( 1971-1982 )
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