Novel neoplasms associated with syndromic pediatric medulloblastoma: integrated pathway delineation for personalized therapy

Abstract

Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in familial adenomatous polyposis (FAP)/Turcot syndrome. Genomic analysis showing XRCC3 alterations suggested radiotherapy as contributing factor to the progression of LFS-associated medulloblastoma, and demonstrated different mechanisms of APC inactivation in the FAP-associated tumors. The integrated genomic-transcriptomic analysis uncovered the growth pathways driving tumorigenesis, including the prolactin-prolactin receptor (PRLR) autocrine loop and Shh pathway in the LFS-associated prolactinoma and medulloblastoma, respectively, the Wnt pathway in both FAP-associated neoplasms, and the TGFβ and Hippo pathways in the soft tissue tumors, regardless of germline predisposition. In addition, the comparative analysis of paired syndromic neoplasms revealed several growth pathways susceptible to therapeutic intervention by PARP, PRLR, and selective receptor tyrosine kinase (RTK) inhibitors. These could target the defective DNA damage repair in the LFS-associated medulloblastoma, the prolactin autocrine loop in the atypical prolactinoma, the EPHA3/7 and ALK overexpression in the FAP-associated medulloblastoma, and the multi-RTK upregulation in the soft tissue neoplasms. This study presents the spatiotemporal evolution of novel neoplastic associations in syndromic medulloblastoma, and discusses the post-radiotherapy risk for secondary malignancies in syndromic pediatric patients, with important implications for the biology, diagnosis, and therapy of these tumors.

Translation into Clinical Practice of the G1-G7 Molecular Subgroup Classification of Glioblastoma: Comprehensive Demographic and Molecular Pathway Profiling

“…Next-generation sequencing (NGS), copy number variation (CNV) and transcriptomics. The DNA and RNA NGS analyses were performed from FFPE samples using the xT-648-gene panel (Tempus Labs, Chicago, IL, USA), as previously described [7,8]. For each case, the same FFPE block was used for DNA and RNA extraction to allow for direct comparison of results.…”

“…For each case, the same FFPE block was used for DNA and RNA extraction to allow for direct comparison of results. Variant and CNV assessment and interpretation, and the RNA expression analysis were performed as extensively described elsewhere [7,8].…”

“…7 % cases with SWI/SNF complex ARID1A, ARID1B, ARID2, SMARCA1, SMARCA4, SMARCD1 or PBRM1 pathogenic mutations. 8 % cases with either YEATS4 amplification or DNM3TA, TET2, EP300, KDM5C, KDM6A, KMT2C, KMT2D, NPM or CREBBP pathogenic mutations. 9 Median survival measured in months; the number of patients is indicated in Figure 5f, except for the G1/EGFRm (N/n = 6/1), G2/FGFR3 (N = 5) and G4/RAF (N = 5).…”

Associação das variantes do gene do receptor de prolactina com a resposta à cabergolina em pacientes com prolactinoma

“…Mas, ao contrário, parece haver maior expressão de PRL-R nesses tumores, proporcional à PRL sérica e a redução em amostras tumorais de pacientes tratados com BRC51 . Em um relato de caso de prolactinoma extremamente agressivo e pouco diferenciado, houve hiperexpressão do gene PRL-R e ausência da expressão do receptor de estrogênio por imunohistoquímica79 . Em cultura de células desse tumor, a adição de Portanto, as ações da dopamina e da prolactina podem ser moduladas por fatores relacionados ao sexo biológico.O câncer de mama é um modelo de estudo para ações de estrogênio e da PRL.Portanto, em paralelo com os estudos em câncer de mama, ainda que as demais variantes do PRL-R não tenham sido relacionadas à presença de prolactinoma em nosso estudoGorvin et al74 .…”