Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

Abstract

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis

“…Somatic DNA methylation status of 50 patients in our cohort (96.2%) have been examined using methylation arrays 16 . The sliding–window analysis of fluorescent intensities detected by the arrays offer information regarding somatic DNA amplifications and deletions 25 .…”

“…We then evaluated the independence of the gene signature-based score and a simple clinical risk stratification scheme proposed previously, where the patients were stratified into three groups, non-metastatic average risk (N = 25), non-metastatic high risk (N = 14), metastatic high risk (N = 13) 16 . Both the non-metastatic and metastatic high risk subgroups have significantly poorer overall survival than the non-metastatic average risk group (Fig.…”

“…We recently reported a cohort of 52 medulloblastoma patients in the light of conventional molecular subgroups (i.e. WNT, SHH, Groups 3 and 4) 16 . To fully explore novel molecular insights underneath the clinical outcome, we further investigated a gene signature which can stratify patients with distinct prognosis.…”

Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas

“…It is not completely understood whether there are differences in genetic drivers of tumors between different racial ethnicities. Only two studies of MBs have been reported from Asian patients including a whole exome study of recurrent MB from only 17 pediatric patients in South Korea ( Phi et al, 2018 ) and a small SHH-subtype MB cohort from Taiwan ( Wu et al, 2020 ), however, a comprehensive analysis of Asian MB subgroups has not been conducted. In this study, we report the genomic landscape across a cohort of 89 MBs in the Han population from China.…”

Magnetic resonance radiomics features and prognosticators in different molecular subtypes of pediatric Medulloblastoma

“…Medulloblastoma (MB) is the most common primary malignant brain tumor in children and is currently treated on the basis of pathological and clinicoradiological risk stratification [1]. Despite progress in disease management, the overall survival remains dismal with 5 year survival rate around 70~75% [2]. Current therapeutic options have debilitating effects on developing children, highlighting the need for molecularly targeted treatments with reduced toxicity.…”