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

Kuo Sheng Wu ,Che-Chang Chang,Alice L Yu,Tai-Tong Wong,Shiann-Tarng Jou,Shian Ying Sung ,Meng‐Li Tsai ,Shih Chieh Lin ,Muh Lii Liang ,Wen Chang Huang ,Chun A Changou ,Huy Tran ,Meng En Chao ,Yi Wei Chen ,Yun Ru Liu ,Hsin Hung Chen ,Kung‐Hao Liang ,Kevin Hsieh ,Feng Chi Chang ,Er Chieh Cho ,Tsung Han Hsieh ,Chonghua Wan ,Donald Ming Tak Ho ,Hsin Lun Lee ,Yen‐Lin Liu ,Yi Yen Lee ,Shing Shung Chu

doi:10.3390/cancers12030653

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.

Highlights

Medulloblastoma (MB) was classified into four core molecular subgroups (WNT, SHH, Group 3, and Group 4) by consensus in a conference in Boston, MA, USA [1] and was further categorized into 12 subtypes in 2017 [2]
Histological variants were classified as classic MB (n = 27, 51.9%), desmoplastic/nodular
We identified somatic mutations in BRCA2, PALB2, MSH6, PMS2, PTCH1, SUFU, TP53, APC, and PTEN from RNA sequencing (RNA-Seq) data analysis

Summary

Introduction

Medulloblastoma (MB) was classified into four core molecular subgroups (WNT, SHH, Group 3, and Group 4) by consensus in a conference in Boston, MA, USA [1] and was further categorized into 12 subtypes in 2017 [2]. Cavalli et al further divided SHH tumors into four subtypes named. SHH α, β, γ, and δ [2] Among these four molecular subtypes, SHH α and β are subtypes of infants. Classification of the four main molecular subgroups was based on transcriptional profiling studies of MB cohorts. These subgroups were distinct in their demographics, clinical features (histology, metastasis, prognosis), genetics, and gene expression [1]

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