2017-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/675322摘要：腦瘤是兒童時期十分常見的惡性腫瘤，發生率僅次於白血病。兒童腦瘤的治療需要藉由多科部的醫療團隊提供整合性的臨床照護，成員包括神經外科、兒童神經腫瘤科、病理科、影像科、放射腫瘤科等。髓母細胞瘤 (medulloblastoma)為兒童腦瘤治療的標竿範例，藉由手術切除、化學治療、與放射線治療，病患的五年存活率可達50%到80%左右。而近年基因體研究的蓬勃發展，髓母細胞瘤的基因突變、蛋白表達、訊息傳遞路徑變異均有突破性的發現，未來朝向個人化精準醫療的發展趨勢將能進一步改善病人預後與減少治療相關的後遺症。目前最新版 2016 年世界衛生組織的髓母細胞瘤分類，包括了過去原有的四種病理組織亞型 (classical, desmoplastic, extensive nodularity, large cell/anaplastic) 與新加入的四種分子亞型 (WNT, SHH, group 3, group 4)。每位病患的腫瘤皆能以兩種方式同時定義其病理型態與分子變化。每一種分子亞型皆有其特定的基因變異與訊息傳遞等改變，其中部分病變可以使用目前已有的標靶藥物予以治療，譬如 SHH (sonic hedgehog) 的抑制劑。而在台灣地區，運用分子亞型來對髓母細胞瘤進行分類尚在起步階段，大多數醫院仍採用舊版 2007 年髓母細胞瘤分類系統與臨床資訊來做治療決策與預後分析。為提供更優質的醫療照顧，落實新版髓母細胞瘤的分子分類系統實為當務之急。本項計畫目標為提供髓母細胞瘤的精準醫療。過去我們的團隊已經使用免疫組織染色與多重基因探針接合放大技術 (MLPA)，成功將髓母細胞瘤進行初步的分子分類。本計畫第一年的部分，將以 mRNA 表達陣列與核酸定序來對髓母細胞瘤進行更精準的分子亞型分類，並與免疫組織染色與 MLPA 結果對照，來分析腫瘤相關基因變化與病患預後關係。第二年的計畫將針對不同亞型的標的基因進行核酸定序，並以甲基化陣列分析表觀基因調控變化，來探討髓母細胞瘤的致病機轉。藉由這項計畫的執行，我們將能對台灣地區髓母細胞瘤的基因圖譜與病理機轉有進一步的瞭解，有助於在未來提供更精準有效的治療給罹患此症的病童。<br> Abstract: Brain tumor is the second most common malignancy in childhood. Management ofpediatric brain tumor requires an integrated program by a multi-discipline team, includingneurosurgeons, pediatric neuro-oncologists, pathologists, radiologists, and radiationoncologists. One of the best models in pediatric brain tumor management ismedulloblastoma. Maximal safe tumor resection followed by chemotherapy andradiotherapy results in long term survival from 50~80%. Breakthrough discovery of themolecular alterations in medulloblastoma have been well elucidated with ongoingrefinement in recent years, and future personalized treatment is promising to improveprognosis and decrease treatment related complications.The new 2016 WHO classification of medulloblastoma includes both histopathologicalsubtyping (classical, desmoplastic, extensive nodularity, large cell/anaplastic) andmolecular subtyping (WNT, SHH, group 3 and group 4). Each molecular subtype isassociated with different genetic alterations, some of which are amenable to target therapy,such as SHH inhibitors. In Taiwan, molecular classification is yet to be incorporated intoroutine clinical practice. Most medical centers still rely on the previous 2007 WHOclassification system plus clinical parameters for risk stratification and treatment decision.The new molecular classification system needs to be implemented in Taiwan to providebetter care of our children with this disease.The aim of this proposal is to apply precision medicine for management ofmedulloblastoma. Previously we have performed preliminary molecular subtyping ofmedulloblastoma by immunohistochemistry (IHC) and multiplex ligation-dependent probeamplification (MLPA). In this project, we will continue our study based on the previous result.In the first fiscal year, we will use mRNA expression arrays and RNA sequencing to classifythe subtype of medulloblastoma and correlate this result with IHC staining. MLPA study forgenetic alteration and its association with expression profile and outcome will be analyzed.In the second fiscal year, we will perform target sequencing of reported genetic mutationsof medulloblastoma. Since epigenetic mechanism has been found to be closely associatedwith development as well as pediatric tumors, we will also check the methylation profile toexplore the underlying etiology of pediatric medulloblastoma.This proposal will help us to understand the genetic and epigenetic profiles, andpathogenesis of medulloblastoma in Taiwan. Patients will benefit from more precisedecision making of treatment in the future.髓母細胞瘤分子分類基因圖譜表觀基因圖譜精準醫療medulloblastomamolecular classificationgenetic profileepigenetic profileprecision medicine