發現骨髓母細胞瘤的主要基因突變


  【24drs.com】根據線上發表於7月22日期刊的一篇研究,發現與發生兒童骨髓母細胞瘤有關的關鍵突變因素,這些突變可作為幫助導引個人化治療與提供預先治療機會的生物標記。
  
  如同其他小兒科腫瘤,骨髓母細胞瘤的突變率低。研究者使用新一代的基因定序技術分析骨髓母細胞瘤,發現在多個已知路徑的突變,包括組蛋白甲基化(如 MLL2)、sonic hedgehog基因(如PTCH1、SUFU)與Wnt (如CTNNB1)和新的基因(如DDX3X、BCOR、LDB1與GPS2)。
  
  整體而言,研究者確認了12個達統計顯著意義的突變基因,包括之前已知和骨髓母細胞瘤有關的: CTNNB1、PTCH1、MLL2、SMARCA4與TP53。
  
  在以前,骨髓母細胞瘤根據切片結果被分類為標準或高風險,但是一直被懷疑它是不同預後之不同基因所產生的一組癌症;廣泛的研究對這些腫瘤的生物進程提出見解,強調了此疾病的分子異質性。
  
  達那-法柏/兒童醫院神經腫瘤科醫師、波士頓兒童醫院神經科主任Scott Pomeroy博士表示,我們現在不僅知道如何以基因組對骨髓母細胞瘤進行分類,我們也掌握了驅使分子亞型的基因突變;這是我們首次可以根據分子類型分類和治療骨髓母細胞瘤,提供最佳治療與最少的長期後遺症。
  
  Pomeroy博士在受訪時強調,這些資料對開業醫師有其意義存在。短期內,它們加上之前有關亞型和特定分子標記的研究,讓我們可以探討各種標記並確認何者影響最大。在去年,這被積極討論著,也有探討這些標記的臨床試驗進行著。
  
  至於更近期的目標,Pomeroy博士指出,他們尋找多種分子突變作為治療標靶,例如,它可能是hedgehog基因亞型的突變,腫瘤可能對針對hedgehog路徑的藥物有反應,這目前已經在第2期試驗評估。
  
  他指出,他們發現一個以前未曾認為和WNT訊號有關的分子,有藥物被發展為阻斷DDX3X,我們將持續進行試驗。
  
  從長遠來看,Pomeroy博士指出,他們希望用這些資料獲得治療這種腫瘤的新方法。但是,還需要幾年,短期目標可望在1、2年內達到,中期目標則是在5年左右。
  
  一篇進行超過20年的大型研究計畫,搜集了足夠的腫瘤樣本數,發現骨髓母細胞瘤有4種不同的分子變化。每種變化有不同的臨床模式,各有立即的治療影響。各特定的亞型也有不同的存活率,介於20%-90%。
  
  同時刊載4篇報告(2011:29:1400-1407, 1408-1414, 1415-1423, 1424-1430)的臨床腫瘤期刊中,編輯們在有關這些研究計畫結果的編輯評論(J Clin Oncol. 2011:29:1395-1398)指出,骨髓母細胞瘤之各項因素的探討時機已經來臨。
  
  腫瘤組織基因型可以獲得這些結果,但是,可以用標準免疫組織化學獲得4種亞型。來自史丹佛大學的Michelle Monje博士、Philip Beachy博士與Paul Fisher醫師等編輯寫道,這被視為是「顯著的」結果;因為這項技術既方便且價格相對低廉,可以讓分子骨髓母細胞瘤分類系統很快地運用到臨床實務。
  
  Pomeroy博士等人使用新一代的定序技術分析完整的體細胞突變,包括92 對主要的骨髓母細胞瘤/正常配對。
  
  在定序的18,863基因中的1,671個基因總共發現1,908個突變,研究者在選定的基因(CTNNB1、DDX3X、SMARCA4、TP53和CTDNEP1)中確認20種可能的突變。
  
  初步功能研究將DDX3X視為病理性WNT/beta-catenin訊號的一個可能因素。更廣義而言,DDX3X突變最近曾在慢性淋巴性白血病與頭頸部癌症中被報導,這兩類腫瘤都有WNT訊號失調的腫瘤亞型。
  
  他們指出,後續研究將探討突變DDX3X功能是否與beta-catenin有關,這些將可對此類分子提出見解,並開創新療法。
  
  研究者結論表示,骨髓母細胞瘤中改變的核受體共抑制因子複合分子的區別,對這類致命的兒童疾病提供了新見解。
  
  這些研究結果有些可能很快地可用在病患上,例如,可能可以迅速區分個別的腫瘤,根據每種已知預後的亞型調整療法。此外,SHH-阻斷劑用於其他癌症的臨床試驗已經在進行,未來幾年,可能可以包括受SHH突變引起之骨髓母細胞瘤亞型的病患。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6893&x_classno=0&x_chkdelpoint=Y
  

Key Genetic Mutations Detected for Medulloblastoma

By Roxanne Nelson
Medscape Medical News

July 25, 2012 — Key mutations that might be associated with the development of childhood medulloblastoma have been identified, according to a study published online July 22 in Nature. These mutations could be biomarkers that could help guide and individualize treatment and provide prospective therapeutic opportunities.

As with other pediatric tumors, medulloblastomas exhibit a low rate of mutations. Using next-generation sequencing technologies in their analysis of medulloblastoma, the researchers found mutations in several known pathways, including histone methylation (e.g., MLL2), sonic hedgehog (e.g., PTCH1, SUFU), and Wnt (e.g., CTNNB1), and in novel genes (e.g., DDX3X, BCOR, LDB1, and GPS2).

Overall, the researchers identified 12 genes that were mutated at statistically significant frequencies, including those previously known in medulloblastoma, such as CTNNB1, PTCH1, MLL2, SMARCA4, and TP53.

Historically, medulloblastoma has been classified as either standard or high risk on the basis of biopsy results, but it has long been suspected that it was a group of genetically distinct cancers with different prognoses. Extensive research has provided insight into the biologic processes involved in these tumors and has underscored the molecular heterogeneity of this disease.

"Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp on what gene mutations drive each molecular subtype," said coauthor Scott Pomeroy, MD, PhD, neurologist-in-chief at Children's Hospital Boston and a neuro-oncologist at Dana-Farber/Children’s Hospital Boston in Massachusetts. "For the first time, we'll be able to classify and treat medulloblastoma based on molecular typing, providing the best therapy with the fewest long-term consequences," he explained.

Short, Intermediate, and Long Term

In an interview, Dr. Pomeroy outlined what these data could mean for practicing clinicians. In the short term, they add to previous research about the subtypes and specific molecular markers. "We will be looking at the various markers and determining which are the most robust," he said. "In the past year, discussions have been active, and clinical trials looking at these markers are being developed."

For more intermediate goals, Dr. Pomeroy pointed out that they are looking at several of the molecular mutations as targets for therapy. For example, it is likely that for mutations in the hedgehog subtype, "tumors would be responsive to drugs that target the hedgehog pathway," he said, adding that "this is being evaluated now in phase 2 trials."

He noted that they discovered a molecule that wasn't previously linked to WNT signaling. "There are drugs being developed to block DDX3X, and we will be going forward with trials."

In the longer term, Dr. Pomeroy notes that they hope to use these data to come up with new approaches for treating this tumor. "But it will take years to get there," he said. "Short-term goals will happen in 1 or 2 years, intermediate goals in the next 5 years."

Subtypes Identified

A large research project, in which it took more than 20 years to collect a sufficient number of tumor samples, revealed that medulloblastoma has 4 distinct molecular variants, as previously reported by Medscape Medical News. Each one has a different clinical pattern, which has immediate treatment implications. The specific subtypes also have distinct survival rates, ranging from 20% to 90%.

In an editorial that accompanied the results of that research project (J Clin Oncol. 2011:29:1395-1398), which were described in 4 separate papers published simultaneously in the Journal of Clinical Oncology (2011:29:1400-1407, 1408-1414, 1415-1423, 1424-1430), the editorialists note that the "the time has come for many things in medulloblastoma."

The tumor tissue was genotyped to obtain some of these results, but the 4 subtypes can be determined with standard immunohistochemistry. This is considered to be "remarkable," write editorialists Michelle Monje, MD, PhD, Philip Beachy, PhD, and Paul Fisher, MD, who are all from Stanford University in Palo Alto, California.

Because this technique is both readily accessible and relatively inexpensive, it "could allow for rapid transition of a molecular medulloblastoma classification system into clinical practice," they explain.

Study Details

In their study, Dr. Pomeroy and colleagues used next-generation sequencing technologies to analyze the full complement of somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs.

A total of 1908 mutations were detected in 1671 of 18,863 genes sequenced, and the researchers confirmed 20 candidate mutations in selected genes (CTNNB1, DDX3X, SMARCA4, TP53, and CTDNEP1).

The preliminary functional studies implicate DDX3X as a candidate component of pathogenic WNT/beta-catenin signaling. In a broader sense, DDX3X mutations have recently been reported in chronic lymphocytic leukemia and head and neck cancers. Both of these tumor types have subsets of tumors with dysregulated WNT signaling.

Studies that will investigate whether mutant DDX3X functions in conjunction with beta-catenin in these contexts can provide insight into this multifaceted molecule and "open potential avenues for novel therapies," they note.

"The delineation of nuclear receptor corepressor complex molecules as altered in medulloblastoma provides new insight into the pathogenesis of this deadly childhood disease," the researchers conclude.

It is possible that some of these findings can be translated to patients relatively quickly. For example, it might be possible to rapidly classify individual tumors and tailor treatment on the basis of each subtype's known prognosis. Additionally, clinical trials of SHH-blocking drugs are underway for other cancers, and could include patients with the medulloblastoma subtype driven by SHH mutations in the next few years.

The study was supported by the National Human Genome Research Institute, the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Canadian Institutes of Health, German Cancer Aid, St. Baldrick's Foundation, the Mullarkey Research Fund, the Pediatric Brain Tumor Foundation, and the Howard Hughes Medical Institute. Coauthor Matthew Meyerson, MD, PhD, reports being a paid consultant for and equity holder in Foundation Medicine, and being a paid consultant for Novartis. Coauthor Yoon-Jae Cho, MD, reports serving on an advisory board for Novartis.

Nature. Published online July 22, 2012.

    
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