专访:华人学者顶级杂志解析脑癌最关键基因突变

【字体: 时间:2009年02月19日 来源:生物通

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生物通报道:脑恶性胶质瘤(malignant glioma)被公认为最恶性的脑部肿瘤,也是成人中最为常见的一种原发性恶性脑瘤,近期来自杜克大学医学中心,约翰霍普金斯大学的研究人员等人发现了这种脑癌的最原始,最关键的基因突变, 这不仅对于脑恶性胶质瘤的诊断和治疗意义重大,而且为1931年诺贝尔生理/医学奖获得者提出的“异常细胞内能量代谢是导致癌症发生的原因之一”理论提供了分子遗传学基础,为癌症研究打开了一扇新窗口。

这项研究成果于2月19日公布在世界上医学界最具影响力的《New England Journal of Medicine》(2007年影响因子52.589)杂志上,领导这项研究的是杜克大学病理学系副教授阎海(Hai Yan)博士,其早年毕业于北京大学医学部,获得美国哥伦比亚大学博士学位,曾在约翰霍普金斯大学进行博士后研究,目前任杜克大学医学中心副教授。

阎博士在接受生物通采访的时候表示,“脑部发生病变治疗起来很困难,脑部肿瘤就像是树根,分枝很多很深,目前主要治疗手段就是手术切除,但是不可能切除干净”,“那么为什么不能采用药物治疗的方法呢?这是因为目前还没有找到疗效比较好的化疗药物,而放射性治疗的副作用又较多. 以分子为基础的治疗方法,也就是基因治疗方法最具希望。”

“我们的这种基因治疗方法就象Magic bullet(魔术弹),通过肿瘤特异性分子,精确捕杀肿瘤细胞,因此首先需要找到关键的靶点,而在这项研究中指的就是突变基因。”

这种基因:异柠檬酸脱氢酶(Isocitrate Dehydrogenase,IDH)是一类能量代谢途径中的关键酶。阎博士领导的研究组通过整体基因组测序筛选,发现IDH1和IDH2这两个基因的突变不仅在脑恶性胶质瘤晚期出现,在早期样品中也存在,从而证实了这是脑恶性胶质瘤最早的基因突变,也就是说癌变组织中每个癌变的细胞中都发生了这一基因突变,而且IDH1和IDH2基因突变只出现在病患样品中,在病人的正常组织细胞中没有,这是这项研究最关键的发现之一,因为这样靶向治疗才有意义,也才可能实现。

除此之外,这项研究的另外一个临床意义就是IDH1和IDH2突变基因可以作为临床标记指针,由于不同的胶质瘤中基因表现不同,因此可以很清楚的区分患有各种胶质瘤的病人,方便医师依据不同的病情进行个体化治疗。而且这种临床诊断的实际操作性也很强,由于IDH突变集中在同一位点, 只需要针对IDH突变所在的DNA片段进行测序(花费不多),就可以判断脑恶性胶质瘤的基因型及表现型。

在基础研究方面,这项研究成果还具有一个重要的意义,阎博士向生物通介绍道,“1924年德国生物化学家Otto Warburg提出,癌症发生的最初原因是细胞线粒体中的能量工厂遭到损害导致细胞受损,这一癌症起源理论使他获得了1931年的诺贝尔生理/医学奖,但是之后一直都没有明确这一理论的分子基础。”

“我们的这项研究中的基因IDH是能量代谢途经中一个关键酶,如果IDH发生了变异,那么细胞内的能量代谢就会发生缺陷,这与近期的其它研究成果一起让我们重新认识Otto Warburg当年的理论”,“并且这也提示我们是否可以通过改善调节细胞的氧气能量代谢,以达到预防癌症的发生的目的。”




目前阎博士等人还在进行IDH的进一步研究,也许用不了多久,脑恶性胶质瘤这种最恶性的脑部肿瘤就会有了更好的治疗方法。

华人学者靳更林博士也参与了这项重大成果的研究。

(生物通:王蕾)

附:
阎海博士简介

教育经历:
1991年 北京大学医学院(M.D)
1996年 美国哥伦比亚大学(Ph.D.)
1997-2002年 美国约翰霍普金斯大学(Postdoctoral Fellow)

学术经历:
2002-2003年  美国约翰霍普金斯大学(Research Faculty)
2003-Present 美国杜克大学医学中心(Assistant Professor)
2006-Present 美国杜克大学综合癌症中心

荣誉与奖励:
2001 Daniel Nathans Research Prize, Young Investigator’s Day Award, The Johns Hopkins University
2004 American Cancer Society Institutional Research Grant Individual Award, Duke University
2005 Damon Runyon Cancer Research Foundation Scholar Award
2005-2008 Duke Brain SPORE Career Development Award
2005 Southeastern Brain Tumor Foundation Research Grant Scholar Award
2005 Peter A. Steck Young Investigator's Award
2005 The Bernard F. Fetter Teaching Scholar Award for outstanding teaching and servicing in the undergraduate medical education program at Duke University School of Medicine
2006 Alex’s Lemonade Stand Foundation Innovative Award
2006 Duke University Comprehensive Cancer Center Young Investigator Award
2007 The V Foundation Cancer Research Award
2008 Brain Tumor Society's 2008 Eliza Lorberbaum Chair of Research


获得专利:
1. Yan, H., Papadopoulos, N., Kinzler, K.W., and Vogelstein, B. (2002) Converting Diploidy to Haploidy for Genetic Diagnosis. US Pat. 6399374, 6,475,794, and 7045352.
2. Yan, H., Vogelstein, B., and Kinzler, K.W. (2002) Allelic Variation in Human Gene Expression.
3. Dressman, D., Yan, H., Traverso, G., Kinzler, K.W., and Vogelstein, B. (2003) Transforming Single DNA Molecules into Fluorescent Magnetic Particles for Detection and Enumeration of Genetic Variations.
4. Yan, H., Parsons, D.W., Kinzler, K.W., Velculescu, V.E., Vogelstein, B., and Bigner, D.D. IDH1 and IDH2 mutations in gliomas. (2008) Pending.
5. Yan, H., Bigner, D.D., and Lu, P. siRNA GBM therapy. (2008) Pending.

发表文章(摘选):
1. Yan, H., Krishnan, K., Greenlund, A., Gupta, S., Lim, J.T.E., Schindler, C., Schreiber, R., and Krolewski, J.J. (1996) Phosphorylated interferon- receptor 1 subunit (IFNR1) acts as a docking site for the latent form of the 113KD STAT2 protein.  EMBO J. 15, 1064-1074.
2. Yan, H., Krishnan, K., Lim, J.T.E., Contillo, L.G., and Krolewski, J.J. (1996) Molecular characterization of an interferon- receptor 1 subunit (IFNR1) domain required for TYK2 binding and signaling transduction.  Mol. Cell. Biol. 16, 2074-2082.
3. Yan, H., Piazza, F., Krishnan, K., Piney, R. and Krolewski, J.J. (1998) Definition of the interferon- receptor binding domain on the TYK2 kinase.  J. Biol. Chem. 273(7), 4046.
4. Yan, H., Papadopoulos, N., Marra, G., Perrera, C., Jiricny, J., Boland, C.R., Lynch H.T., Chadwick R.B., de la Chapelle, A., Berg, K., Eshleman, J.R., Yuan, W., Markowitz, S., Laken, S.J., Lengauer, C., Kinzler, K.W., and Vogelstein, B. (2000) Conversion of diploidy to haploidy. Nature 17(403), 723-724.
5. Yan, H., Kinzler, K.W., and Vogelstein, B. (2000) Genetic testing-present and future. (Review) Science 289, 1890-1892.
7. Yan, H., Dobbies, S., Gruber, S.B., Markowitz, S., Romans, K., Gianardiello, F.M., Kinzler, K.W., and Vogelstein, B. (2002) Small changes in expression affect predisposition to tumorigenesis. Nat. Genet. 30, 25-26.
8. Yan, H., Yuan, W.S., Velculescu, V.E., Vogelstein, B., and Kinzler, K.W. (2002) Allelic variation in human gene expression. Science 297, 1143.
9. Dressman, D., Yan, H., Traverso, G., Kinzler, K.W., and Vogelstein, B. (2003) Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. PNAS 100, 8817-8822.
10. Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A., Powell, S.M., Riggins, G.J., Willson, J.K., Markowitz, S., Kinzler, K.W., Vogelstein, B., and Velculescu, V.E. (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554.
7. Wang, Z.H., Shen, D., Parsons D.W., Bardelli, A., Sager, J., Szabo, S., Ptak, J., Silliman, N., Peters, B., van der Heijden, M.S., Parmigiani, G., Yan, H., Wang, TL., Riggins, G., Powell, S.M., Willson, J.K.V., Markowitz, S., Kinzler, K.W., Vogelstein, B., and Velculescu, V.E. (2004) Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304, 1164-1166.
8. Broderick, D.K., Di, C.H., Parrett, T.J., Samuels, Y.R., Cummins, J.M., McLendon, R.E., Fults, D.W., Velculescu, V.E., Bigner, D.D. and Yan, H. (2004) Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas and medulloblastomas. Cancer Res. 64: 5048-5050.
9. Rich, J.N., Rasheed, B.K., Yan, H. (2004) EGFR mutations and sensitivity to gefitinib. N. Engl. J. Med. 351(12):1260-1.
10. Yan, H., and Zhou, W. (2004) Allelic variations in gene expression. (Review) Curr. Opin. Oncol. 16 (1), 39-43.
11.Parrett, T.J., and Yan, H. (2005) Digital karyotyping technology: exploring the cancer genome. (Review)  Expert Rev. Mol. Diagn. 5(6), 917-925.
12. Di, C.H., Liao, S.H., Adamson, D.C., Parrett, T.J., Broderick, D.K., Shi, Q., Lengauer, C., Cummins, J.M., Velculescu, V.E., Fults, D.W., McLendon, R.E., Bigner, D.D., and Yan, H. (2005) Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans-retinoic acid. Cancer Res. 65(3), 919-924.
13. Yan, H. (2005) Snapshot of the allele-specific variation in human gene expression. Methods in Molecular Biology, Pharmacogenomics: Methods and Applications, 311:31-38, Federico Innocenti, Ed.  Humana Press Inc., Totowa, NJ.
14. Yan, H., and Giardiello, F.M. (2006) Brain tumor-polyposis (BTP) syndrome. In: Russell & Rubinstein’s Pathology of Tumors of the Nervous System, 7th ed. McLendon, R.E., Rosenblum, M.K., and Bigner, D.D., Eds. Arnold, London.
15. Yan, H., and Bigner, D. (2006) Digital karyotyping: a powerful tool for cancer gene discovery. Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics. Dunn, M., Jorde, L., Little, P., and Subramaniam, S., Eds. John Wiley & Son, Ltd, Chichester, West Sussex.
16. Solomon, D., Kim, J., Jenkins, S., Ressom, H., Huang, M., Coppa, N., Mabanta, L., Bigner, D., Yan, H., Jean, W., and Waldman, T. (2008) Identification of p18INK4c as a tumor suppressor gene in glioblastoma multiforme. Cancer Res. 68(8), 2564-2569.
17. Parsons, D.W., Jones, S., Zhang, X., Lin, J.H., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.M., Gallia, G.L., Olivi, A., McLendon, R., Rasheed, A., Keir, S., Nikolskaya, T., Nikolsky, Y., Busam, D.A., Tekleab, H., Diaz, L., Jr., Hartigan, J., Smith, D.R., Strausberg, R.L., Marie, S., Shinjo, S., Yan, H., Riggins, G.R., Bigner. D.D., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V.E., Kinzler, K.W. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807 – 1812.
18. Solomon, D., Kim, J., Cronin, J., Sibenaller, Z., Ryken, T., Rosenberg, S., Ressom, H., Jean, W., Bigner, D., Yan, H., Samuels, Y., and Waldman, T. (2008) Mutational Inactivation of PTPRD in Glioblastoma Multiforme and Malignant Melanoma. Cancer Res. 68 (24), 10300-10306.
19. Yan, H., Parsons, D.W., Jin, G., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G.J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K.W., Velculescu, V.E., Vogelstein, B., and Bigner, D.D. (2009) IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360 (8): 765-73.
20. Wortham, M., and Yan, H. (2009) The use of retinoids as differentiation agents against medulloblastoma. CNS Cancer, Models, Prognostic Factors, Targets, and Therapeutic Approaches. Erwin Van Meir, Ed. Springer-Humana, New York..

 

 

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