Nat Genet:靶向疗法难奏效?都是肿瘤异质性惹的祸!

2017-07-12 佚名 转化医学网

2016年,来自美国希德斯-西奈医疗中心(Cedars Sinai Medical Center)研究人员的一项新研究在食管肿瘤组织样本中鉴定出超过2,000个遗传突变,在阐明了癌症复杂性的同时,他们的研究结果显示甚至是在同一肿瘤组织的不同区域,不同的肿瘤细胞也有着大相径庭的遗传模式。

2016年,来自美国希德斯-西奈医疗中心(Cedars Sinai Medical Center)研究人员的一项新研究在食管肿瘤组织样本中鉴定出超过2,000个遗传突变,在阐明了癌症复杂性的同时,他们的研究结果显示甚至是在同一肿瘤组织的不同区域,不同的肿瘤细胞也有着大相径庭的遗传模式。

该研究对应的论文发表在最新出版的NatureGenetic上。该研究在一定程度上解释了为什么根据特定遗传缺陷设计的靶向疗法战胜癌症是如此困难。对患者的肿瘤进行单次活检之后,外科医生仅仅可以解码部分肿瘤细胞的遗传变异。除此之外,肿瘤组织在生长过程中会不断地改变他们的区域构成,这也在极大程度上为癌症的靶向治疗带来了障碍。

Cedars-Sinai医学院血液学和肿瘤学副教授和研究科学家,此次多中心联合项目的协调员Dechen Lin博士说:“肿瘤并不是一种单一疾病。肿瘤组织中有数百万个细胞,这些细胞中的很大一部分彼此各不相同。”

长久以来,Cedars Sinai研究团队一直在关注难治性的食管鳞状细胞癌。这类癌变细胞会在不同程度上对食道进行攻击,尤其是连接喉咙与胃的中空管。根据美国癌症协会的数据,食道癌患者的五年存活率仅仅约为20%。

为了建立食道癌的突变目录,研究使用大功率计算机对13个病人的51个肿瘤样本测序数据进行了深入挖掘。通过复杂的算法,他们在表观遗传学层面对食道癌的发生过程进行了深入分析。

有赖于上述技术与研究,研究人员在选择的肿瘤样本中确定了2,178个与食道癌发病显着相关的遗传变异,其中几十个变异已被证明与已知的食管癌风险变异相关。另外,研究人员还在同一肿瘤样本的一些区域中检测到许多不同的重要突变,突出了癌细胞的复杂性。这一发现同时证明了使用单活检方法(临床中的标准方法)对癌症遗传构成不准确解释的可能性。

除了建立了这些食道癌发病相关基因突变目录之外,研究人员重建了食道癌的发展“传记”,前所未有地揭示了食道癌细胞生命周期中存在的一些特异突变。

“这项研究开拓了肿瘤异质性和癌相关变异研究的前沿,同时,这项研究也是全球最先专注于来自单个肿瘤内不同区域的表观遗传变化研究。”本研究的共同资深作者,生物医学科学副教授和Cedars Sinai生物信息和功能基因组中心主任Benjamin Berman博士说。

为了应对多样性数据带来的挑战,项目合作单位Berman实验室项目科学家和该研究的共同主要作者之一Huy Dinh博士开发了针对于表观遗传和基因组数据的创新计算方法。

展望未来,研究者计划将他们的分析技术应用于其他癌症,接着探索他们迄今确定的食道癌相关基因组和表观遗传变化。他们认为他们的工作是有着解决个性化治疗过程中日益凸显的耐药性产生问题。

“证据表明,肿瘤异质性是癌症耐药性产生和治疗失败的主要原因之一,”该研究的另一位作者,医学教授Phillip Koeffler和Cedars-Sinai肿瘤研究中心的Mark Goodson教授说。 “鉴于这种情况,破译肿瘤的基因组多样性和进化多样性可以为识别新靶标和设计个性化医疗策略提供基础。”


原始出处:

Jia-Jie Hao, De-Chen Lin, Huy Q Dinhet al. Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma, Nature Genetics (2016).

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    2018-05-22 canlab
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Nature:T细胞疗法可延长白血病患者生存期?

当免疫学家Michel Sadelain在2007年时首次对一种经过基因工程改良的抗癌性T细胞进行试验时,他努力寻找着愿意参与该试验的患者。他所提出的治疗方案是:从肿瘤患者体内分离一些T细胞,利用基因工程技术对其进行改良,使其具有肿瘤识别能力,随后再将T细胞注射回患者体内;小鼠研究已经表明这种治疗方法具有可行性。但是Sadelain并没有因为同事拒绝提供患者而迁怒于他们。他说:“

JAMA综述:对肥胖患者的评估及生活方式管理(下)

作者:罗伯特·F·库什纳等(美国芝加哥西北大学范伯格医学院内分泌学、代谢和分子医学部等) 接上:JAMA综述:对肥胖患者的评估及生活方式管理 来自系统评价的临床建议(上) 治疗 给初级保健机构临床医师的指导 成人超重和肥胖管理指南(2013年)为减重的实现和维持提供了循证建议。指南基于一篇系统评价,为超重和肥胖危险的评估给出了推荐建议,介绍了减重的益处,并且为实现减

老年痴呆靶向性疗法新希望

近日,一项发表于国际著名杂志Nature Structural and Molecular Biology上的研究论文中,来自伊利诺伊大学的科学家们通过研究确定了一种存在于大脑斑块细纤维中的特殊分子结构,该分子结构或是阿尔兹海默氏症发病的标志,这种分子名为β淀粉样蛋白-42,其对神经细胞具有毒性,而且被认为可以刺激疾病的级联反应。 理解纤维中β淀粉样蛋白-42的氨基酸长链形式的物质结构,对于揭示