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Sci Trans Med:致命脑瘤为何“男女有别”?科学家发现背后遗传机制

2019-01-04 探索菌 生物探索

胶质母细胞瘤是最常见的恶性脑瘤,约一半患者在诊断后生存期不超过14个月。而与女性相比,更多的男性患有并死于这种癌症。

胶质母细胞瘤是最常见的恶性脑瘤,约一半患者在诊断后生存期不超过14个月。而与女性相比,更多的男性患有并死于这种癌症。

尽管几十年来,科学家们已经认识到这种男女差异,但这其中的原因他们一直不清楚。近日,圣路易斯华盛顿大学医学院的一个研究小组发现了男女胶质母细胞瘤的不同分子特征,其中细胞周期是影响男性患者存活期的关键,而整合素及其信号传导则对女性患者存活期起关键决定作用。这一重要发现有助于解释患者在治疗反应和存活期上的差异。

01、女性治疗效果更好

在这项研究之前,研究人员先是发现了女性对胶质母细胞瘤的标准治疗比男性更有效。为了帮助理解治疗反应中的性别差异,他们通过MRI扫描对肿瘤生长速度进行了测量,“这可以让你有机会更深入地思考你给病人的药物是否真的有帮助。”华盛顿大学儿科学和神经科学教授、通讯作者Joshua Rubin说。

然后,他们每两个月计算63名(40名男性和23名女性)胶质母细胞瘤患者治疗期间的肿瘤生长速度,这些患者在手术后接受了标准的化学放射治疗。期间研究小组观察到男女性之间最初的肿瘤生长速度相似,但在用常见化疗药替莫唑胺治疗后,只有女性肿瘤生长表现出稳定和显著下降。

为了进一步了解为什么会产生这种差异,作者们接下来研究了患者肿瘤的潜在遗传机制。

02、发现遗传机制

基于2005年启动的一个癌症基因组图谱(TCGA)项目,研究人员运用统计算法将男性或女性特有的基因表达模式与男女患者共有的模式区分开来,并将重点放在性别特异性基因表达上,以确定与男性和女性生存差异相对应的分子亚型。

结果发现,胶质母细胞瘤患者的肿瘤中存在巨大的遗传性别差异,且这些差异与生存率相关。

具体来说,研究人员揭示了,胶质母细胞瘤患者的肿瘤可分为10个不同的亚型——男性和女性各占5个。这些集群的区分以基因活性和男女生存期为特征,且显示出男性生存期均短于女性的特征。随后研究人员在三个其他数据集中验证了这些分型,结果仍表明,即使肿瘤中相似水平激活的基因也可能因性别差异而导致患者存活期不同。

“此外,我们还发现了与最长存活时间相关的遗传途径,男性和女性的遗传途径非常不同。”Rubin说,“例如,在男性中,生存与调节细胞分裂有关,这表明阻止细胞周期进程的药物对男性可能更有效;对女性来说,生存与调节侵袭性(invasiveness)有关,这表明针对整合素及其信号传导的药物对女性可能更有效。这告诉我们,在治疗时最好将男性和女性分开,并检查他们的性别特异性遗传特征。我们通过一系列体外药物筛选来检验这个假设,在这些筛选中,我们让参与者服用了四种相对常见的化学药物,并观察了这些基因的表达与这些药物反应之间的关联,在男性和女性中,都存在明显的相关性。”

03、与荷尔蒙无关

一般来说,由性别差异导致的疾病差异通常与荷尔蒙有关。例如,女性雌激素对女性乳腺癌的发病率显著高于男性。然而,对胶质母细胞瘤的研究发现,性激素并没有直接导致女性和男性的差异。“胶质母细胞瘤中的性别特异性遗传活动不依赖于循环性激素的急性作用,因为该病在生命的各个阶段都存在明显差异。”Rubin解释到。

从更广泛的意义上来说,Rubin期望,这项研究可以鼓励人们更多地思考疾病是如何特异性地影响男性和女性的。“也许我们在治疗男性和女性疾病时不应该使用相同的标准,下一步,我们应该明确制定和评估针对胶质母细胞瘤的性别特异性治疗方案,希望这项研究能启发更具体的治疗方法。”

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    2019-10-28 bsmagic9140
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    2019-01-06 jxrzshh
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源自肿瘤特异性蛋白质编码突变的新抗原可以免于中枢耐受,并且其可产生强烈的免疫应答,作为促进肿瘤排斥的真正抗原。

Nature:用于脑癌治疗的新型个体化治疗性疫苗进行首次人体试验

最近出版Nature杂志公布了I期GAPVAC-101研究的有利数据,测试了治疗具有特定的胶质母细胞瘤的新型治疗概念。

mBio:科学家发现寨卡病毒减毒活疫苗可用于治疗恶性脑瘤

胶质母细胞瘤是人类肿瘤中恶性程度最高的肿瘤之一,患者平均生存期只有14个月左右,常规的治疗后患者复发率几乎达到100%。近日,军事医学研究院秦成峰研究员与国家生物医学分析中心满江红研究员、美国德克萨斯大学史佩勇教授联合攻关等联合攻关,成功将寨卡病毒疫苗株开发为新型溶瘤病毒,为胶质母细胞瘤的临床治疗开辟了新的方向。

Radiology:能从MRI图像中发现提示胶质母细胞瘤生存期、手术效果的线索吗?

本研究旨在通过术前增强容积T1W MRI序列作为评价胶质母细胞瘤预测手术效果及生存期影像学指标的价值。

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