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Nat Genet:为何癌症偏爱男性?是X染色体拯救了她们

2016-11-23 生物探索

导语:美国国家癌症研究所的数据显示,男性比女性患癌风险高出20%。那么为何癌症偏爱男性?这个问题长期以来一直困扰着人们。近日,科学家们从遗传学的角度给出了答案。他们发现女性失活的那一条X染色体对此作出了重要的贡献。为何男性比女性更容易患癌?这是个古老的难题。在一项新研究中,波士顿的科学家给出了遗传学解释。相关结果于11月21日发表在Nature Genetics杂志。研究人员揭示,女性细胞中携

导语:美国国家癌症研究所的数据显示,男性比女性患癌风险高出20%。那么为何癌症偏爱男性?这个问题长期以来一直困扰着人们。近日,科学家们从遗传学的角度给出了答案。他们发现女性失活的那一条X染色体对此作出了重要的贡献。

为何男性比女性更容易患癌?这是个古老的难题。在一项新研究中,波士顿的科学家给出了遗传学解释。相关结果于11月21日发表在Nature Genetics杂志。研究人员揭示,女性细胞中携带有一些能保护基因的额外拷贝,这些拷贝可以防御细胞生长失控。

“男性比女性患癌风险高出20%”

“几乎每一种癌症,男性的发生率都比女性高。在某些情况下,这种差异可能很小,只有几个百分点,但在某些癌症,男性发病率是女性的两到三倍。”本文共同作者,Broad研究所和马萨诸塞州综合医院的医学博士Andrew Lane说,“美国国家癌症研究所的数据显示,男性比女性患癌风险高出20%。通过数据的转化可以得知,每年大约有150000例新增男性癌症病例。”


从Nature Genetics统计的图表可以看出,从1975年至2015年,男性在肺癌、支气管癌、膀胱癌、肾癌以及脑癌中的发病率始终高于总女性的发病率。

将目标锁定在失活的X染色体上

尽管两性之前的癌症风险差距一直存在,但很难分辨出原因。过去人们认为,男性吸烟或者暴露在危险的化工环境中使他们更容易患癌。但后来证明这是不充分的,因为即使吸烟率下降以及职业模式发生了改变,男性仍比女性更容易患多种癌症,包括一些与烟草相关的肾癌、膀胱癌以及口腔癌等。

以前的研究发现,一种白血病与KDM6A基因突变有关,该基因位于X染色体。如果KDM6A是一种抑癌基因,负责阻止细胞分裂失控,那么它发生突变会导致癌症。

人们可能认为女性因为具有两条X染色体,因而细胞更容易受到该突变的攻击。在胚胎形成的过程中,女性细胞中的其中一条X染色体是关闭的,因而KDM6A突变只在具有活性的X染色体上活跃,因此对女性细胞分裂的影响与对男性的影响相同。事实证明,女性细胞中失活的X染色体上的某些基因可以“避开”一些状态和功能的关闭,被“唤醒”的基因恰好可以进行KDM6A复制,这些“有益”的拷贝数可以防止细胞癌变。

在这项新研究中,研究人员探讨了位于失活的X染色体上的全功能肿瘤抑制基因,以解释为何癌症偏爱男性细胞的现象。研究人员将这类基因称为“EXITS”,是“Escape from X-Inactivation Tumor Suppressors”的简称。

Lane说,“根据这项理论,癌症在男性中更常见的原因是,男性细胞中EXITS 基因只需一个拷贝存在一个有害突变就会发生癌变。相比之下,女性细胞需要两个拷贝都发生突变才会癌变。”

EXITS基因,让癌症偏爱男性

为了验证这一假说,研究人员仔细检查了4000多份肿瘤样本的基因组。这些样本涉及到了21种癌症。他们寻找了这些癌症中的各类异常,包括突变等,并检查这些异常在男性细胞中更常见还是在女性细胞中更常见。

最后研究人员得到了一个惊人的结果,他们发现近800个基因只存在于X染色体中,其中6个基因在男性细胞中更容易突变,分别为ATRX、CNKSR2、DDX3X、KDM5C、KDM6A和MAGEC3。另外的18000个基因没有表现出性别失衡的突变率。6个常在男性细胞中发生突变的基因,其中5个是已知的能避开X染色体失活,因而成为了EXITS基因的候选基因。

“事实上,容易在男性细胞中发生突变的基因仅被发现于X染色体上,其中一些被称为肿瘤抑制基因且能避开X染色体失活,因而它充分证明了我们上面的假说。” Lane 说,“在女性细胞中,某些基因中具有功能的拷贝所提供的保护,有助于解释女性的癌症发病率为何比较低。”

这项研究的另一种启示是,许多癌症在男性和女性中可能会通过不同的分子途径来发生。为了避免遗传自身对癌症的抵抗,与男性相比,女性体内的肿瘤可能会利用其他的遗传途径来发展。为了探索这种可能性,研究人员建议,未来癌症治疗的临床研究能利用到统计动力学,也就是说采用足够的肿瘤组织样本来研究男性和女性由于肿瘤遗传差异而产生的不同治疗反应。

一图了解为何肿瘤偏爱男性

如果通过以上描述,你还是不明白为何癌症偏爱男性,那么就来看看以下示意图吧。


图B为男性和女性X染色体上的传统肿瘤抑制基因(TSGs)。肿瘤抑制基因的单一有害突变在男性和女性细胞中发生的概率相同。因为男性只有一条X染色体,女性虽然具有两条X染色体,但只有一条具有活性(Xa,粉红色),另外一条没有活性(Xi,紫色)。

图C为EXITS基因的行为模型。在女性细胞中,EXITS基因有两个活跃的等位基因,因而等位基因能使细胞免受单个基因突变带来的影响。EXITS基因完全失活可能需要等位基因都发生突变,或者是说失活的那条染色体上的基因也发生突变。

对于男性,一个突变可能就会带来严重的影响,因为Y染色体上没有EXITS基因的等位基因。因而男性更容易因为传统肿瘤抑制基因突变而生成癌症。另外,由于能逃脱X染色体失活的基因具有Y染色体同源基因的冗余功能,因而这些基因突变更容易使那些Y染色体缺失的男性患癌。

本文图表均来自Nature Genetics官网。

原始出处:

Andrew Dunford, David M Weinstock,Virginia Savova,Steven E Schumacher,John P Cleary,Akinori Yoda,Timothy J Sullivan,Julian M Hess, Alexander A Gimelbrant,Rameen Beroukhim.Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.NATURE GENETICS.21 November 2016


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    2017-02-20 cy0324
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  3. [GetPortalCommentsPageByObjectIdResponse(id=2048745, encodeId=5ea52048e45ef, content=<a href='/topic/show?id=4363e929ad' target=_blank style='color:#2F92EE;'>#Gene#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=87, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7929, encryptionId=4363e929ad, topicName=Gene)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=63a4277, createdName=cy0324, createdTime=Mon Feb 20 13:28:00 CST 2017, time=2017-02-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1951862, encodeId=371419518624c, content=<a href='/topic/show?id=8cb2188852b' target=_blank style='color:#2F92EE;'>#X染色体#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=85, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=18885, encryptionId=8cb2188852b, topicName=X染色体)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=845e216, createdName=cqlidoudou, createdTime=Sat Aug 05 08:28:00 CST 2017, time=2017-08-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1733806, encodeId=70881e3380618, content=<a href='/topic/show?id=d4f412668a4' target=_blank style='color:#2F92EE;'>#NET#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12668, encryptionId=d4f412668a4, topicName=NET)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7ea033781210, createdName=canlab, createdTime=Wed Jun 14 06:28:00 CST 2017, time=2017-06-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1686043, encodeId=2fbb1686043d0, content=<a href='/topic/show?id=66f3e93862' target=_blank style='color:#2F92EE;'>#Genet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=72, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7938, encryptionId=66f3e93862, topicName=Genet)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d3e128296421, createdName=江川靖瑶, createdTime=Mon Feb 20 22:28:00 CST 2017, time=2017-02-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1881453, encodeId=e50918814531a, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Thu May 25 00:28:00 CST 2017, time=2017-05-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1331627, encodeId=06cc133162e47, content=<a href='/topic/show?id=d85a6181e4d' target=_blank style='color:#2F92EE;'>#染色体#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=61817, encryptionId=d85a6181e4d, topicName=染色体)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKnILSXam1GxPwj04ylEzibYLFA2eGl5Ev02klt80JA0xejMPqrn0mYHNNnLEgyqYTPbicXpY3tn6SA/132, createdBy=38fd2500059, createdName=新生儿张玉军, createdTime=Fri Nov 25 00:28:00 CST 2016, time=2016-11-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=157692, encodeId=e02f15e69211, content=染色体真的好强大啊!, beContent=null, objectType=article, channel=null, level=null, likeNumber=88, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=7a3e1928208, createdName=顾小北大魔王, createdTime=Wed Nov 23 20:05:34 CST 2016, time=2016-11-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=157598, encodeId=0f4815e598a2, content=好文章,值得学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=89, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/12/17/3872cad7a53dc9dcbd08202fb6313cf4.jpg, createdBy=2cb71609450, createdName=KO229256262, createdTime=Wed Nov 23 09:44:58 CST 2016, time=2016-11-23, status=1, ipAttribution=)]
    2017-06-14 canlab
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    2017-05-25 liye789132251
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    2016-11-23 顾小北大魔王

    染色体真的好强大啊!

    0

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    2016-11-23 KO229256262

    好文章,值得学习

    0

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美国福克斯蔡斯癌症中心的 Zaorsky 博士在 Annals of Oncology 上发表了对癌症患者死亡原因的研究结果。癌症是人类死亡的第二大原因,仅次于心脏疾病,该研究旨在依据日历年、患者年龄和确诊后的生存时长来阐明癌症患者的死亡特征,从而识别不同死亡风险的患者、可能继发第二种癌症的患者和非癌症死亡高风险的患者。Zaorsky 博士提取了美国国家癌症研究所 SEER 项目的数据,涵盖 19

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