Nature Genetics:癌症的武器是“进化”?科学家发现癌基因在染色体外DNA中扩增,可促进肿瘤发展

2020-08-21 生物探索 生物探索

ecDNA的存在将改变驱动癌症的癌基因的表达方式,癌基因和其周围的调控区域摆脱了染色体的束缚,从而促进了肿瘤生长。

染色体外DNA(ecDNA),是一种从稳定的基因组DNA上脱落下来的DNA,以单链或双链环状存在,可促进肿瘤细胞的癌基因的表达。此外,ecDNA上带有的原癌基因使肿瘤细胞对环境具有更强的适应性,可以响应肿瘤内部环境的变化。

先前的研究推测,本质上来说,癌症的诱发是一种“进化”的表现。ecDNA的存在将改变驱动癌症的癌基因的表达方式,癌基因和其周围的调控区域摆脱了染色体的束缚,从而促进了肿瘤生长,也在肿瘤耐药中发挥了关键的作用。

近日,加利福尼亚大学圣迭戈分校的一支研究团队发表在《Nature Genetics》上的一篇名为“Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers”的文章,首次揭示了多种癌症存在ecDNA扩增的现象。具体而言,至少14%的肿瘤存在ecDNA,其他恶性肿瘤中的ecDNA扩增频率会更高。因此,通过靶向ecDNA来干扰肿瘤生长、治疗耐药和预防复发是治疗癌症的一个有潜力的方向。

Doi:10.1038/s41588-020-0678-2

在这项研究中,研究人员通过对3,212名癌症患者的全基因组测序数据的分析,考察了ecDNA扩增的频率。结果显示,ecDNA扩增经常发生在多种癌症中,而不是血液或正常组织中。这意味着,癌基因主要富集在在扩增的ecDNA上,包括最常见的复发性癌基因,这将导致更高的癌基因转录水平,从而加速了癌症的进展。

值得注意的是,在25种癌症类型中均观察到了基于ecDNA的环状扩增子。甚至,在最具侵袭性的的癌症中,例如胶质母细胞瘤,肉瘤和食道癌,高频出现环状ecDNA的扩增子。

跨肿瘤和非肿瘤组织的环状扩增频率(部分截图)

于是,研究人员对环状ecDNA扩增的转录结果进行分析。正如预期推测的那样, 他们发现在所有扩增子类别中,DNA拷贝数(DNA-CN)与癌基因的表达水平高度相关。这意味着,环状ecDNA的扩增可能是导致肿瘤异质性的根本性原因,简单来讲,这种扩增现象会促进肿瘤的生长和侵袭能力。

扩增子类的基因表达

为了进一步研究发生ecDNA扩增的癌症是否与侵袭性生物学特征相关,研究人员检查了ecDNA的扩增对淋巴结的影响。结果发现,ecDNA的扩增与肿瘤侵袭性相关。此外,与无扩增的肿瘤患者相比,含有ecDNA扩增的肿瘤患者的5年生存率明显更差。

循环扩增造成的不良影响

总之,该项研究发现了环状ecDNA在癌症的发生和发展中的关键作用,它不仅促进了DNA的“压缩”和癌基因的转录,而且对癌症患者的可能病程和结局有着不良的影响。

当然,如果我们能找到ecDNA上的某个和癌症直接相关的基因,那么不仅可以将ecDNA的扩增作为癌症检测标记物,而且还能利用靶向ecDNA来干扰肿瘤生长、治疗耐药和预防复发。

原始出处:

Hoon Kim, Nam-Phuong Nguyen, et al. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nature Genetics , 1–7, 2020.

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    2020-10-11 liye789132251
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    2020-11-25 huperzia
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encryptionId=4363e929ad, topicName=Gene)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=63a4277, createdName=cy0324, createdTime=Sat May 01 04:00:30 CST 2021, time=2021-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1802659, encodeId=df4d180265924, content=<a href='/topic/show?id=acfae485578' target=_blank style='color:#2F92EE;'>#科学家发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74855, encryptionId=acfae485578, topicName=科学家发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e572480, createdName=旅苦化文_208, createdTime=Sun Aug 01 11:00:30 CST 2021, time=2021-08-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1734250, encodeId=c32d1e3425095, content=<a href='/topic/show?id=d4f412668a4' target=_blank style='color:#2F92EE;'>#NET#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, 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=Sat Apr 17 05:00:30 CST 2021, time=2021-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1686350, encodeId=428d1686350d6, content=<a href='/topic/show?id=66f3e93862' target=_blank style='color:#2F92EE;'>#Genet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, 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 Jun 14 17:00:30 CST 2021, time=2021-06-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1331737, encodeId=e8bd1331e3791, 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=26, 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=Sat Aug 22 15:00:30 CST 2020, time=2020-08-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1373967, encodeId=110213e396797, content=<a href='/topic/show?id=3644e1286f1' target=_blank style='color:#2F92EE;'>#癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71286, encryptionId=3644e1286f1, topicName=癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Aug 22 15:00:30 CST 2020, time=2020-08-22, status=1, ipAttribution=)]
    2021-05-01 cy0324
  5. [GetPortalCommentsPageByObjectIdResponse(id=1969131, encodeId=6b2e196913132, content=<a href='/topic/show?id=44b482858c1' target=_blank style='color:#2F92EE;'>#肿瘤发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=82858, encryptionId=44b482858c1, topicName=肿瘤发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a885259, createdName=yourmama, createdTime=Thu Jun 17 17:00:30 CST 2021, time=2021-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884606, encodeId=7329188460664, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, 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encryptionId=4363e929ad, topicName=Gene)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=63a4277, createdName=cy0324, createdTime=Sat May 01 04:00:30 CST 2021, time=2021-05-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1802659, encodeId=df4d180265924, content=<a href='/topic/show?id=acfae485578' target=_blank style='color:#2F92EE;'>#科学家发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74855, encryptionId=acfae485578, topicName=科学家发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e572480, createdName=旅苦化文_208, createdTime=Sun Aug 01 11:00:30 CST 2021, time=2021-08-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1734250, encodeId=c32d1e3425095, content=<a href='/topic/show?id=d4f412668a4' target=_blank style='color:#2F92EE;'>#NET#</a>, beContent=null, objectType=article, channel=null, 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createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Aug 22 15:00:30 CST 2020, time=2020-08-22, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=1969131, encodeId=6b2e196913132, content=<a href='/topic/show?id=44b482858c1' target=_blank style='color:#2F92EE;'>#肿瘤发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=82858, encryptionId=44b482858c1, topicName=肿瘤发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a885259, createdName=yourmama, createdTime=Thu Jun 17 17:00:30 CST 2021, time=2021-06-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884606, encodeId=7329188460664, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, 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level=null, likeNumber=27, 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=Sat Apr 17 05:00:30 CST 2021, time=2021-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1686350, encodeId=428d1686350d6, content=<a href='/topic/show?id=66f3e93862' target=_blank style='color:#2F92EE;'>#Genet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, 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 Jun 14 17:00:30 CST 2021, time=2021-06-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1331737, encodeId=e8bd1331e3791, 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=26, 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=Sat Aug 22 15:00:30 CST 2020, time=2020-08-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1373967, encodeId=110213e396797, content=<a href='/topic/show?id=3644e1286f1' target=_blank style='color:#2F92EE;'>#癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71286, encryptionId=3644e1286f1, topicName=癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Aug 22 15:00:30 CST 2020, time=2020-08-22, status=1, ipAttribution=)]
    2021-04-17 canlab
  7. 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createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Aug 22 15:00:30 CST 2020, time=2020-08-22, status=1, ipAttribution=)]
  8. 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