人类癌症基因组中的反复复扩张
Graham S Erwin1, Gamze Gürsoy2,3, Rashid Al-Abri4
1Department of Genetics, Stanford University, Stanford, CA, USA. gerwin@stanford.edu.
Nature
|December 14, 2022
概括
已知会导致疾病的DNA重复扩张最近被认为是各种癌症的重要因素. 研究人员发现了与癌症亚型和潜在基因调节相关的特定重复扩张,为癌症研究提供了新的途径.
科学领域:
- 基因组学
- 癌症生物学
- 分子遗传学
背景情况:
- 双重重复 (TR) 扩张导致50多种疾病,但它们在癌症中的作用尚未得到充分研究.
- 虽然短TR的微卫星不稳定性在癌症中已知,但更大的TR扩张在很大程度上尚未研究.
- 现有的研究主要集中在神经系统疾病上,忽视了其他疾病的TR扩散.
研究的目的:
- 系统地识别和分析不同癌症类型的并列重复扩散.
- 研究癌症中复发性复发扩张的基因组分布和潜在的调节作用.
- 探索针对癌细胞中特定的重复扩张的治疗潜力.
主要方法:
- 对来自29种不同癌症的2622个癌症基因组进行分析,以确定TR扩散.
- 生物信息分析以检测复发性扩张 (rRE) 并评估其基因组分布.
- 长读DNA测序用于验证特定的rRE,包括在UGT2B7附近的GAAA重复扩展.
- 预先的体外实验,以评估针对特定rRE对癌细胞增殖的影响.
主要成果:
- 在29种癌症类型的2622种癌症基因组中发现了TR扩张.
- 在七种癌症类型中发现了160种复发性扩散 (rREs),其中大多数是亚型特异性的.
- 发现rRE在候选 cis调节元素附近富含,这表明它在基因调节中的作用.
- 在34%的细胞癌样本中检测到UGT2B7附近的GAAA重复扩张,通过测序验证.
- 在初步实验中观察到与GAAA向分子治疗后癌细胞增殖的剂量依赖性降低.
结论:
- 经常重复扩散是人类癌症遗传变异的重要而未被探索的来源.
- 这些发现突显了rRE在推动癌症发展方面的潜力,并表明它们作为癌症生物标志物的实用性.
- 提供了全面的rRE目录,为进一步研究其功能作用和瘤治疗向铺平了道路.
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