小柯机器人

美国斯坦福大学Michael P. Snyder等研究人员合作揭示人类癌症基因组中反复出现的重复扩展。2022年12月14日，《自然》杂志在线发表了这项成果。

研究人员在横跨29种癌症类型的2622个癌症基因组中确定了串联重复（TR）的扩展。在7种癌症类型中，研究人员发现了160个反复出现的重复扩增（rRE），其中大部分（155/160）是亚型特异的。研究人员发现rRE在基因组中的分布是不均匀的，在候选顺式调控元件附近富集，这表明在基因调控中的潜在作用。在34%的肾细胞癌样本中检测到一个rRE，即GAA-重复扩增，位于UGT2B7第一个内含子的调控元件附近，并通过长读DNA测序进行了验证。此外，在初步实验中，用一种GAA靶向分子处理藏有这种rRE的细胞，导致细胞增殖的剂量依赖性下降。总的来说，这些结果表明，rRE可能是人类癌症遗传变异的一个重要但未开发的来源，研究人员提供了一个全面的图谱供进一步研究。

据介绍，单一重复性DNA序列的扩展，被称为TR，已知可引起50多种疾病。然而，除了神经系统和神经退行性疾病之外，人们往往没有对重复扩张进行探讨。在一些癌症中，突变在TR的短链中积累，这种现象被称为微卫星不稳定性；然而，较大的重复扩增在癌症中还没有被系统地分析过。

附：英文原文

Title: Recurrent repeat expansions in human cancer genomes

Author: Erwin, Graham S., Grsoy, Gamze, Al-Abri, Rashid, Suriyaprakash, Ashwini, Dolzhenko, Egor, Zhu, Kevin, Hoerner, Christian R., White, Shannon M., Ramirez, Lucia, Vadlakonda, Ananya, Vadlakonda, Alekhya, von Kraut, Konor, Park, Julia, Brannon, Charlotte M., Sumano, Daniel A., Kirtikar, Raushun A., Erwin, Alicia A., Metzner, Thomas J., Yuen, Ryan K. C., Fan, Alice C., Leppert, John T., Eberle, Michael A., Gerstein, Mark, Snyder, Michael P.

Issue&Volume: 2022-12-14

Abstract: Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3,4,5,6,7,8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.

DOI: 10.1038/s41586-022-05515-1

Source: https://www.nature.com/articles/s41586-022-05515-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html