特殊“跳跃基因”或可驱动食道癌发生

  来自英国癌症研究中心的研究人员在杂志BMC Genomics上刊登了他们的一项最新研究成果，研究者发现一种“跳跃基因”或可驱动食道癌的发生，增加超过四分之三食道癌患者病例。
  研究人员利用一种可以阅读DNA信息的尖端技术对43份食道肿瘤和血液样本中的基因信息进行了分析，从而揭示了这些遗传移动元件如何发生“跳跃”？，名为L1的跳跃基因完全离开原有的位点移动到DNA的新区域中，有时候则会偶然间移动到可以控制细胞生长的基因区域中去。
  研究者发现，在单一肿瘤样本中基因跳跃发生的频率是正常组织中的100倍，而在有些肿瘤中则高达700倍；如果跳跃基因停留在重要基因区域中或附近位置，其就会引发大灾难的发生，比如改变基因的工作机制，使得细胞无限制生长，最终引发癌症。而跳跃基因往往在癌细胞的遗传代码间耍着“跳房子”的游戏，当移动遗传序列置于控制细胞生长的基因中时，其就会改变细胞的行为方式，有时候甚至会引发癌症的发生。
  这或许和肺癌及肠癌的发生相关，因此清楚阐明“跳跃基因”的工作原理或将帮助我们理解癌症的发生机制；最后研究者Kat Arney教授指出，食道癌是最难治疗的癌症之一，而且我们付出了大量努力来阐明引发食道癌的原因，本文研究发现为我们阐明引发食道癌的遗传混乱提供了新的思路，为后期开发新型疗法来诊断、治疗并且监测食道癌的发生提供了新的希望。（转化医学网360zhyx.com）
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Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis
BMC Genomics    doi:10.1186/s12864-015-1685-z
Anna L. Paterson123, Jamie M.J. Weaver12, Matthew D. Eldridge4, Simon Tavaré4, Rebecca C. Fitzgerald2*, Paul A.W. Edwards1* and the OCCAMs Consortium
Background
Mobile elements are active in the human genome, both in the germline and cancers, where they can mutate driver genes.

Results
While analysing whole genome paired-end sequencing of oesophageal adenocarcinomas to find genomic rearrangements, we identified three ways in which new mobile element insertions appear in the data, resembling translocation or insertion junctions: inserts where unique sequence has been transduced by an L1 (Long interspersed element 1) mobile element; novel inserts that are confidently, but often incorrectly, mapped by alignment software to L1s or polyA tracts in the reference sequence; and a combination of these two ways, where different sequences within one insert are mapped to different loci. We identified nine unique sequences that were transduced by neighbouring L1s, both L1s in the reference genome and L1s not present in the reference. Many of the resulting inserts were small fragments that include little or no recognisable mobile element sequence. We found 6 loci in the reference genome to which sequence reads from inserts were frequently mapped, probably erroneously, by alignment software: these were either L1 sequence or particularly long polyA runs. Inserts identified from such apparent rearrangement junctions averaged 16 inserts/tumour, range 0–153 insertions in 43 tumours. However, many inserts would not be detected by mapping the sequences to the reference genome, because they do not include sufficient mappable sequence. To estimate total somatic inserts we searched for polyA sequences that were not present in the matched normal or other normals from the same tumour batch, and were not associated with known polymorphisms. Samples of these candidate inserts were verified by sequencing across them or manual inspection of surrounding reads: at least 85 % were somatic and resembled L1-mediated events, most including L1Hs sequence. Approximately 100 such inserts were detected per tumour on average (range zero to approximately 700).

Conclusions
Somatic mobile elements insertions are abundant in these tumours, with over 75 % of cases having a number of novel inserts detected. The inserts create a variety of problems for the interpretation of paired-end sequencing data.