Cooke Susanna L, Shlien Adam, Marshall John, Pipinikas Christodoulos P, Martincorena Inigo, Tubio Jose M C, Li Yilong, Menzies Andrew, Mudie Laura, Ramakrishna Manasa, Yates Lucy, Davies Helen, Bolli Niccolo, Bignell Graham R, Tarpey Patrick S, Behjati Sam, Nik-Zainal Serena, Papaemmanuil Elli, Teixeira Vitor H, Raine Keiran, O'Meara Sarah, Dodoran Maryam S, Teague Jon W, Butler Adam P, Iacobuzio-Donahue Christine, Santarius Thomas, Grundy Richard G, Malkin David, Greaves Mel, Munshi Nikhil, Flanagan Adrienne M, Bowtell David, Martin Sancha, Larsimont Denis, Reis-Filho Jorge S, Boussioutas Alex, Taylor Jack A, Hayes Neil D, Janes Sam M, Futreal P Andrew, Stratton Michael R, McDermott Ultan, Campbell Peter J
Cancer Genome Project, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Lungs for Living Research Centre, Rayne Institute, University College London, London WC1E 6JF, UK.
Nat Commun. 2014 Apr 9;5:3644. doi: 10.1038/ncomms4644.
Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
癌症通过突变而演变，逆转录转座子的体细胞重新激活就是这样一种突变过程。种系逆转录转座可导致加工假基因的产生，但这种情况是否会在体细胞中发生尚未得到评估。在此，我们在660个癌症样本的测序数据中筛查体细胞获得的假基因。我们在17个样本中发现了42个此类事件，尤其在非小细胞肺癌（27个样本中有5个）和结直肠癌（11个样本中有2个）中。基因组特征与种系LINE元件逆转录转座的特征相似，常见靶位点重复（67%）、插入点处的共有TTTTAA位点、反向重排（21%）、5'端截短（74%）和多聚腺苷酸尾巴（88%）。转录结果包括假基因从靶基因的非翻译区或内含子表达。此外，一个整合到肿瘤抑制基因MGA的启动子和第一个外显子中的体细胞假基因，消除了该等位基因的表达。因此，加工假基因的形成代表了癌症发展过程中出现的一类新的突变，其功能后果可能因基因组背景而异。
