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Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia
Nature ( IF 50.5 ) Pub Date : 2018-08-27 , DOI: 10.1038/s41586-018-0465-8
Shih-Han Lee 1 , Irtisha Singh 2, 3 , Sarah Tisdale 1 , Omar Abdel-Wahab 4 , Christina S Leslie 2 , Christine Mayr 1
Affiliation  

DNA mutations are known cancer drivers. Here we investigated whether mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. RNA sequencing or 3′-end sequencing techniques were applied to normal and malignant B cells from 59 patients with chronic lymphocytic leukaemia (CLL)1–3. We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but instead occurred by intronic polyadenylation. Truncated mRNAs caused by intronic polyadenylation were recurrent (n = 330) and predominantly affected genes with tumour-suppressive functions. The truncated proteins generated by intronic polyadenylation often lack the tumour-suppressive functions of the corresponding full-length proteins (such as DICER and FOXN3), and several even acted in an oncogenic manner (such as CARD11, MGA and CHST11). In CLL, the inactivation of tumour-suppressor genes by aberrant mRNA processing is substantially more prevalent than the functional loss of such genes through genetic events. We further identified new candidate tumour-suppressor genes that are inactivated by intronic polyadenylation in leukaemia and by truncating DNA mutations in solid tumours4,5. These genes are understudied in cancer, as their overall mutation rates are lower than those of well-known tumour-suppressor genes. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through the inactivation of tumour-suppressor genes.The inactivation of tumour suppressor genes at the level of mRNA occurs by the generation of truncated proteins in leukaemia.

中文翻译:

广泛的内含子多腺苷酸化使白血病中的肿瘤抑制基因失活

DNA突变是已知的癌症驱动因素。在这里,我们研究了癌症中上调的 mRNA 事件是否可以在功能上模拟遗传改变的结果。RNA 测序或 3' 端测序技术应用于来自 59 名慢性淋巴细胞白血病 (CLL) 1-3 患者的正常和恶性 B 细胞。我们发现原代 CLL 细胞中截短的 mRNA 和蛋白质普遍上调,这些上调不是由遗传改变产生的,而是由内含子多聚腺苷酸化产生的。由内含子多腺苷酸化引起的截短 mRNA 反复出现(n = 330),并且主要影响具有肿瘤抑制功能的基因。内含子多聚腺苷酸化产生的截短蛋白通常缺乏相应全长蛋白(如 DICER 和 FOXN3)的抑癌功能,一些甚至以致癌方式起作用(例如 CARD11、MGA 和 CHST11)。在 CLL 中,异常 mRNA 加工导致肿瘤抑制基因失活比遗传事件导致此类基因功能丧失更为普遍。我们进一步鉴定了新的候选肿瘤抑制基因,这些基因在白血病中通过内含子多聚腺苷酸化和通过截断实体瘤中的 DNA 突变而失活4,5。这些基因在癌症中的研究不足,因为它们的总体突变率低于众所周知的肿瘤抑制基因。我们的研究结果表明,在癌症诊断中需要超越基因组分析,因为在 DNA 水平上沉默的 mRNA 事件是通过肿瘤抑制基因失活而导致癌症发病机制的广泛因素。
更新日期:2018-08-27
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