Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature. 2018 Sep;561(7721):127-131. doi: 10.1038/s41586-018-0465-8. Epub 2018 Aug 27.
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). 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 tumours. 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.
DNA 突变是已知的癌症驱动因素。在这里，我们研究了在癌症中上调的 mRNA 事件是否能够在功能上模拟遗传改变的结果。我们应用 RNA 测序或 3'-末端测序技术，对 59 例慢性淋巴细胞白血病（CLL）患者的正常和恶性 B 细胞进行了研究。我们发现，在原发性 CLL 细胞中广泛地上调了截断的 mRNA 和蛋白质，这些截断的 mRNA 和蛋白质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。内含子多聚腺苷酸化产生的截断 mRNA 是反复出现的（n=330），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断蛋白通常缺乏相应全长蛋白的肿瘤抑制功能（如 DICER 和 FOXN3），并且有几个甚至以致癌方式发挥作用（如 CARD11、MGA 和 CHST11）。在 CLL 中，通过异常 mRNA 处理使肿瘤抑制基因失活的情况比通过遗传事件导致这些基因功能丧失的情况更为普遍。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失活，在实体瘤中通过截断的 DNA 突变失活。这些基因在癌症研究中尚未得到充分研究，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 事件通过肿瘤抑制基因失活，广泛地成为癌症发病机制的贡献因素。
