BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, 518083, China.
BGI Genomics BGI-Shenzhen, Shenzhen, 518083, China.
Mol Genet Genomics. 2018 Jun;293(3):737-746. doi: 10.1007/s00438-018-1416-7. Epub 2018 Jan 12.
The key roles of the TP53 mutation in cancer have been well established. TP53 is the most frequently mutated gene, and its inactivation is widespread among human cancer types. However, the landscape of genomic alterations in human cancers stratified by the TP53 mutation has not yet been described. We obtained somatic mutation and copy number change data of 6551 regular-mutated samples from the Cancer Genome Atlas (TCGA) and compared significantly mutated genes (SMGs), copy number alterations, mutational signatures and mutational strand asymmetries between cancer samples with and without the TP53 mutation. We identified 126 SMGs, 30 of which were statistically significant in both the TP53 mutant and wild-type groups. Several SMGs, such as VHL, SMAD4 and PTEN, showed a mutation bias towards the TP53 wild-type group, whereas ATRX, IDH1 and RB1 were more prevalent in the TP53 mutant group. Five mutational signatures were extracted from the combined TCGA dataset on which mutational asymmetry analysis was performed, revealing that the TP53 mutant group exhibited substantially greater replication and transcription biases. Furthermore, we found that alterations of multiple genes in a merged mutually exclusive network composed of BRAF, EGFR, PAK1, PIK3CA, PTEN, APC and TERT were related to shortened survival in the TP53 wild-type group. In summary, we characterized the genomic differences and similarities underlying human cancers stratified by the TP53 mutation and identified multi-gene alterations of a merged mutually exclusive network to be a poor prognostic factor for the TP53 wild-type group.
TP53 突变在癌症中的关键作用已经得到充分证实。TP53 是最常发生突变的基因，其失活在人类癌症类型中广泛存在。然而，尚未描述按 TP53 突变分层的人类癌症的基因组改变图谱。我们从癌症基因组图谱（TCGA）中获得了 6551 个常规突变样本的体细胞突变和拷贝数变化数据，并比较了有和没有 TP53 突变的癌症样本中显著突变基因（SMGs）、拷贝数改变、突变特征和突变链不对称性。我们确定了 126 个 SMGs，其中 30 个在 TP53 突变和野生型组中均具有统计学意义。一些 SMGs，如 VHL、SMAD4 和 PTEN，显示出对 TP53 野生型组的突变偏向性，而 ATRX、IDH1 和 RB1 在 TP53 突变组中更为常见。从 TCGA 综合数据集提取了 5 个突变特征，并对其进行了突变不对称性分析，结果表明 TP53 突变组表现出明显更大的复制和转录偏向性。此外，我们发现，由 BRAF、EGFR、PAK1、PIK3CA、PTEN、APC 和 TERT 组成的合并互斥网络中的多个基因的改变与 TP53 野生型组的生存时间缩短有关。总之，我们对按 TP53 突变分层的人类癌症的基因组差异和相似性进行了特征描述，并确定了合并互斥网络中的多个基因改变是 TP53 野生型组不良预后的一个因素。
