Clinical implications of genomic profiles in metastatic breast cancer with a focus on TP53 and PIK3CA, the most frequently mutated genes.
Clinical implications of genomic profiles in metastatic breast cancer with a focus on TP53 and PIK3CA, the most frequently mutated genes.
复制标题
DOI：
10.18632/oncotarget.15881
复制
发表时间：
2017-04-25
期刊：
影响因子：
--
通讯作者：
Park YH
中科院分区：
文献类型：
--
作者：
Kim JY;Lee E;Park K;Park WY;Jung HH;Ahn JS;Im YH;Park YH
乳腺癌（BC）已经通过大规模基因组分析进行了基因分析。然而，转移性BC（MBC）中遗传改变的作用和临床意义尚未得到评估。因此，我们对37个MBC样品进行了全外显子组测序（WES）和RNA-Seq，并对另外29个MBC进行了靶向深度测序。我们评估了WES的体细胞突变和靶向测序，评估了基因表达，并通过RNA-Seq进行了途径分析。在这项分析中，PIK 3CA是雌激素受体（ER）阳性BC中最常见的突变基因，而在ER阴性BC中，TP 53是最常见的突变基因（分别为p = 0.018和p < 0.001）。TP 53失增突变和移码突变与TP 53的低表达有关，而非同义突变与TP 53的高表达有关。TP 53突变对临床结果的影响因ER状态而异。在ER阳性BC中，野生型TP 53比突变型TP 53具有更好的预后（中位总生存期（OS）（野生型与突变型）：88.5 ± 54.4与32.6 ± 10.7（月），p = 0.002）。相比之下，突变的TP 53在ER阴性BC中具有保护作用（中位OS：0.10对32.6 ± 8.2，p = 0.026）。然而，PIK 3CA突变并不影响患者的生存率。在基因表达分析中，CALM 1，一个潜在的AKT调节因子，在PIK 3CA突变的BCs中高度表达。总之，TP 53基因突变与乳腺癌的表达状态相关，并根据ER状态影响乳腺癌的临床结局。尽管在本研究中PIK 3CA突变与生存率无关，但PIK 3CA突变改变了其他基因和途径（包括CALM 1）的表达，可能是PI 3 K抑制剂有效性的潜在预测标志物。
Breast cancer (BC) has been genetically profiled through large-scale genome analyses. However, the role and clinical implications of genetic alterations in metastatic BC (MBC) have not been evaluated. Therefore, we conducted whole-exome sequencing (WES) and RNA-Seq of 37 MBC samples and targeted deep sequencing of another 29 MBCs. We evaluated somatic mutations from WES and targeted sequencing and assessed gene expression and performed pathway analysis from RNA-Seq. In this analysis, PIK3CA was the most commonly mutated gene in estrogen receptor (ER)-positive BC, while in ER-negative BC, TP53 was the most commonly mutated gene (p = 0.018 and p < 0.001, respectively). TP53 stopgain/loss and frameshift mutation was related to low expression of TP53 in contrast nonsynonymous mutation was related to high expression. The impact of TP53 mutation on clinical outcome varied with regard to ER status. In ER-positive BCs, wild type TP53 had a better prognosis than mutated TP53 (median overall survival (OS) (wild type vs. mutated): 88.5 ± 54.4 vs. 32.6 ± 10.7 (months), p = 0.002). In contrast, mutated TP53 had a protective effect in ER-negative BCs (median OS: 0.10 vs. 32.6 ± 8.2, p = 0.026). However, PIK3CA mutation did not affect patient survival. In gene expression analysis, CALM1, a potential regulator of AKT, was highly expressed in PIK3CA-mutated BCs. In conclusion, mutation of TP53 was associated with expression status and affect clinical outcome according to ER status in MBC. Although mutation of PIK3CA was not related to survival in this study, mutation of PIK3CA altered the expression of other genes and pathways including CALM1 and may be a potential predictive marker of PI3K inhibitor effectiveness.