Background: The phosphoinositide 3-kinase (PI3K) pathway is activated in multiple cancers. However, the significance ofPIK3R1encoding the PI3K regulatory subunit, an inhibitor of the PI3K catalytic subunit encoded byPIK3CA, in ovarian cancer development is largely unknown. Methods: Here, we investigatedPIK3R1genomic alterations and gene expression by direct sequencing and qPCR methods in 197 ovarian cancers. The results were correlated with clinicopathological and molecular variables and patient outcomes. Results: In addition to mutations (3.5%) and allelic losses (28.4%), we observed a very high frequency of decreasedPIK3R1mRNA levels in ovarian carcinomas (95.8%). Tumors withPIK3R1mutations mostly represented low-stage cancers of endometrioid and clear-cell type. Tumors withPIK3R1deletion and underexpression shared similar phenotypes of high-grade carcinomas (p= 0.003 andp= 0.025, respectively). Allelic loss was also associated with advanced stages (p= 0.003) and high-grade serous histotypes (p= 0.004). ThePIK3R1copy number correlated with mRNA levels (p= 0.009).PIK3R1mutations coexisted withPTENmutations (p= 0.041), whereasPIK3R1deletion and underexpression were linked toPIK3CAamplification (p= 0.038 andp= 0.033, respectively). LowPIK3R1expression diminished the probability of a complete response (OR 0.07,p= 0.03) in patients treated with platinum-based regimens. Conclusions:PIK3R1alterations may contribute to the development of ovarian cancers with different malignant potential and molecular changes. The high frequency ofPIK3R1aberrations suggests their importance in PI3K pathway deregulation, and they may potentially serve as an alternative toPIK3CAmarkers for therapy with these pathway inhibitors.
背景：磷酸肌醇3-激酶（PI3K）通路在多种癌症中被激活。然而，编码PI3K调节亚基的PIK3R1基因（该亚基是PIK3CA编码的PI3K催化亚基的抑制剂）在卵巢癌发展中的意义尚不明确。方法：本研究通过直接测序和qPCR方法，对197例卵巢癌样本的PIK3R1基因组改变及基因表达进行分析，并将结果与临床病理学特征、分子变量及患者预后进行关联性研究。结果：除突变（3.5%）和等位基因缺失（28.4%）外，我们观察到卵巢癌中PIK3R1 mRNA水平降低的频率极高（95.8%）。携带PIK3R1突变的肿瘤主要为低分期子宫内膜样和透明细胞型癌。而存在PIK3R1缺失和低表达的肿瘤则表现出相似的高级别癌表型（分别为p=0.003和p=0.025）。等位基因缺失还与晚期分期（p=0.003）和高级别浆液性组织学类型（p=0.004）相关。PIK3R1拷贝数与mRNA水平具有相关性（p=0.009）。PIK3R1突变与PTEN突变共存（p=0.041），而PIK3R1缺失和低表达则与PIK3CA扩增相关（分别为p=0.038和p=0.033）。在接受铂类方案治疗的患者中，低PIK3R1表达降低了获得完全缓解的可能性（OR 0.07，p=0.03）。结论：PIK3R1改变可能参与具有不同恶性潜能和分子特征的卵巢癌的发生发展。PIK3R1异常的高发频率提示其在PI3K通路失调中的重要性，并可能作为PIK3CA标志物的替代指标，用于该通路抑制剂治疗的潜在靶点。
肿瘤(癌症)患者之家