Abstract：
The significance of the prominent tumor suppressor gene for RAS protein activator-like 1 (RASAL1) could be better understood by combined genetic, clinical, and functional studies. Here, we investigated the oncogenic and clinical impacts of genetic alterations of RASAL1, particularly when coexisting with genetic alterations of the gene for phosphatase and tensin homolog (PTEN), in 9924 cancers of 33 types in the TCGA database. We found common concurrent genetic alterations of the two genes, which were cooperatively associated with activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, with cancer progression and mortality rates being 46.36% and 31.72% with concurrent gene alterations, versus 29.80% and 16.93% with neither gene alteration (HR 1.64, 95% CI 1.46-1.84 and 1.77, 95% CI 1.53-2.05), respectively. This was enhanced by additional tumor protein p53 (TP53) gene alterations, with cancer progression and mortality rates being 47.65% and 34.46% with coexisting RASAL1, PTEN, and TP53 alterations versus 25.30% and 13.11% with no alteration (HR 2.21, 95% CI 1.92-2.56 and 2.76, 95% CI 2.31-3.30), respectively. In the case of breast cancer, this genetic trio was associated with a triple-negative risk of 68.75% versus 3.83% with no genetic alteration (RR 17.94, 95% CI 9.60-33.51), consistent with the aggressive nature of triple-negative breast cancer. Mice with double knockouts of Rasal1 and Pten displayed robust Pi3k pathway activation, with the development of metastasizing malignancies, while single gene knockout resulted in only benign neoplasma. These results suggest that RASAL1, like PTEN, is a critical player in negatively regulating the PI3K-AKT pathway; defect in RASAL1 causes RAS activation, thus initiating the PI3K-AKT pathway signaling, which cannot terminate with concurrent PTEN defects. Thus, the unique concurrent RASAL1 and PTEN defects drive oncogenesis and cancer aggressiveness by cooperatively activating the PI3K-AKT pathway. This represents a robust genetic mechanism to promote human cancer.
摘要：
RAS蛋白激活因子样1(RASAL1)的显著抑癌基因的意义可以通过联合遗传,临床,和功能研究。这里,我们调查了RASAL1基因改变的致癌和临床影响，特别是当与磷酸酶和张力蛋白同源物（PTEN）基因的遗传改变共存时，在TCGA数据库中的33种类型的9924种癌症中。我们发现了这两个基因的共同遗传改变，它们与磷脂酰肌醇3-激酶（PI3K）-AKT途径的激活相关，癌症进展和死亡率分别为46.36%和31.72%，同时存在基因改变，与无基因改变的29.80%和16.93%相比（HR1.64，95%CI1.46-1.84和1.77，95%CI1.53-2.05），分别。这通过额外的肿瘤蛋白p53（TP53）基因改变而增强，与癌症进展和死亡率为47.65%和34.46%共存的RASAL1，PTEN，TP53改变与没有改变的25.30%和13.11%（HR2.21，95%CI1.92-2.56和2.76，95%CI2.31-3.30），分别。在乳腺癌的情况下，该遗传三重奏与三阴性风险68.75％和3.83％相关，没有遗传改变（RR17.94，95％CI9.60-33.51），符合三阴性乳腺癌的侵袭性。Rasal1和Pten双敲除的小鼠显示出强大的Pi3k通路激活，随着转移性恶性肿瘤的发展，而单基因敲除仅导致良性肿瘤。这些结果表明RASAL1和PTEN一样，是负调节PI3K-AKT途径的关键参与者；RASAL1的缺陷导致RAS激活，从而启动PI3K-AKT通路信号，不能以并发PTEN缺陷终止。因此，独特的并发RASAL1和PTEN缺陷通过协同激活PI3K-AKT通路驱动肿瘤发生和癌症侵袭性.这代表了促进人类癌症的强大遗传机制。
