通过结合遗传、临床和功能研究，可以更好地理解 RAS 蛋白激活剂样 1 (RASAL1) 的重要肿瘤抑制基因的重要性。在这里，我们在 TCGA 数据库中 33 种类型的 9924 种癌症中研究了 RASAL1 基因改变的致癌和临床影响，特别是与磷酸酶和张力蛋白同源物 (PTEN) 基因的基因改变共存时。我们发现这两个基因存在共同的并发遗传改变，这些改变与磷脂酰肌醇 3 激酶 (PI3K)-AKT 通路的激活协同相关，并发基因改变的癌症进展和死亡率分别为 46.36% 和 31.72%，而同时发生的基因改变为 29.80%。没有基因改变的比例分别为 16.93%（HR 1.64，95% CI 1.46-1.84 和 1.77，95% CI 1.53-2.05）。额外的肿瘤蛋白 p53 (TP53) 基因改变增强了这一点，共存 RASAL1、PTEN 和 TP53 改变的癌症进展和死亡率分别为 47.65% 和 34.46%，而没有改变的癌症进展和死亡率分别为 25.30% 和 13.11%（HR 2.21，95%） CI 分别为 1.92-2.56 和 2.76，95% CI 2.31-3.30）。就乳腺癌而言，这三种基因与三阴性风险相关，分别为 68.75% 和无基因改变的 3.83%（RR 17.94，95% CI 9.60-33.51），这与三阴性乳腺癌的侵袭性一致。癌症。 Rasal1 和 Pten 双基因敲除的小鼠表现出强烈的 Pi3k 通路激活，并伴有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 与 PTEN 一样，是负向调节 PI3K-AKT 通路的关键角色。 RASAL1 缺陷会导致 RAS 激活，从而启动 PI3K-AKT 通路信号传导，该信号传导不能因并发 PTEN 缺陷而终止。因此，独特的同时发生的 RASAL1 和 PTEN 缺陷通过协同激活 PI3K-AKT 通路来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。© 2024 作者。约翰·威利出版的《分子肿瘤学》

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.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.