Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Department of Obstetrics and Gynecology, Kumagaya General Hospital, Kumagaya, Saitama, Japan.
Cancer Med. 2024 Jul;13(14):e70052. doi: 10.1002/cam4.70052.
PIK3CA mutations are implicated in various cancers, but the implications of multiple concurrent mutations and their orientations within the gene have not been fully explored.
In this study, we analyzed multi-PIK3CA mutations across a diverse pan-cancer cohort comprising 3564 tumors.
Multi-PIK3CA mutations were present in 10.3% of all PIK3CA-mutant tumors, predominantly occurring in breast and gynecological cancers. Notably, mutations within the helical domain (E542:E545) exclusively occurred in the trans-orientation, contrasting with mutations in the kinase ABD and C2 domains, which mainly appeared in the cis orientation.
The distinct pattern of mutation orientations in PIK3CA suggests variable oncogenic potential, with helical domain mutations in the trans-orientation potentially being less oncogenic. These findings highlight the importance of mutation orientation in the PIK3CA gene as potential biomarkers for targeted therapy. This understanding is crucial for designing clinical trials that leverage PI3K inhibitors, aiming for more effective and precise cancer treatment.
PIK3CA 突变与多种癌症相关，但多个同时发生的突变及其在基因内的取向的影响尚未得到充分探索。
在这项研究中，我们分析了包含 3564 个肿瘤的多样化泛癌队列中的多 PIK3CA 突变。
所有 PIK3CA 突变肿瘤中，多 PIK3CA 突变的存在率为 10.3%，主要发生在乳腺和妇科癌症中。值得注意的是，螺旋域（E542：E545）内的突变仅以反式取向发生，与激酶 ABD 和 C2 结构域内的突变形成对比，后者主要以顺式取向出现。
PIK3CA 中突变取向的独特模式提示了不同的致癌潜能，反式取向的螺旋域突变可能致癌性较低。这些发现强调了 PIK3CA 基因中突变取向作为潜在的靶向治疗生物标志物的重要性。这种理解对于设计利用 PI3K 抑制剂的临床试验至关重要，旨在实现更有效和精确的癌症治疗。
