National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huan-Hu Road, Ti Yuan Bei, Hexi District, Tianjin, 300060, China.
Tianjin' S Clinical Research Center for Cancer, Tianjin, 300060, China.
BMC Med Genomics. 2022 Jul 1;15(1):146. doi: 10.1186/s12920-022-01297-7.
To analyze the mutational landscape of pan-cancer patients with PIK3CA mutations in Chinese population in real-world.
We analyzed PIK3CA mutation status in sequencing data of cell-free DNA from plasma and genomic DNA from matched peripheral blood lymphocyte in 11,904 Chinese pan-cancer patients, and compared them with genomic data from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Besides, concomitant genomic aberrations in PIK3CA-mutated samples were detected to investigate cancer driver genes, as well as their enriched pathways. Meanwhile, the mutations of Alpelisib targeting genes were screened and their co-alterations were analyzed according to OncoKB definition to identify the potential actionable ones.
The proportion of patients with PIK3CA mutations varied among 21 types of cancer, with the top being BRCA, CESC, SCL, and UCEC. The most common PIK3CA mutation hotspots were found to be E545K, E542K and H1047R. The Chinese cohort had significantly lower frequencies of PIK3CA mutations in breast and stomach cancers, but markedly higher PIK3CA mutation frequencies in large intestine, kidney and lung cancers than the COSMIC cohort. Compared with COSMIC cohort, the mutation frequencies of Alpelisib-targeted genes in breast cancer were significantly reduced in the Chinese cohort. All PIK3CA-mutated patients had concomitant genomic aberrations. While the most common concomitant genomic alterations occurred in TP53, EGFR and FAT1, these co-mutated genes were mainly enriched in RTK/RAS pathway, PI3K pathway and P53 pathway. Moreover, 83.6% of patients carrying mutations in Alpelisib-targeted genes had at least one actionable concomitant alteration. Level 1 actionable alteration was identified in LUAD, BRCA, COAD, LUSC, READ, and STAD.
Compared with the Western cohort, the mutation frequency of PIK3CA in breast cancer was reduced in the Chinese cohort. RTK/RAS pathway, PI3K pathway and P53 pathway were identified as the most common co-mutation pathways, suggesting that they may potentially serve as targets for possible Alpelisib-based combination therapy.
分析中国人群中 pan-cancer 患者 PIK3CA 突变的突变特征。
我们分析了来自 11904 例中国 pan-cancer 患者血浆游离 DNA 测序数据和配对外周血淋巴细胞基因组 DNA 的 PIK3CA 突变状态，并与 Catalogue of Somatic Mutations in Cancer（COSMIC）数据库的基因组数据进行比较。此外，还检测了 PIK3CA 突变样本中的伴随基因组异常，以研究癌症驱动基因及其富集通路。同时，根据 OncoKB 定义筛选了 Alpelisib 靶向基因的突变，并分析其共改变，以确定潜在的可操作靶点。
21 种癌症中患者的 PIK3CA 突变比例不同，其中 BRCA、CESC、SCL 和 UCEC 最为常见。发现最常见的 PIK3CA 突变热点为 E545K、E542K 和 H1047R。与 COSMIC 队列相比，中国队列中乳腺癌和胃癌的 PIK3CA 突变频率较低，但结直肠癌、肾癌和肺癌的 PIK3CA 突变频率显著较高。与 COSMIC 队列相比，中国队列中乳腺癌中 Alpelisib 靶向基因的突变频率显著降低。所有 PIK3CA 突变患者均有伴随的基因组异常。虽然最常见的伴随基因组改变发生在 TP53、EGFR 和 FAT1，但这些共突变基因主要富集在 RTK/RAS 通路、PI3K 通路和 P53 通路。此外，携带 Alpelisib 靶向基因突变的患者中，83.6%至少有一个可操作的伴随改变。在 LUAD、BRCA、COAD、LUSC、READ 和 STAD 中确定了 1 级可操作改变。
与西方队列相比，中国队列中乳腺癌的 PIK3CA 突变频率降低。RTK/RAS 通路、PI3K 通路和 P53 通路被确定为最常见的共突变通路，提示它们可能作为可能的 Alpelisib 为基础的联合治疗的潜在靶点。
