Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics.
Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics.
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DOI：
10.7150/jca.52993
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发表时间：
2021
影响因子：
3.9
通讯作者：
Liao N
中科院分区：
文献类型：
--
作者：
Xiao W;Zhang G;Chen B;Chen X;Wen L;Lai J;Li X;Li M;Liu H;Liu J;Han-Zhang H;Lizaso A;Liao N
背景：综合分析乳腺癌PI 3 K-AKT-mTOR通路基因改变可能有助于靶向治疗。研究方法：我们使用一组520个癌症相关基因进行靶向测序，以研究589名连续诊断为I-III期乳腺癌的中国女性的PI 3 K-AKT-mTOR通路中的基因改变。使用来自METABRIC的公开可用的临床和基因组数据进行总生存期（OS）分析。结果：PI 3 K-AKT-mTOR通路基因异常检出率为62.6%（369/589）。最常见的改变基因是PIK 3CA（45%）、PTEN（7.5%）、AKT 1（5.9%）、PIK 3R 1（2.7%）和PIK 3CG（2%）。在所有乳腺癌分子亚型中检测到四种PIK 3CA突变（E545 K、H1047 R、E542 K和H1047 L）。仅在HR+亚型中检测到7种PIK 3CA突变（E545 G、E418_L422delinsV、E726 K、E110 del、G1049 R、G118 D和D350 G）。仅在非三阴性亚型中检测到两种PIK 3CA突变（C420 R和N345 K）。PTEN基因突变以HR+/HER 2-亚型为主（77.3%），其次为三阴性亚型（18.2%）。在METABRIC乳腺癌数据集中，在PIK 3CA突变体组和野生型组之间未观察到显著OS差异。然而，具有多个PIK 3CA突变（mOS：131 vs. 159个月，P= 0.029）或位于C2结构域的PIK 3CA突变的患者的OS（mOS：130 vs. 154个月，P=0.020）显著短于无突变的患者。结论：本研究揭示了乳腺癌分子亚型之间PI 3 K-AKT-mTOR通路的异质性。此外，PIK 3CA突变的数量和特定位点具有明显的预后影响。
Background: Comprehensive analysis of PI3K-AKT-mTOR pathway gene alterations in breast cancer may be helpful for targeted therapy. Methods: We performed targeted sequencing using a panel of 520 cancer-related genes to investigate gene alterations in the PI3K-AKT-mTOR pathway from 589 consecutive Chinese women diagnosed with stage I-III breast cancer. Analyses of overall survival (OS) were performed using the publicly available clinical and genomic data from METABRIC. Results: PI3K-AKT-mTOR pathway gene alterations were detected in 62.6% (369/589) of our cohort. The most commonly altered genes were PIK3CA (45%), PTEN (7.5%), AKT1 (5.9 %), PIK3R1 (2.7%), and PIK3CG (2%). Four PIK3CA mutations (E545K, H1047R, E542K, and H1047L) were detected in all the breast cancer molecular subtypes. Seven PIK3CA mutations (E545G, E418_L422delinsV, E726K, E110del, G1049R, G118D, and D350G) were only detected in HR+ subtypes. Two PIK3CA mutations (C420R and N345K) were only detected in non-triple-negative subtypes. Most cases with PTEN mutation were HR+/HER2- subtype (77.3%), followed by triple-negative subtype (18.2%). In the METABRIC breast cancer dataset, no significant OS difference was observed between the PIK3CA-mutant and wild-type groups. However, patients with multiple PIK3CA mutations (mOS: 131 vs. 159 months, P= 0.029), or PIK3CA mutations located in the C2 domain had significantly shorter OS (mOS, 130 vs. 154 months, P=0.020) than those without the mutations. Conclusions: Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.
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