浸润性导管癌亚型的低频突变异质性：指导精准肿瘤学的信息。
Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology.
机构信息
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
出版信息
Int J Mol Sci. 2019 Feb 26;20(5):1011. doi: 10.3390/ijms20051011.
Information regarding the role of low-frequency hotspot cancer-driver mutations (CDMs) in breast carcinogenesis and therapeutic response is limited. Using the sensitive and quantitative Allele-specific Competitor Blocker PCR (ACB-PCR) approach, mutant fractions (MFs) of six CDMs ( H1047R and E545K, G12D and G12V, G12D, and V600E) were quantified in invasive ductal carcinomas (IDCs; including ~20 samples per subtype). Measurable levels (i.e., ≥ 1 × 10, the lowest ACB-PCR standard employed) of the H1047R, E545K, G12D, G12V, G12D, and V600E mutations were observed in 34/81 (42%), 29/81 (36%), 51/81 (63%), 9/81 (11%), 70/81 (86%), and 48/81 (59%) of IDCs, respectively. Correlation analysis using available clinicopathological information revealed that H1047R and V600E MFs correlate positively with maximum tumor dimension. Analysis of IDC subtypes revealed minor mutant subpopulations of critical genes in the MAP kinase pathway (, , and ) were prevalent across IDC subtypes. Few triple-negative breast cancers (TNBCs) had appreciable levels of mutation, suggesting that individuals with TNBC may be less responsive to inhibitors of the PI3K/AKT/mTOR pathway. These results suggest that low-frequency hotspot CDMs contribute significantly to the intertumoral and intratumoral genetic heterogeneity of IDCs, which has the potential to impact precision oncology approaches.
有关低频热点致癌驱动突变（CDMs）在乳腺癌发生和治疗反应中的作用的信息有限。使用敏感和定量的等位基因特异性竞争阻断 PCR（ACB-PCR）方法，在浸润性导管癌（IDC；包括每个亚型约 20 个样本）中定量测定了六个 CDMs（ H1047R 和 E545K、G12D 和 G12V、G12D 和 V600E）的突变分数（MFs）。可测量水平（即≥1×10，采用的最低 ACB-PCR 标准）的 H1047R、E545K、G12D、G12V、G12D 和 V600E 突变分别在 34/81（42%）、29/81（36%）、51/81（63%）、9/81（11%）、70/81（86%）和 48/81（59%）的 IDC 中观察到。使用可用的临床病理信息进行的相关性分析表明， H1047R 和 V600E MFs 与最大肿瘤尺寸呈正相关。对 IDC 亚型的分析表明，MAP 激酶途径中的关键基因（ 、 和 ）的突变亚群在 IDC 亚型中普遍存在。少数三阴性乳腺癌（TNBC）具有可观水平的 突变，这表明 TNBC 个体对 PI3K/AKT/mTOR 通路抑制剂的反应可能较差。这些结果表明，低频热点 CDMs 对 IDC 的肿瘤间和肿瘤内遗传异质性有重要贡献，这有可能影响精准肿瘤学方法。
Zotero 插件