Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei, 430060, People's Republic of China.
Department of Breast Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, 430060, People's Republic of China.
BMC Med Genomics. 2024 Jan 19;17(1):25. doi: 10.1186/s12920-023-01762-x.
Breast cancer is the second leading cause of cancer-related death in women, and drug resistance during treatment is a major challenge. However, the mechanisms underlying drug resistance are not fully understood. Here we applied whole-exome sequencing (WES) to clarify resistant rules to Herceptin and tyrosine kinase inhibitors (TKIs).
There are 12 HER2+ breast cancer patients who were done WES. Samples from tumor and surrounding tissues underwent DNA sequencing and analysis. Various experimental and bioinformatics techniques were employed, including genomic capture, mutation analysis (Genome Analysis Toolkit (GATK), etc.), bioinformatics assessments, and drug-gene interaction investigations. Ultimately, the study explored the association of APOB gene expression with breast cancer recurrence rates, immune cell infiltration, and drug response.
The C > T mutation frequency was highest in the Herceptin-insensitive (HI) and verification groups, codenamed YI, contrasting with the Herceptin-sensitive (HE) group. No microsatellite instability (MSI)-H patients were in the HE group, but both HI and YI groups had 1 each. Significant differences in transition-transversion (TiTv) were observed in the HI and YI groups rather than the HE group. In the TKI- insensitive (TI) group, C > T mutations were highest, differing from the TKI-sensitive (TE) group. TE group included 2 MSI-H patients. Significant differences in TiTv were found in the TI group rather than the TE group. Mutated APOB may resist Herceptin and TKI, increasing immune infiltration. We identified potential drugs targeting it.
Our study suggested that a higher percentage of C > T mutations, significant differences in TiTv, and MSI-H status may indicate Herceptin resistance, while a higher percentage of C > T mutations, significant differences in TiTv, and the absence of MSI-H may indicate TKI resistance in breast cancer patients. For patients resistant to both Herceptin and TKI, mutated APOB may play a crucial role in resistance.
乳腺癌是女性癌症相关死亡的第二大主要原因，治疗过程中的耐药性是一个主要挑战。然而，耐药性的机制尚未完全阐明。在这里，我们应用全外显子组测序（WES）阐明曲妥珠单抗和酪氨酸激酶抑制剂（TKIs）耐药的规律。
共有 12 名 HER2+乳腺癌患者进行了 WES。对肿瘤和周围组织的样本进行了 DNA 测序和分析。使用了各种实验和生物信息学技术，包括基因组捕获、突变分析（基因组分析工具包（GATK）等）、生物信息学评估和药物-基因相互作用研究。最终，研究探讨了 APOB 基因表达与乳腺癌复发率、免疫细胞浸润和药物反应的关系。
在曲妥珠单抗不敏感（HI）和验证组（命名为 YI）中，C>T 突变频率最高，与曲妥珠单抗敏感（HE）组形成对比。HE 组中没有微卫星不稳定（MSI-H）患者，但 HI 和 YI 组各有 1 例。在 HI 和 YI 组中观察到转换-颠换（TiTv）的显著差异，而在 HE 组中则没有。在 TKI 不敏感（TI）组中，C>T 突变最高，与 TKI 敏感（TE）组形成对比。TE 组包括 2 例 MSI-H 患者。在 TI 组中观察到 TiTv 的显著差异，而在 TE 组中则没有。突变的 APOB 可能会抵抗曲妥珠单抗和 TKI，增加免疫浸润。我们确定了针对它的潜在药物。
我们的研究表明，较高百分比的 C>T 突变、TiTv 显著差异和 MSI-H 状态可能提示曲妥珠单抗耐药，而较高百分比的 C>T 突变、TiTv 显著差异和 MSI-H 缺失可能提示乳腺癌患者对 TKI 耐药。对于同时对曲妥珠单抗和 TKI 耐药的患者，突变的 APOB 可能在耐药中起关键作用。
