PO.CL12.02 · 临床研究
整合蛋白质基因组学揭示HER2阳性乳腺癌中超越HER2 IHC的复发分子预测因子
Integrated proteogenomics reveals molecular predictors of recurrence beyond HER2 IHC in HER2-positive breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：乳腺癌仍然是女性中最常见的恶性肿瘤，其中约20%由HER2过表达驱动。尽管HER2靶向治疗改善了结局，但获得性耐药和复发依然存在。临床HER2免疫组织化学（IHC）常常无法反映实际的HER2丰度，如在IHC阴性/高蛋白和IHC 3+/低蛋白病例中所见。因此，我们进行了整合蛋白质基因组学分析，以界定HER2异质性并识别复发相关特征。
方法：从韩国国立癌症中心纳入了共62例患者，中位年龄41.5岁（范围25-60），使用整合蛋白质基因组学工作流程分析乳腺肿瘤组织，该流程结合了全外显子组测序、全转录组、全局蛋白质组学、磷酸化蛋白质组学和基于PRM的HER2定量。比较了46例非复发和15例复发患者之间的差异基因组和蛋白质组学特征，并在TCGA和CPTAC队列中进行了验证。
结果：在10%的低HER2病例和25%的高HER2病例中观察到临床IHC与定量HER2测量之间的不一致。复发患者在基因组分析中显示出频繁的TP53突变、MYC扩增和ERBB2热点变异（E192*和D844*）。整合RNA和蛋白质组学表达的DEG分析识别出一组共享的复发相关基因，包括ATXN7L3B、GPRC5A和WNT5A，它们共同反映了与细胞外基质重塑、转移、信号传导、代谢重编程和转录调控相关的通路。METABRIC比较显示出与复发肿瘤中观察到的相似的ERBB2/MYC扩增、TP53缺失和基因组不稳定性模式。突变特征分析表明主要贡献来自衰老相关、APOBEC驱动和同源重组缺陷过程。拷贝数特征谱进一步识别出五种复发性基因组亚型（CNV48 A-E），包括与TCGA和METABRIC HER2阳性肿瘤共享的染色体碎裂样和杂合性缺失模式。
结论：这些发现表明，HER2阳性乳腺癌的复发风险更多地由初始肿瘤分期而非HER2 IHC状态决定。这凸显了定量蛋白质基因组学评估作为一种补充工具的临床价值，可在超越传统HER2检测的基础上改善风险分层。本工作由国立癌症中心资助（资助号2510692-1）。
查看英文原文 English abstract
Purpose: Breast cancer remains the most common malignancy among women, with about 20% driven by HER2 overexpression. Although HER2-targeted therapies have improved outcomes, acquired resistance and recurrence persist. Clinical HER2 Immunohistochemistry(IHC) often fails to reflect actual HER2 abundance, as seen in both IHC-negative/high-protein and IHC 3+/low-protein cases. Thus we conducted an integrated proteogenomic analysis to define HER2 heterogeneity and identify recurrence-associated signatures.
Methods: Total of 62 patients with a median age of 41.5 years (range, 25-60) were included from National Cancer Center in Korea, and breast tumor tissues analyzed using an integrated proteogenomic workflow combining whole-exome sequencing, whole-transcriptome, global proteomics, phosphoproteomics, and PRM-based HER2 quantification. Differential genomic and proteomic features between the 46 non-recurrence and 15 recurrence patients were compared and validated in TCGA and CPTAC cohorts.
Results: Description between clinical IHC and quantitative HER2 measurement were observed in 10% of low HER2 and in 25% of high HER2 cases. Recurrent patients revealed frequent TP53 mutations, MYC amplification, and ERBB2 hotspot variants (E192* and D844*) in genomic profiling. DEGs analyses integrating RNA and proteomic expression identified a shared set of recurrence-associated genes, including ATXN7L3BM GPRC5A and GPRC5A and WNT5A, which collectively reflected pathways related to extracellular matrix remodeling, metastatic, signaling, metabloic reprogramming, and transcriptional regulation. METABRIC comparison showed similar patterns of ERBB2/MYC amplification, TP53 loss, and genomic instability observed in recurrent tumors. Mutational signature analysis indicated dominant contributions from aging-related, APOBEC-driven, and homologous recombination-defective processes. Copy-number signature profiling further identified five recurrent genomic subtypes (CNV48 A-E), including chromothripsis-like and loss of heterozygosity patterns shared with TCGA and METABRIC HER2-positive tumors.
Conclusions: These findings indicate that recurrence risk in HER2-positive breast cancer is determined more by initial tumor stage than by HER2 IHC status. This underscores the clinical value of quantitative proteogenomic assessment as a complementary tool to improve risk stratification beyond conventional HER2 testing. This work was supported by grant from the National Cancer Center. (Grant No. 2510692-1)
利益披露 Disclosure
E. Lee, None..
S. Park, None..
K. Kim, None..
G. Lee, None..
E. Lee, None..
J. Park, None.