PO.CL12.03 · 临床研究

HER2扩增结直肠癌的分子和免疫图谱

Molecular and immune landscape of HER2-amplified colorectal cancer

编号 5286 展板 6 时间 4/21 09:00–12:00 区域 Section 44 主讲 Sunyoung Lee, MD;PhD

分会场 Epigenetics, Cytogenetics, and Clinical Molecular Genetics

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作者与单位 Authors & Affiliations

Sunyoung Lee¹, Michelle Weitz², Adam Dugan², Saif Nirzhor², Kayla Layng², Scott Kopetz¹, James Yu¹, Asif Rashid³, Funda Meric-Bernstam¹, Mohamed Nuh⁴, Monica Hsiang⁴, Kanwal Pratap Singh Raghav¹

¹UT MD Anderson Cancer Center, Houston, TX,²Tempus AI, Inc, Chicago, IL,³Div. of Path. & Lab. Med., UT MD Anderson Cancer Center, Houston, TX,⁴Department of Medicine, Baylor College of Medicine, Houston, TX

摘要 Abstract

中文摘要

背景：HER2扩增定义了结直肠癌（CRC）中一个生物学上独特的亚群，但其转录组和免疫相关特征仍未被完全表征。我们对HER2扩增的CRC进行分析，以描绘与ERBB2驱动的致癌相关的临床基因组、免疫和转录组特征。方法：我们使用Tempus Lens（Tempus AI, Inc., 芝加哥, IL）查询Tempus多模态去标识化数据库，识别接受Tempus xT（DNA）和xR（RNA）检测且肿瘤纯度≥30%的III/IV期CRC患者。HER2扩增定义为ERBB2拷贝数（CN）≥6。比较了人口统计学和临床特征、体细胞和种系改变、基于quanTIseq的免疫细胞浸润估计值以及生物标志物（TMB、PD-L1、MSI）。RNA-seq数据被标准化为log₂(TPM+1)，并使用fgsea对标志基因集进行差异表达和通路富集分析，以比较HER2扩增和非扩增肿瘤。结果：在16,394例诊断为结肠或直肠腺癌的患者中，445例（2.7%）为HER2扩增。这些肿瘤发生于较年轻的中位年龄（58岁对60岁，p=0.001），且更常见于左侧（70%对57%，p=0.011）。在有数据可用的情况下，ERBB2扩增与外部HER2 IHC/ISH显示88%（36/41）的一致性，且ERBB2拷贝数与mRNA表达之间存在相关性（ρ=0.38，p<0.001），证明了DNA、RNA和蛋白质水平间的一致性。ERBB2激活突变，最常见的是V777L（3.15%），其次为G776V、S310F和H878Y，在9.2%的扩增肿瘤中共同出现，提示基因组和结构的双重激活。HER2扩增的CRC具有较少的KRAS突变（14%对48%，p<0.001；G12D最常见）、较低的平均TMB（5对8 mut/Mb，p<0.001），且普遍为MSS（MSI-H 0%）。两组间种系突变频率相似，以CHEK2和MUTYH最为常见。HER2扩增肿瘤表现出M1巨噬细胞、NK细胞和Treg浸润减少（均p<0.01），且缺乏抗原呈递、Th1、检查点或共刺激特征的显著富集（q=0.06-0.08），表明与非扩增CRC相比其微环境相对免疫失活。基因集富集分析揭示了细胞周期和DNA复制程序（E2F、MCM、PLK1、AURKB、TOP2A）正向富集的趋势，以及HER2扩增患者中KRAS信号的抑制。结论：HER2扩增的CRC表现出一条协调的ERBB2激活轴，将DNA扩增、mRNA过表达和蛋白质上调联系起来。这些肿瘤的特征是高度增殖但免疫耗竭的转录谱。HER2信号、增殖和免疫调节之间的生物学相互作用值得进一步研究，未来的工作应包括临床结局相关性分析。

查看英文原文 English abstract

Background: HER2 amplification defines a biologically distinct subset of colorectal cancer (CRC), yet its transcriptomic and immune correlates remain incompletely characterized. We profiled HER2-amplified CRCs to delineate clinicogenomic, immune, and transcriptomic features associated with ERBB2-driven oncogenesis. Methods: We used Tempus Lens (Tempus AI, Inc., Chicago, IL) to query the Tempus multimodal de-identified database and identify patients with stage III/IV CRC who underwent Tempus xT (DNA) and xR (RNA) testing with tumor purity ≥30%. HER2 amplification was defined as ERBB2 copy number (CN) ≥6. Demographic and clinical characteristics, somatic and germline alterations, quanTIseq-based immune cell infiltration estimates, and biomarkers (TMB, PD-L1, MSI) were compared. RNA-seq data were normalized to log₂(TPM+1), and differential expression and pathway enrichment analyses on the hallmark gene set using fgsea compared HER2-amplified and non-amplified tumors. Results: Among 16,394 patients with diagnoses of colon or rectal adenocarcinoma, 445 (2.7%) were HER2-amplified. These tumors occurred at a younger median age (58 vs. 60 years, p=0.001) and were more often left-sided (70% vs. 57%, p=0.011). Where data were available, ERBB2 amplification showed 88% (36/41) concordance with external HER2 IHC/ISH and a correlation between ERBB2 copy number and mRNA expression (ρ=0.38, p<0.001), demonstrating concordance across DNA, RNA, and protein levels. ERBB2 -activating mutations, most frequently V777L (3.15%), followed by G776V, S310F, and H878Y, co-occurred in 9.2% of amplified tumors, suggesting dual genomic and structural activation. HER2-amplified CRCs had fewer KRAS mutations (14% vs. 48%, p<0.001; G12D most common), lower mean TMB (5 vs. 8 mut/Mb, p<0.001), and were universally MSS (MSI-H 0%). Germline mutation frequencies were similar between groups, with CHEK2 and MUTYH most frequent. HER2-amplified tumors demonstrated reduced infiltration of M1 macrophages, NK cells, and Tregs (all p<0.01) and lacked significant enrichment of antigen-presentation, Th1, checkpoint, or co-stimulatory signatures (q=0.06-0.08), indicating a relatively immune-inactive microenvironment compared to non-amplified CRCs. Gene set enrichment analysis revealed a trend toward positive enrichment of cell-cycle and DNA replication programs ( E2F, MCM, PLK1, AURKB, TOP2A ) and suppression of KRAS signaling in HER2-amplified patients. Conclusions: HER2-amplified CRCs exhibit a coordinated ERBB2 activation axis linking DNA amplification, mRNA overexpression, and protein upregulation. These tumors are characterized by a hyperproliferative yet immune-depleted transcriptional profile. The biological interplay between HER2 signaling, proliferation, and immune modulation warrants further study, and future work should include clinical outcome correlations.

利益披露 Disclosure

S. Lee, None.. M. Weitz, None.. A. Dugan, None.. S. Nirzhor, None.. K. Layng, None.. J. Yu, None.. M. Nuh, None.. M. Hsiang, None.. K. P. Raghav, None.

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