深入了解 ERBB2 驱动的癌症对于开发 ERBB2 乳腺癌 (BC) 新的治疗方法至关重要。我们采用协作交叉 (CC) 小鼠模型来挖掘支持 Erbb2 驱动的乳腺肿瘤发展和转移的遗传因素。对 FVB/N MMTV-Erbb2 和 30 个 CC 品系之间的 732 只 F1 杂交雌性小鼠进行乳腺肿瘤表型监测。 GWAS 精确定位了影响各种肿瘤表型的 SNP。使用多变量分析和模型构建多基因评分并开发小鼠肿瘤易感性基因特征（mTSGS），其中相应的人类直向同源物被鉴定并命名为hTSGS。使用公共数据集（包括 TCGA、METABRIC、GSE96058 和 I-SPY2 队列）评估 hTSGS 在人类 BC 中的重要性和临床价值。使用遗传多样性的 MMTV-Erbb2 小鼠体内验证了 mTSGS 对化疗反应的预测能力。在 FVB/N MMTV-Erbb2 和 30 CC 之间的 F1 杂交雌性小鼠中观察到肿瘤发病、多重性和转移模式的明显差异菌株。除肺转移外，特定CC菌株还出现肝和肾转移。 GWAS 鉴定出与肿瘤发病、多重性、肺转移和肝转移显着相关的特定 SNP。多变量分析独立标记 20 个基因（Stx6、Ramp1、Traf3ip1、Nckap5、Pfkfb2、Trmt1l、Rprd1b、Rer1、Sepsecs、Rhobtb1、Tsen15、Abcc3、Arid5b、Tnr、Dock2、Tti1、Fam81a、Oxr1、Plxna2 和 Tbc1d31）中的 SNP与各种肿瘤特征相关，称为 mTSGS。基于转录水平的 hTSGS 评分 (hTSGSS) 显示了预后价值，在多个人类 BC 队列中取代了临床因素和 PAM50 亚型，并在 I-SPY2 研究中预测了独立于且优于 MammaPrint 评分的病理完全缓解。 mTSGS 评分预测化疗反应的能力在小鼠 MMTV-Erbb2 体内模型中得到了进一步验证，表明与人类患者的研究结果一样，mTSGS 评分较低的小鼠肿瘤最有可能对治疗产生反应。我们的研究揭示了许多使个体易患 ERBB2 驱动的癌症的新基因。转化研究结果表明，hTSGS 有希望作为一种生物标志物，用于改进 BC 患者的治疗策略。美国国防部 (DoD) 乳腺癌研究计划 (BCRP) (BC190820)，美国； MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00、PDC2021-121735-I00)、“欧盟下一代 EU/PRTR”、卡斯蒂利亚和莱昂地区政府 (CSI144P20)、欧盟。版权所有 © 2024作者。由 Elsevier B.V. 出版。保留所有权利。

Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis.732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice.Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment.Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC.The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the "European Union Next Generation EU/PRTR," the Regional Government of Castile and León (CSI144P20), European Union.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.