背景:深入了解ERBB2驱动的癌症对于开发ERBB2+乳腺癌(BC)的新治疗方法至关重要。我们采用协作交叉(CC)小鼠模型来发掘支持Erbb2驱动的乳腺肿瘤发展和转移的遗传因素。
方法:监测FVB/NMMTV-Erbb2和30个CC品系之间的732只F1杂种雌性小鼠的乳腺肿瘤表型。GWAS精确定位影响各种肿瘤表型的SNP。多变量分析和模型用于构建多基因评分并开发小鼠肿瘤易感性基因标签(mTSGS)。其中相应的人类直系同源物被鉴定并指定为hTSGS。使用公共数据集评估了hTSGS在人类BC中的重要性和临床价值,包括TCGA,金属,GSE96058和I-SPY2队列。使用遗传多样性的MMTV-Erbb2小鼠在体内验证了mTSGS对化疗反应的预测能力。
结果:肿瘤发病的明显差异,多重性,在FVB/NMMTV-Erbb2和30个CC品系之间的F1杂交雌性小鼠中观察到转移模式。除了肺转移,在特定CC菌株中出现肝和肾转移。GWAS鉴定出与肿瘤发病显著相关的特定SNP,多重性,肺转移,和肝转移。多变量分析20个基因(Stx6,Ramp1,Traf3ip1,Nckap5,Pfkfb2,Trmt1l,Rprd1b,Rer1,9秒,Rhobtb1,Tsen15,Abcc3,Arid5b,TNR,Dock2,Tti1,Fam81a,Oxr1,Plxna2和Tbc1d31)独立地与各种肿瘤特征联系在一起,指定为MTSGS。基于其转录水平的hTSGS评分(hTSGSS)显示出预后价值,在多个人类BC队列中取代临床因素和PAM50亚型,在I-SPY2研究中,预测病理完全缓解独立于并优于MammaPrint评分。mTSGS评分预测化疗反应的能力在体内小鼠MMTV-Erbb2模型中得到进一步验证,证明这一点,就像人类患者的发现一样,mTSGS评分较低的小鼠肿瘤最有可能对治疗产生反应.
结论:我们的研究揭示了许多易患ERBB2驱动癌症的新基因。转化结果表明,hTSGS有望作为改善BC患者治疗策略的生物标志物。
背景: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),欧盟下一代欧盟/PRTR,卡斯蒂利亚和莱昂地区政府(CSI144P20),欧洲联盟。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.