A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross miceResearch in context
Hui Yang,
Xinzhi Wang,
Adrián Blanco-Gómez,
Li He,
Natalia García-Sancha,
Roberto Corchado-Cobos,
Manuel Jesús Pérez-Baena,
Alejandro Jiménez-Navas,
Pin Wang,
Jamie L. Inman,
Antoine M. Snijders,
David W. Threadgill,
Allan Balmain,
Hang Chang,
Jesus Perez-Losada,
Jian-Hua Mao
Affiliations
Hui Yang
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Xinzhi Wang
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Adrián Blanco-Gómez
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain
Li He
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430079, China
Natalia García-Sancha
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain
Roberto Corchado-Cobos
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain
Manuel Jesús Pérez-Baena
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain
Alejandro Jiménez-Navas
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain
Pin Wang
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210008, China
Jamie L. Inman
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Antoine M. Snijders
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
David W. Threadgill
Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA; Department of Molecular and Cellular Medicine and Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843, USA
Allan Balmain
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA
Hang Chang
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; Corresponding author. Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Jesus Perez-Losada
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain; Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain; Corresponding author. Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain.
Jian-Hua Mao
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; Corresponding author. Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Summary: 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. Findings: 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. Interpretation: 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. Funding: 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.
