Distinct Gene Expression Profiles of Matched Primary and Metastatic Triple-Negative Breast Cancers

Jaspreet Kaur; Darshan S Chandrashekar; Zsuzsanna Varga; Bettina Sobottka; Emiel Janssen; Jeanne Kowalski; Umay Kiraz; Sooryanarayana Varambally; Ritu Aneja

doi:10.3390/cancers14102447

Distinct Gene Expression Profiles of Matched Primary and Metastatic Triple-Negative Breast Cancers

Cancers (Basel). 2022 May 16;14(10):2447. doi: 10.3390/cancers14102447.

Authors

Jaspreet Kaur¹, Darshan S Chandrashekar², Zsuzsanna Varga³, Bettina Sobottka³, Emiel Janssen^{4

5}, Jeanne Kowalski⁶, Umay Kiraz^{4

5}, Sooryanarayana Varambally², Ritu Aneja^{1

7}

Affiliations

¹ Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
² Department of Pathology-Molecular and Cellular, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
³ Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
⁴ Department of Pathology, Stavanger University Hospital, Health Stavanger HF, P.O. Box 8100, 4068 Stavanger, Norway.
⁵ Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, P.O. Box 8600, 4036 Stavanger, Norway.
⁶ Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
⁷ Department of Clinical and Diagnostics Sciences, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Abstract

Background: Although triple-negative breast cancer (TNBC) is associated with an increased risk of recurrence and metastasis, the molecular mechanisms underlying metastasis in TNBC remain unknown. To identify transcriptional changes and genes regulating metastatic progression in TNBC, we compared the transcriptomic profiles of primary and matched metastatic tumors using massively parallel RNA sequencing. Methods: We performed gene expression profiling using formalin-fixed paraffin-embedded (FFPE) TNBC tissues of patients from two cohorts: the Zurich cohort (n = 31) and the Stavanger cohort (n = 5). Among the 31 patients in the Zurich cohort, 18 had primary TNBC tumors that did not metastasize, and 13 had primary tumors that metastasized (11 paired primary and locoregional recurrences). The Stavanger cohort included five matched primary and metastatic TNBC tumors. Significantly differentially expressed genes (DEGs; absolute fold change ≥2, p < 0.05) were identified and subjected to functional analyses. We investigated if there was any overlap between DEGs from both the cohorts with epithelial-to-mesenchymal-to-amoeboid transition (EMAT) gene signature. xCell was used to estimate relative fractions of 64 immune and stromal cell types in each RNA-seq sample. Results: In the Zurich cohort, we identified 1624 DEGs between primary TNBC tumors and matched metastatic lesions. xCell analysis revealed a significantly higher immune scores for metastatic lesions compared to paired primary tumors in the Zurich cohort. We also found significant upregulation of three MammaPrint signature genes (HRASLS, TGFB3 and RASSF7) in primary tumors that metastasized compared to primary tumors that remained metastasis-free. In the Stavanger cohort, we identified 818 DEGs between primary tumors and matched metastatic lesions. No significant differences in xCell immune scores were observed. We found that 21 and 14 DEGs from Zurich and Stavanger cohort, respectively, overlapped with the EMAT gene signature. In both cohorts, genes belonging to the MMP, FGF, and PDGFR families were upregulated in primary tumors compared to matched metastatic lesions. Conclusions: Our results suggest that distinct gene expression patterns exist between primary TNBCs and matched metastatic tumors. Further studies are warranted to explore whether these discrete expression profiles underlie or result from disease status.

Keywords: DEGs; RNA-seq; metastases; triple-negative breast cancer.

Abstract

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