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A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients

Xu, Qi; Kaur, Jaspreet; Wylie, Dennis; Mittal, Karuna; Li, Hongxiao; Kolachina, Rishab; Aleskandarany, Mohammed; Toss, Michael S.; Green, Andrew R.; Yang, Jianchen; Yankeelov, Thomas E.; Bhattarai, Shristi; Janssen, Emiel A.M.; Kong, Jun; Rakha, Emad A.; Kowalski, Jeanne; Aneja, Ritu

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Authors

Qi Xu

Dennis Wylie

Karuna Mittal

Hongxiao Li

Rishab Kolachina

Mohammed Aleskandarany

Michael S. Toss

Jianchen Yang

Thomas E. Yankeelov

Shristi Bhattarai

Emiel A.M. Janssen

Jun Kong

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Jeanne Kowalski

Ritu Aneja



Abstract

Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on TNBC. In this study, we explored ITH in TNBC by evaluating gene expression-derived and imaging-derived multi-region differences within the same tumor. We obtained tissue specimens from 10 TNBC patients and conducted RNA sequencing analysis of 2–4 regions per tumor. We developed a novel analysis framework to dissect and characterize different types of variability: between-patients (inter-tumoral heterogeneity), between-patients across regions (inter-tumoral and region heterogeneity), and within-patient, between-regions (regional intratumoral heterogeneity). We performed a Bayesian changepoint analysis to assess and classify regional variability as low (convergent) versus high (divergent) within each patient feature (TNBC and PAM50 subtypes, immune, stroma, tumor counts and tumor infiltrating lymphocytes). Gene expression signatures were categorized into three types of variability: between-patients (108 genes), between-patients across regions (183 genes), and within-patients, between-regions (778 genes). Based on the between-patient gene signature, we identified two distinct patient clusters that differed in menopausal status. Significant intratumoral divergence was observed for PAM50 classification, tumor cell counts, and tumor-infiltrating T cell abundance. Other features examined showed a representation of both divergent and convergent results. Lymph node stage was significantly associated with divergent tumors. Our results show extensive intertumoral heterogeneity and regional ITH in gene expression and image-derived features in TNBC. Our findings also raise concerns regarding gene expression based TNBC subtyping. Future studies are warranted to elucidate the role of regional heterogeneity in TNBC as a driver of treatment resistance.

Citation

Xu, Q., Kaur, J., Wylie, D., Mittal, K., Li, H., Kolachina, R., …Aneja, R. (2022). A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients. International Journal of Molecular Sciences, 23(21), Article 13322. https://doi.org/10.3390/ijms232113322

Journal Article Type Article
Acceptance Date Oct 13, 2022
Online Publication Date Nov 1, 2022
Publication Date Nov 1, 2022
Deposit Date Jan 4, 2023
Publicly Available Date Jan 4, 2023
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Peer Reviewed Peer Reviewed
Volume 23
Issue 21
Article Number 13322
DOI https://doi.org/10.3390/ijms232113322
Keywords intratumoral heterogeneity; triple negative breast cancer; gene expression
Public URL https://nottingham-repository.worktribe.com/output/15712581
Publisher URL https://www.mdpi.com/1422-0067/23/21/13322