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Breast Cancer Research
Published in: Breast Cancer Research 1/2021

01-12-2021 | Breast Cancer | Research article

Transcriptome and genome evolution during HER2-amplified breast neoplasia

Authors: Peipei Lu, Joseph Foley, Chunfang Zhu, Katherine McNamara, Korsuk Sirinukunwattana, Sujay Vennam, Sushama Varma, Hamid Fehri, Arunima Srivastava, Shirley Zhu, Jens Rittscher, Parag Mallick, Christina Curtis, Robert West

Published in: Breast Cancer Research | Issue 1/2021

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Abstract

Background

The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia’s fitness is less understood.

Methods

Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue.

Results

By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage.

Conclusion

By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level.
Appendix
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Metadata
Title
Transcriptome and genome evolution during HER2-amplified breast neoplasia
Authors
Peipei Lu
Joseph Foley
Chunfang Zhu
Katherine McNamara
Korsuk Sirinukunwattana
Sujay Vennam
Sushama Varma
Hamid Fehri
Arunima Srivastava
Shirley Zhu
Jens Rittscher
Parag Mallick
Christina Curtis
Robert West
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-021-01451-6

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