Transcriptome and genome evolution during HER2-amplified breast neoplasia

Area of Science:

• Oncology
• Genomics
• Cancer Biology

Background:

• Oncogenic drivers are key to cancer progression, with early and late genetic events observed in carcinomas.
• The selection mechanisms and fitness advantages conferred by these drivers remain poorly understood.

Purpose of the Study:

• To investigate transcriptomic and genetic alterations at a single-duct level in precursor lesions of invasive breast cancer.
• To analyze HER2 amplification in ductal carcinoma in situ (DCIS) and its impact on neoplastic progression.

Main Methods:

• Spatially oriented genomic approaches, including HER2-FISH and laser capture microdissection (LCM) Smart-3SEQ.
• Analysis of transcriptomic profiles and copy number variations (CNVs) in DCIS.

Main Results:

• HER2 amplification in DCIS alters transcriptomic profiles and increases CNV diversity.
• Interferon signaling pathway activation is linked to HER2 amplification in DCIS.
• Multiple subclones of HER2-amplified DCIS suggest sequential genetic events.
• Transcriptomic changes and CNV events were observed prior to HER2 amplification.

Conclusions:

• Spatially oriented genomic methods provide insights into neoplastic progression at the single-duct level.
• Pre-amplified DCIS may establish a cellular state conducive to acquiring HER2 amplification for growth advantage.