Transcriptome and genome evolution during HER2-amplified breast neoplasia
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....
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2021
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| _version_ | 1797090791910277120 |
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| author | Lu, P Foley, J Zhu, C McNamara, K Sirinukunwattana, K Vennam, S Varma, S Fehri, H Srivastava, A Zhu, S Rittscher, J Mallick, P Curtis, C West, R |
| author_facet | Lu, P Foley, J Zhu, C McNamara, K Sirinukunwattana, K Vennam, S Varma, S Fehri, H Srivastava, A Zhu, S Rittscher, J Mallick, P Curtis, C West, R |
| author_sort | Lu, P |
| collection | OXFORD |
| description | 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.
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| first_indexed | 2024-03-07T03:23:48Z |
| format | Journal article |
| id | oxford-uuid:b8582f56-7946-44a8-bfe7-00d76c5faf1d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:23:48Z |
| publishDate | 2021 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:b8582f56-7946-44a8-bfe7-00d76c5faf1d2022-03-27T04:55:13ZTranscriptome and genome evolution during HER2-amplified breast neoplasiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b8582f56-7946-44a8-bfe7-00d76c5faf1dEnglishSymplectic ElementsBioMed Central2021Lu, PFoley, JZhu, CMcNamara, KSirinukunwattana, KVennam, SVarma, SFehri, HSrivastava, AZhu, SRittscher, JMallick, PCurtis, CWest, RBackground 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. |
| spellingShingle | Lu, P Foley, J Zhu, C McNamara, K Sirinukunwattana, K Vennam, S Varma, S Fehri, H Srivastava, A Zhu, S Rittscher, J Mallick, P Curtis, C West, R Transcriptome and genome evolution during HER2-amplified breast neoplasia |
| title | Transcriptome and genome evolution during HER2-amplified breast neoplasia |
| title_full | Transcriptome and genome evolution during HER2-amplified breast neoplasia |
| title_fullStr | Transcriptome and genome evolution during HER2-amplified breast neoplasia |
| title_full_unstemmed | Transcriptome and genome evolution during HER2-amplified breast neoplasia |
| title_short | Transcriptome and genome evolution during HER2-amplified breast neoplasia |
| title_sort | transcriptome and genome evolution during her2 amplified breast neoplasia |
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