Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer
Abstract Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-05502-6 |
| _version_ | 1819280813041123328 |
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| author | Marco Silvestri Matteo Dugo Marta Vismara Loris De Cecco Davide Lanzoni Andrea Vingiani Secondo Folli Maria Carmen De Santis Filippo de Braud Giancarlo Pruneri Serena Di Cosimo Vera Cappelletti |
| author_facet | Marco Silvestri Matteo Dugo Marta Vismara Loris De Cecco Davide Lanzoni Andrea Vingiani Secondo Folli Maria Carmen De Santis Filippo de Braud Giancarlo Pruneri Serena Di Cosimo Vera Cappelletti |
| author_sort | Marco Silvestri |
| collection | DOAJ |
| description | Abstract Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including copy number alterations (CNAs). We analyzed CNA profiles of 31 TNBC primary tumor samples before and after NAC and of 35 single circulating tumor cells (CTCs) collected prior, during and after treatment by using next-generation sequencing targeted profile and low-pass whole genome sequencing, respectively. In pre-treatment tissue samples, the most common gains occurred on chromosomes 1, 2 and 8, and SOX11 and MYC resulted the most altered genes. Notably, amplification of MSH2 (4/4 versus 0/12, p < 0.01) and PRDM1 and deletion of PAX3 (4/4 versus 1/12, p < 0.01) significantly characterized primary tumors of patients with pathological complete response. All patients with paired pre- and post-NAC samples reported a change in post-treatment CNAs compared to baseline, despite they showed at least one common alteration. CNAs detected after treatment involved genes within druggable pathways such as EGFR, cell cycle process and Ras signaling. In two patients, CTCs shared more alterations with residual rather than primary tumor involving genes such as MYC, BCL6, SOX2, FGFR4. The phylogenetic analysis of CTCs within a single patient revealed NAC impact on tumor evolution, suggesting a selection of driver events under treatment pressure. In conclusion, our data showed how chemoresistance might arise early from treatment-induced selection of clones already present in the primary tumor, and that the characterization of CNAs on single CTCs informs on cancer evolution and potential druggable targets. |
| first_indexed | 2024-12-24T00:49:45Z |
| format | Article |
| id | doaj.art-17de89a9b7ba4af3af391bf099663691 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-24T00:49:45Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-17de89a9b7ba4af3af391bf0996636912022-12-21T17:23:36ZengNature PortfolioScientific Reports2045-23222022-01-011211710.1038/s41598-022-05502-6Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancerMarco Silvestri0Matteo Dugo1Marta Vismara2Loris De Cecco3Davide Lanzoni4Andrea Vingiani5Secondo Folli6Maria Carmen De Santis7Filippo de Braud8Giancarlo Pruneri9Serena Di Cosimo10Vera Cappelletti11Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei TumoriBreast Cancer Unit, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Radiotherapy, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei TumoriAbstract Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including copy number alterations (CNAs). We analyzed CNA profiles of 31 TNBC primary tumor samples before and after NAC and of 35 single circulating tumor cells (CTCs) collected prior, during and after treatment by using next-generation sequencing targeted profile and low-pass whole genome sequencing, respectively. In pre-treatment tissue samples, the most common gains occurred on chromosomes 1, 2 and 8, and SOX11 and MYC resulted the most altered genes. Notably, amplification of MSH2 (4/4 versus 0/12, p < 0.01) and PRDM1 and deletion of PAX3 (4/4 versus 1/12, p < 0.01) significantly characterized primary tumors of patients with pathological complete response. All patients with paired pre- and post-NAC samples reported a change in post-treatment CNAs compared to baseline, despite they showed at least one common alteration. CNAs detected after treatment involved genes within druggable pathways such as EGFR, cell cycle process and Ras signaling. In two patients, CTCs shared more alterations with residual rather than primary tumor involving genes such as MYC, BCL6, SOX2, FGFR4. The phylogenetic analysis of CTCs within a single patient revealed NAC impact on tumor evolution, suggesting a selection of driver events under treatment pressure. In conclusion, our data showed how chemoresistance might arise early from treatment-induced selection of clones already present in the primary tumor, and that the characterization of CNAs on single CTCs informs on cancer evolution and potential druggable targets.https://doi.org/10.1038/s41598-022-05502-6 |
| spellingShingle | Marco Silvestri Matteo Dugo Marta Vismara Loris De Cecco Davide Lanzoni Andrea Vingiani Secondo Folli Maria Carmen De Santis Filippo de Braud Giancarlo Pruneri Serena Di Cosimo Vera Cappelletti Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer Scientific Reports |
| title | Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer |
| title_full | Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer |
| title_fullStr | Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer |
| title_full_unstemmed | Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer |
| title_short | Copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early-stage triple negative breast cancer |
| title_sort | copy number alterations analysis of primary tumor tissue and circulating tumor cells from patients with early stage triple negative breast cancer |
| url | https://doi.org/10.1038/s41598-022-05502-6 |
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