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Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Ng, Charlotte K. Y. and Bidard, Francois-Clement and Piscuoglio, Salvatore and Geyer, Felipe C. and Lim, Raymond S. and de Bruijn, Ino and Shen, Ronglai and Pareja, Fresia and Berman, Samuel H. and Wang, Lu and Pierga, Jean-Yves and Vincent-Salomon, Anne and Viale, Agnes and Norton, Larry and Sigal, Brigitte and Weigelt, Britta and Cottu, Paul and Reis-Filho, Jorge S.. (2017) Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases. Clinical cancer research, 23 (15). pp. 4402-4415.

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Official URL: https://edoc.unibas.ch/68141/

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Abstract

Purpose:; Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with; de novo; metastatic disease who had not received local or systemic therapy.; Experimental Design:; Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods.; Results:; Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including; TP53, PIK3CA; , and; GATA3; were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including; SMAD4, TCF7L2; , and; TCF4; (; ITF2; ), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases.; Conclusions:; Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Piscuoglio, Salvatore
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for Cancer Research
ISSN:1078-0432
e-ISSN:1557-3265
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:25 Jan 2019 14:34
Deposited On:25 Jan 2019 14:33

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