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Supplementary Figure S3 from Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

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posted on 2023-03-31, 20:29 authored by Charlotte K.Y. Ng, Francois-Clement Bidard, Salvatore Piscuoglio, Felipe C. Geyer, Raymond S. Lim, Ino de Bruijn, Ronglai Shen, Fresia Pareja, Samuel H. Berman, Lu Wang, Jean-Yves Pierga, Anne Vincent-Salomon, Agnes Viale, Larry Norton, Brigitte Sigal, Britta Weigelt, Paul Cottu, Jorge S. Reis-Filho

Supplementary Fig. S3: Evolution of mutational signatures in treatment-naïve patients with de novo synchronous metastatic breast cancer. (A) Heatmap represents the similarity of the observed mutational signatures (blue, see color key) to those previously observed in human cancers (15, 36), separately for the trunk mutations (yellow), the mutations specific to the primary tumor (green) and the mutations specific to the metastatic lesion (pink). (B) Barplots illustrate the mutational signatures of the mutations specific to the primary tumor and the metastatic lesion of Cases 2, 4, 7 and 9. In each panel, the colored barplot illustrates each mutational signature according to the 96 substitution classification defined by the substitution classes (C>A, C>G, C>T, T>A, T>C and T>G bins) and the 5' and 3' sequence context, normalized using the observed trinucleotide frequency in the human exome to that in the human genome. The bars are ordered first by mutation class (C>A/G>T, C>G/G>C, C>T/G>A, T>A/A>T, T>C/A>G, T>G/A >C), then by the 5' flanking base (A, C, G, T) and then by the 3' flanking base (A, C, G, T). *: >20%.

Funding

INCa - French Ministry of Health

Swiss National Science Foundation

Breast Cancer Research Foundation

National Institutes of Health/National Cancer Institute

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ARTICLE 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. Clin Cancer Res; 23(15); 4402–15. ©2017 AACR.

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