title: Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases.
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 withde novometastatic 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 includingTP53, PIK3CA, andGATA3were 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, includingSMAD4, TCF7L2, andTCF4(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.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Charlotte K Y
authors.initials: CKY
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. reisfilj@mskcc.org nortonl@mskcc.org francois-clement.bidard@curie.fr.|Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.
authors.forename: Francois-Clement
authors.initials: FC
authors.lastname: Bidard
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pathology, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, Brazil.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ino
authors.initials: I
authors.lastname: de Bruijn
authors.affiliation: Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Fresia
authors.initials: F
authors.lastname: Pareja
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Berman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.|University Paris Descartes, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Department of Pathology, Institut Curie, PSL Research University, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Integrated Genomics Operations, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York. reisfilj@mskcc.org nortonl@mskcc.org francois-clement.bidard@curie.fr.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Pathology, Institut Curie, PSL Research University, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sigal
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Cottu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. reisfilj@mskcc.org nortonl@mskcc.org francois-clement.bidard@curie.fr.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D018740:Genetic Heterogeneity; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human