J L Dillon1, S M Mockus2, G Ananda3, V Spotlow4, W A Wells5, G J Tsongalis6, J D Marotti7. 1. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, NH 03756, USA; Geisel School of Medicine, Hanover, NH, USA. Electronic address: Jessica.L.Dillon@hitchcock.org. 2. The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA. Electronic address: Susan.Mockus@jax.org. 3. The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA. Electronic address: Guru.Ananda@jax.org. 4. The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA. Electronic address: Vanessa.Spotlow@jax.org. 5. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, NH 03756, USA; Geisel School of Medicine, Hanover, NH, USA. Electronic address: Wendy.A.Wells@hitchcock.org. 6. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, NH 03756, USA; Geisel School of Medicine, Hanover, NH, USA; The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA. Electronic address: Gregory.J.Tsongalis@hitchcock.org. 7. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center and Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, NH 03756, USA; Geisel School of Medicine, Hanover, NH, USA. Electronic address: Jonathan.D.Marotti@hitchcock.org.
Abstract
OBJECTIVES: The aims of this study were to analyze triple negative breast cancer (TNBC) using an expanded next generation sequencing (NGS) assay, assess the clinical relevance using a recently described database, and correlate tumor morphology with detected genetic alterations. METHODS: DNA was isolated from twenty primary TNBCs and genes of interest were enriched and sequenced with hybrid capture, followed by variant detection and functional and clinical annotation. The JAX-CTP™ assay detects actionable variants in the form of single nucleotide variations, small insertions and deletions (≤50 bp), and copy number variants in 358 genes in specimens containing a neoplastic cell content of ≥50%. The JAX-CKB is a comprehensive database that curates tumor phenotype, genetic variant and protein effect, therapeutic relevance, and available treatment options. RESULTS: 18/20 (90%) of TNBCs contained at least one somatic mutation detected by the JAX-CTP™. MYC amplification was the most common alteration, present in 75% of tumors. TP53, AURKA, and KDR mutations were each present in 30% (6/20) of cases. Related recruiting clinical trials, extracted from JAX-CKB, included 166 for breast cancer, of which 17 were specific to only the TNBC subtype. All 17 trials were testing at least one therapy that targets a mutation identified in this sample set. The majority (89%) of tumors with basal-like histologic features had MYC amplification. CONCLUSIONS: The expanded gene panel identified a variety of clinically actionable gene alterations in TNBCs. The identification of such variants increases the possibility for new therapeutic interventions and clinical trial eligibility for TNBC patients.
OBJECTIVES: The aims of this study were to analyze triple negative breast cancer (TNBC) using an expanded next generation sequencing (NGS) assay, assess the clinical relevance using a recently described database, and correlate tumor morphology with detected genetic alterations. METHODS: DNA was isolated from twenty primary TNBCs and genes of interest were enriched and sequenced with hybrid capture, followed by variant detection and functional and clinical annotation. The JAX-CTP™ assay detects actionable variants in the form of single nucleotide variations, small insertions and deletions (≤50 bp), and copy number variants in 358 genes in specimens containing a neoplastic cell content of ≥50%. The JAX-CKB is a comprehensive database that curates tumor phenotype, genetic variant and protein effect, therapeutic relevance, and available treatment options. RESULTS: 18/20 (90%) of TNBCs contained at least one somatic mutation detected by the JAX-CTP™. MYC amplification was the most common alteration, present in 75% of tumors. TP53, AURKA, and KDR mutations were each present in 30% (6/20) of cases. Related recruiting clinical trials, extracted from JAX-CKB, included 166 for breast cancer, of which 17 were specific to only the TNBC subtype. All 17 trials were testing at least one therapy that targets a mutation identified in this sample set. The majority (89%) of tumors with basal-like histologic features had MYC amplification. CONCLUSIONS: The expanded gene panel identified a variety of clinically actionable gene alterations in TNBCs. The identification of such variants increases the possibility for new therapeutic interventions and clinical trial eligibility for TNBC patients.
Authors: Stefano Annunziato; Julian R de Ruiter; Linda Henneman; Chiara S Brambillasca; Catrin Lutz; François Vaillant; Federica Ferrante; Anne Paulien Drenth; Eline van der Burg; Bjørn Siteur; Bas van Gerwen; Roebi de Bruijn; Martine H van Miltenburg; Ivo J Huijbers; Marieke van de Ven; Jane E Visvader; Geoffrey J Lindeman; Lodewyk F A Wessels; Jos Jonkers Journal: Nat Commun Date: 2019-01-23 Impact factor: 14.919
Authors: Miquel Ensenyat-Mendez; Pere Llinàs-Arias; Javier I J Orozco; Sandra Íñiguez-Muñoz; Matthew P Salomon; Borja Sesé; Maggie L DiNome; Diego M Marzese Journal: Front Oncol Date: 2021-06-16 Impact factor: 6.244