title: Uncovering the genomic heterogeneity of multifocal breast cancer.
abstract: Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples). We selected only patients with lesions presenting the same grade, ER, and HER2 status. Mutations were classified as 'oncogenic' in the case of recurrent substitutions reported in COSMIC or truncating mutations affecting tumour suppressor genes. All mutations identified in a given patient were further interrogated in all samples from that patient through deep resequencing using an orthogonal platform. Whole-genome rearrangement screen was further conducted in 8/36 patients. Twenty-four patients (67%) had substitutions/indels shared by all their lesions, of which 11 carried the same mutations in all lesions, and 13 had lesions with both common and private mutations. Three-quarters of those 24 patients shared oncogenic variants. The remaining 12 patients (33%) did not share any substitution/indels, with inter-lesion heterogeneity observed for oncogenic mutation(s) in genes such as PIK3CA, TP53, GATA3, and PTEN. Genomically heterogeneous lesions tended to be further apart in the mammary gland than homogeneous lesions. Genome-wide analyses of a limited number of patients identified a common somatic background in all studied MFBCs, including those with no mutation in common between the lesions. To conclude, as the number of molecular targeted therapies increases and trials driven by genomic screening are ongoing, our findings highlight the presence of genomic inter-lesion heterogeneity in one-third, despite similar pathological features. This implies that deeper molecular characterization of all MFBC lesions is warranted for the adequate management of those cancers.
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Christine
authors: C
authors: Desmedt
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Debora
authors: D
authors: Fumagalli
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumouri (IRST) - IRCCS, Meldola, Italy.
authors: Elisabetta
authors: E
authors: Pietri
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.|Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino - IST, Genoa, Italy.
authors: Gabriele
authors: G
authors: Zoppoli
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: David
authors: D
authors: Brown
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Serena
authors: S
authors: Nik-Zainal
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Gunes
authors: G
authors: Gundem
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Françoise
authors: F
authors: Rothé
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Samira
authors: S
authors: Majjaj
authors: Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino - IST, Genoa, Italy.
authors: Anna
authors: A
authors: Garuti
authors: Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino - IST, Genoa, Italy.
authors: Enrico
authors: E
authors: Carminati
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.|Translational Breast Cancer Genomics Lab, Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Sherene
authors: S
authors: Loi
authors: VIB Vesalius Research Center, KU Leuven, Campus Gasthuisberg, Herestraat 49, Bus 912, Leuven, Belgium.
authors: Thomas
authors: T
authors: Van Brussel
authors: VIB Vesalius Research Center, KU Leuven, Campus Gasthuisberg, Herestraat 49, Bus 912, Leuven, Belgium.
authors: Bram
authors: B
authors: Boeckx
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Marion
authors: M
authors: Maetens
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
authors: Laura
authors: L
authors: Mudie
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Delphine
authors: D
authors: Vincent
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Naima
authors: N
authors: Kheddoumi
authors: Pathology Unit, 'G.B. Morgagni-L. Pierantoni' Hospital, Forlì, Italy.
authors: Luigi
authors: L
authors: Serra
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumouri (IRST) - IRCCS, Meldola, Italy.
authors: Ilaria
authors: I
authors: Massa
authors: Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino - IST, Genoa, Italy.
authors: Alberto
authors: A
authors: Ballestrero
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumouri (IRST) - IRCCS, Meldola, Italy.
authors: Dino
authors: D
authors: Amadori
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.|Breast International Group Headquarters (BIG-aisbl), Brussels, Belgium.
authors: Roberto
authors: R
authors: Salgado
authors: Pathology Department, Jules Bordet Institute, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Alexandre
authors: A
authors: de Wind
authors: VIB Vesalius Research Center, KU Leuven, Campus Gasthuisberg, Herestraat 49, Bus 912, Leuven, Belgium.
authors: Diether
authors: D
authors: Lambrechts
authors: Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Martine
authors: M
authors: Piccart
authors: Pathology Department, Jules Bordet Institute, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Denis
authors: D
authors: Larsimont
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.|Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
authors: Peter J
authors: PJ
authors: Campbell
authors: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels, Belgium.
authors: Christos
authors: C
authors: Sotiriou
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009378:Neoplasms, Multiple Primary / Q000737:chemistry / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human
keywords: breast cancer; genomic heterogeneity; multicentric; multifocal; oncogenic mutations; targeted sequencing