title: Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients.
abstract: Somatic mosaicism for DNA copy-number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array-based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC-CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ronowicz
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janaszak-Jasiecka
authors.affiliation: The Central Bank of Tissues and Genetic Specimens, Medical University of Gdansk, Gdansk, Poland.|Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Skokowski
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Madanecki
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Bartoszewski
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bałut
authors.affiliation: The Central Bank of Tissues and Genetic Specimens, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seroczyńska
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Kochan
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Bogdan
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Butkus
authors.affiliation: Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Pęksa
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ratajska
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Alina
authors.initials: A
authors.lastname: Kuźniacka
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasąg
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gucwa
authors.affiliation: Department of Forensic Medicine, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzyżanowski
authors.affiliation: Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Jaśkiewicz
authors.affiliation: Department of Forensic Medicine, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Jankowski
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Forsberg
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: J Renata
authors.initials: JR
authors.lastname: Ochocka
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
authors.affiliation: Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Crowley
authors.affiliation: Molecular Pathology Laboratory, Beaumont Hospital, Dublin, Ireland.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Buckley
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D015203:Reproducibility of Results; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor
keywords: CNA; CNV; breast cancer; driver mutations; genome stability; rearrangement; somatic mosaicism