title: Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer.
abstract: Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Lars A
authors.initials: LA
authors.lastname: Forsberg
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Chiara
authors.initials: C
authors.lastname: Rasi
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden; Department of Pathology, Central Hospital Falun, 791 82 Falun, Sweden;
authors.forename: Gyula
authors.initials: G
authors.lastname: Pekar
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Hanna
authors.initials: H
authors.lastname: Davies
authors.affiliation: Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, 80-416 Gdansk, Poland;
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA;
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Razzaghian
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ambicka
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Halaszka
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Marcin
authors.initials: M
authors.lastname: Przewoźnik
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczak
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Geeta
authors.initials: G
authors.lastname: Mandava
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Saichand
authors.initials: S
authors.lastname: Pasupulati
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Julia
authors.initials: J
authors.lastname: Hacker
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: K Reddy
authors.initials: KR
authors.lastname: Prakash
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Ravi Chandra
authors.initials: RC
authors.lastname: Dasari
authors.affiliation: Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden; Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden;
authors.forename: Joey
authors.initials: J
authors.lastname: Lau
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Nelly
authors.initials: N
authors.lastname: Penagos-Tafurt
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Helena M
authors.initials: HM
authors.lastname: Olofsson
authors.affiliation: Department of Women's and Children's Health, Uppsala University, 751 85 Uppsala, Sweden;
authors.forename: Gunilla
authors.initials: G
authors.lastname: Hallberg
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Piotr
authors.initials: P
authors.lastname: Skotnicki
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Jerzy
authors.initials: J
authors.lastname: Mituś
authors.affiliation: Department of Surgical Oncology, Medical University of Gdansk, 80-952 Gdansk, Poland; Bank of Frozen Tissues and Genetic Specimens, Department of Medical Laboratory Diagnostics, Medical University of Gdansk, 80-211 Gdansk, Poland;
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Skokowski
authors.affiliation: Surgical Oncology, Collegium Medicum, Oncology Center, Nicolaus Copernicus University, 85-796 Bydgoszcz, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Jankowski
authors.affiliation: Surgical Oncology, Collegium Medicum, Oncology Center, Nicolaus Copernicus University, 85-796 Bydgoszcz, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Śrutek
authors.affiliation: Surgical Oncology, Collegium Medicum, Oncology Center, Nicolaus Copernicus University, 85-796 Bydgoszcz, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zegarski
authors.affiliation: Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden;
authors.forename: Eva
authors.initials: E
authors.lastname: Tiensuu Janson
authors.affiliation: Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków Branch, 31-115 Kraków, Poland;
authors.forename: Janusz
authors.initials: J
authors.lastname: Ryś
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden; Department of Pathology, Central Hospital Falun, 791 82 Falun, Sweden;
authors.forename: Tibor
authors.initials: T
authors.lastname: Tot
authors.affiliation: Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, 715 85 Uppsala, Sweden;
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000033:anatomy & histology* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D018734:Genes, erbB-2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D012307:Risk Factors
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D017978:Receptors, Growth Factor