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Hum Mutat. 2015 Nov;36(11):1088-99. doi: 10.1002/humu.22845. Epub 2015 Aug 14.

Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients.

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Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
The Central Bank of Tissues and Genetic Specimens, Medical University of Gdansk, Gdansk, Poland.
Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland.
Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland.
Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
Department of Forensic Medicine, Medical University of Gdansk, Gdansk, Poland.
Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden.
Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama.
Molecular Pathology Laboratory, Beaumont Hospital, Dublin, Ireland.
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.


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.


CNA; CNV; breast cancer; driver mutations; genome stability; rearrangement; somatic mosaicism

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