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Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients.
Hum Mutat 2015; 36(11):1088-99HM

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+Show Affiliations

Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.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.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.The Central Bank of Tissues and Genetic Specimens, Medical University of Gdansk, Gdansk, Poland.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.Faculty of Pharmacy, 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 Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.Department of Forensic Medicine, Medical University of Gdansk, Gdansk, Poland.Department of Surgical Oncology, 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.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.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.Department of Immunology, Genetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden.Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26219265

Citation

Ronowicz, Anna, et al. "Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue From Breast Cancer Patients." Human Mutation, vol. 36, no. 11, 2015, pp. 1088-99.
Ronowicz A, Janaszak-Jasiecka A, Skokowski J, et al. Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients. Hum Mutat. 2015;36(11):1088-99.
Ronowicz, A., Janaszak-Jasiecka, A., Skokowski, J., Madanecki, P., Bartoszewski, R., Bałut, M., ... Piotrowski, A. (2015). Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients. Human Mutation, 36(11), pp. 1088-99. doi:10.1002/humu.22845.
Ronowicz A, et al. Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue From Breast Cancer Patients. Hum Mutat. 2015;36(11):1088-99. PubMed PMID: 26219265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients. AU - Ronowicz,Anna, AU - Janaszak-Jasiecka,Anna, AU - Skokowski,Jarosław, AU - Madanecki,Piotr, AU - Bartoszewski,Rafal, AU - Bałut,Magdalena, AU - Seroczyńska,Barbara, AU - Kochan,Kinga, AU - Bogdan,Adam, AU - Butkus,Małgorzata, AU - Pęksa,Rafał, AU - Ratajska,Magdalena, AU - Kuźniacka,Alina, AU - Wasąg,Bartosz, AU - Gucwa,Magdalena, AU - Krzyżanowski,Maciej, AU - Jaśkiewicz,Janusz, AU - Jankowski,Zbigniew, AU - Forsberg,Lars, AU - Ochocka,J Renata, AU - Limon,Janusz, AU - Crowley,Michael R, AU - Buckley,Patrick G, AU - Messiaen,Ludwine, AU - Dumanski,Jan P, AU - Piotrowski,Arkadiusz, Y1 - 2015/08/14/ PY - 2014/12/21/received PY - 2015/07/10/accepted PY - 2015/7/30/entrez PY - 2015/7/30/pubmed PY - 2016/7/28/medline KW - CNA KW - CNV KW - breast cancer KW - driver mutations KW - genome stability KW - rearrangement KW - somatic mosaicism SP - 1088 EP - 99 JF - Human mutation JO - Hum. Mutat. VL - 36 IS - 11 N2 - 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/26219265/Concurrent_DNA_Copy_Number_Alterations_and_Mutations_in_Genes_Related_to_Maintenance_of_Genome_Stability_in_Uninvolved_Mammary_Glandular_Tissue_from_Breast_Cancer_Patients_ L2 - https://doi.org/10.1002/humu.22845 DB - PRIME DP - Unbound Medicine ER -