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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
Author(s) -
Ronowicz Anna,
JanaszakJasiecka Anna,
Skokowski Jarosław,
Madanecki Piotr,
Bartoszewski Rafal,
Bałut Magdalena,
Seroczyńska Barbara,
Kochan Kinga,
Bogdan Adam,
Butkus Małgorzata,
Pęksa Rafał,
Ratajska Magdalena,
Kuźniacka Alina,
Wasąg Bartosz,
Gucwa Magdalena,
Krzyżanowski Maciej,
Jaśkiewicz Janusz,
Jankowski Zbigniew,
Forsberg Lars,
Ochocka J. Renata,
Limon Janusz,
Crowley Michael R.,
Buckley Patrick G.,
Messiaen Ludwine,
Dumanski Jan P.,
Piotrowski Arkadiusz
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22845
Subject(s) - biology , breast cancer , comparative genomic hybridization , cancer , somatic cell , cancer research , copy number variation , brca2 protein , genetics , gene , mutation , germline mutation , genome
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.