{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:37:32Z","timestamp":1791405452464,"version":"4.3.3"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,10,16]],"date-time":"2009-10-16T00:00:00Z","timestamp":1255651200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2010,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Multiple biopsies of normal breast tissue from 10 <jats:italic>BRCA1<\/jats:italic> mutation carriers have been analyzed using array\u2010based comparative genomic hybridization. Normal breast tissue from five age\u2010matched control subjects without a family history of breast cancer was included for reference purposes. We repeatedly found multiple low copy number aberrations at a significantly higher frequency in histopathologically normal tissue from <jats:italic>BRCA1<\/jats:italic> mutation carriers than in normal control tissue. Some of these aberrations were similar across samples from different patients and linked to biological functions such as transcriptional regulation and DNA binding. We also observed a high degree of genomic heterogeneity between samples from the same patient, suggestive of tissue heterogeneity and etiological clonality in the breast epithelium. We show that neither loss of heterozygosity nor promoter methylation of the wild\u2010type <jats:italic>BRCA1<\/jats:italic> allele is the predominant mechanistic origin of the observed genomic instability. Instead, we propose that haploinsufficiency of <jats:italic>BRCA1<\/jats:italic> might be the underlying cause responsible for initiation of breast cancer in these predisposed women, making cells vulnerable to mitotic recombination. We also propose that loss of ER\u03b1 expression is preceded by genetic instability in the initiation of <jats:italic>BRCA1<\/jats:italic>\u2010dependent tumorigenesis, indicating that the breast epithelium of <jats:italic>BRCA1<\/jats:italic> mutation carriers may initially be estrogen\u2010responsive. Our results imply that genomic instability instigated by BRCA1 haploinsufficiency may be required for breast cancer initiation in <jats:italic>BRCA1<\/jats:italic> mutation carriers. Finding molecular markers of tumor initiation and progression, for the potential use in early disease detection, may be of great clinical importance for the improved management of at\u2010risk women. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/gcc.20723","type":"journal-article","created":{"date-parts":[[2009,10,16]],"date-time":"2009-10-16T17:21:24Z","timestamp":1255713684000},"page":"78-90","source":"Crossref","is-referenced-by-count":35,"title":["Genomic alterations in histopathologically normal breast tissue from <i>BRCA1<\/i> mutation carriers may be caused by BRCA1 haploinsufficiency"],"prefix":"10.1002","volume":"49","author":[{"given":"Karin","family":"Rennstam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Ringberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather 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