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NPJ Breast Cancer. 2016 May 4;2:16007. doi: 10.1038/npjbcancer.2016.7. eCollection 2016.

DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas.

Author information

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
The McDonnell Genome Institute, Washington University, St Louis, MO, USA.
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
USC Epigenome Center, University of Southern California, Los Angeles, CA, USA.
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA.
Department of Pathology, Division of Anatomical Pathology, Beth Isreal Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology, Harvard Medical School, Boston, MA, USA.
Buck Institute for Research on Aging, Novato, CA, USA.
The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
National Cancer Institute, Rockville, MD, USA.
Department of Surgery, Duke University Comprehensive Cancer Center, Durham, NC, USA.
Department of Genetics, Washington University, St Louis, MO, USA.


Recurrence rates after breast-conserving therapy may depend on genomic characteristics of cancer-adjacent, benign-appearing tissue. Studies have not evaluated recurrence in association with multiple genomic characteristics of cancer-adjacent breast tissue. To estimate the prevalence of DNA defects and RNA expression subtypes in cancer-adjacent, benign-appearing breast tissue at least 2 cm from the tumor margin, cancer-adjacent, pathologically well-characterized, benign-appearing breast tissue specimens from The Cancer Genome Atlas project were analyzed for DNA sequence, copy-number variation, DNA methylation, messenger RNA (mRNA) sequence, and mRNA/microRNA expression. Additional samples were also analyzed by at least one of these genomic data types and associations between genomic characteristics of normal tissue and overall survival were assessed. Approximately 40% of cancer-adjacent, benign-appearing tissues harbored genomic defects in DNA copy number, sequence, methylation, or in RNA sequence, although these defects did not significantly predict 10-year overall survival. Two mRNA/microRNA expression phenotypes were observed, including an active mRNA subtype that was identified in 40% of samples. Controlling for tumor characteristics and the presence of genomic defects, this active subtype was associated with significantly worse 10-year survival among estrogen receptor (ER)-positive cases. This multi-platform analysis of breast cancer-adjacent samples produced genomic findings consistent with current surgical margin guidelines, and provides evidence that extratumoral RNA expression patterns in cancer-adjacent tissue predict overall survival among patients with ER-positive disease.

Conflict of interest statement

All authors declare no competing financial interests, except C.M.P. holds a patent applying the PAM50 algorithm; this algorithm was used to subtype the breast cancer specimens in the current work. C.M.P. is an equity stock holder, and Board of Director Member, of BioClassifier L.L.C. and GeneCentric Diagnostics.

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