TY - JOUR
T1 - Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers
T2 - Field cancerization or contaminating tumor cells?
AU - Sadanandam, Anguraj
AU - Lal, Aseem
AU - Benz, Stephen C.
AU - Eppenberger-Castori, Serenella
AU - Scott, Gary
AU - Gray, Joe W.
AU - Spellman, Paul
AU - Waldman, Fred
AU - Benz, Christopher C.
N1 - Funding Information:
Acknowledgments This work was supported by National Institutes of Health grants U24-CA14358 (CCB), R21-CA155679 (CCB), P50-CA58207 (CCB, JWG), the Department of Defense grant W81XWH-11-1-0549-BC100597P1 (JWG), the U.S. Army Medical Research Acquisition Activity, 820 Chandler St., Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office; and Hazel P. Munroe memorial funding (Buck Institute).We appreciate the valuable technical and bioinformatic assistance from Rachel Puckett (Buck Institute), Cathy Vitelli (Buck Institute Morphology & Imaging Core), Sandy DeVries (UCSF), Adam Olshen (UCSF), Victoria Carlton (Affymetrix) and Yuker Wang (Affymetrix).
PY - 2012/12
Y1 - 2012/12
N2 - Field cancerization effects as well as isolated tumor cell foci extending well beyond the invasive tumor margin have been described previously to account for local recurrence rates following breast conserving surgery despite adequate surgical margins and breast radiotherapy. To look for evidence of possible tumor cell contamination or field cancerization by genetic effects, a pilot study (Study 1: 12 sample pairs) followed by a verification study (Study 2: 20 sample pairs) were performed on DNA extracted from HER2-positive breast tumors and matching normal adjacent mammary tissue samples excised 1-3 cm beyond the invasive tumor margin. High-resolution molecular inversion probe (MIP) arrays were used to compare genomic copy number variations, including increased HER2 gene copies, between the paired samples; as well, a detailed histologic and immunohistochemical (IHC) re-evaluation of all Study 2 samples was performed blinded to the genomic results to characterize the adjacent normal tissue composition bracketing the DNA-extracted samples. Overall, 14/32 (44 %) sample pairs from both studies produced genome-wide evidence of genetic aberrations including HER2 copy number gains within the adjacent normal tissue samples. The observed single-parental origin of monoallelic HER2 amplicon haplotypes shared by informative tumor-normal pairs, as well as commonly gained loci elsewhere on 17q, suggested the presence of contaminating tumor cells in the genomically aberrant normal samples. Histologic and IHC analyses identified occult 25-200 μm tumor cell clusters overexpressing HER2 scattered in more than half, but not all, of the genomically aberrant normal samples re-evaluated, but in none of the genomically normal samples. These genomic and microscopic findings support the conclusion that tumor cell contamination rather than genetic field cancerization represents the likeliest cause of local clinical recurrence rates following breast conserving surgery, and mandate caution in assuming the genomic normalcy of histologically benign appearing peritumor breast tissue.
AB - Field cancerization effects as well as isolated tumor cell foci extending well beyond the invasive tumor margin have been described previously to account for local recurrence rates following breast conserving surgery despite adequate surgical margins and breast radiotherapy. To look for evidence of possible tumor cell contamination or field cancerization by genetic effects, a pilot study (Study 1: 12 sample pairs) followed by a verification study (Study 2: 20 sample pairs) were performed on DNA extracted from HER2-positive breast tumors and matching normal adjacent mammary tissue samples excised 1-3 cm beyond the invasive tumor margin. High-resolution molecular inversion probe (MIP) arrays were used to compare genomic copy number variations, including increased HER2 gene copies, between the paired samples; as well, a detailed histologic and immunohistochemical (IHC) re-evaluation of all Study 2 samples was performed blinded to the genomic results to characterize the adjacent normal tissue composition bracketing the DNA-extracted samples. Overall, 14/32 (44 %) sample pairs from both studies produced genome-wide evidence of genetic aberrations including HER2 copy number gains within the adjacent normal tissue samples. The observed single-parental origin of monoallelic HER2 amplicon haplotypes shared by informative tumor-normal pairs, as well as commonly gained loci elsewhere on 17q, suggested the presence of contaminating tumor cells in the genomically aberrant normal samples. Histologic and IHC analyses identified occult 25-200 μm tumor cell clusters overexpressing HER2 scattered in more than half, but not all, of the genomically aberrant normal samples re-evaluated, but in none of the genomically normal samples. These genomic and microscopic findings support the conclusion that tumor cell contamination rather than genetic field cancerization represents the likeliest cause of local clinical recurrence rates following breast conserving surgery, and mandate caution in assuming the genomic normalcy of histologically benign appearing peritumor breast tissue.
KW - HER2/ERBB2-amplified breast tumors
KW - Normal adjacent tissue
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UR - http://www.scopus.com/inward/citedby.url?scp=84878767379&partnerID=8YFLogxK
U2 - 10.1007/s10549-012-2290-3
DO - 10.1007/s10549-012-2290-3
M3 - Article
C2 - 23104223
AN - SCOPUS:84878767379
SN - 0167-6806
VL - 136
SP - 693
EP - 703
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -