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Genomic Instability Within Tumor Stroma and Clinicopathological Characteristics of Sporadic Primary Invasive Breast Carcinoma
Koichi Fukino, MD, PhD;
Lei Shen, PhD;
Attila Patocs, MD, PhD;
George L. Mutter, MD;
Charis Eng, MD, PhD
JAMA. 2007;297:2103-2111.
Context That genomic alterations occur in both the epithelium and stroma of sporadic breast cancers has been documented by several groups. However, whether these microenvironmental alterations relate to clinicopathological features is unknown.
Objective To analyze the relationship between stromal genomic alterations and presenting clinicopathological features in sporadic breast cancer.
Design, Setting, and Participants A retrospective cross-sectional analysis of DNA from the epithelium and stroma of 220 primary sporadic invasive breast carcinomas for global genomic alterations manifested by loss of heterozygosity/allelic imbalance with 386 microsatellite markers. Data were collected from October 2003 through June 2006 from samples at Brigham and Women's Hospital, Boston, Mass.
Main Outcome Measures Association of the loss of heterozygosity/allelic imbalance, in both the stroma and epithelium, with presenting clinicopathological features, such as tumor grade, expression status of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2, clinical stage, and regional lymph node metastasis status. Associations were assessed in regression models and tested with Fisher exact test. Bonferroni correction was applied to P values, with significance set at P<.0022.
Results We found significant associations between loss of heterozygosity/allelic imbalance on chromosome 11 in the stroma and tumor grade (P = .0013), on chromosomes 1, 2, 5, 18, 20, and 22 in the stroma and regional lymph node metastasis (P = .0002-.0016), and on chromosome 14 in the epithelium and progesterone-receptor expression status (P = .002). Specific markers contributing to the loss of heterozygosity/allelic imbalance on chromosome 11 in the stroma associated with tumor grade were D11S1999 (P = .00055) and D11S1986 (P = .042). The loss of heterozygosity/allelic imbalance at various markers in the stroma was significantly associated with regional lymph node metastasis: ATA42G12 (chromosome 1, P = .00095), D5S1457 (P = .00095), D5S1501 (P = .0011), D5S816 (P = .0008), D18S858 (P = .0026), D20S103 (P = .0027), D20S851 (P = .0045), D22S683 (P = .00033), and D22S1045 (P = .0013).
Conclusions There were more correlations between clinicopathological features and the loss of heterozygosity/allelic imbalance in the stroma than in the epithelium, suggesting that stromal genomic alterations may help account for clinical diversity. Future research is necessary to validate these results and investigate their significance for prognosis and outcome.
Author Affiliations: Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (Drs Fukino, Shen, Patocs, and Eng); Department of Neurosurgery, Nippon Medical School, Tokyo, Japan (Dr Fukino); Division of Biostatistics, The Ohio State University School of Public Health, Columbus (Dr Shen); Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Dr Mutter); and Department of Genetics and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (Dr Eng).
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