Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma.
BACKGROUND
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.


METHODS
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.


METHODS
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.
Fukino
Koichi
K
Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Shen
Lei
L
Patocs
Attila
A
Mutter
George L
GL
Eng
Charis
C
D022981:Allelic Imbalance; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D003430:Cross-Sectional Studies; D004273:DNA, Neoplasm; D004848:Epithelium / Q000737:chemistry; D005260:Female; D042822:Genomic Instability; D006801:Humans; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D018895:Microsatellite Repeats; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D017154:Stromal Cells / Q000737:chemistry*
D004273:DNA, Neoplasm