Breast cancer-associated high-order SNP-SNP interaction of CXCL12/CXCR4-related genes by an improved multifactor dimensionality reduction (MDR-ER).

In association studies, the combined effects of single nucleotide polymorphism (SNP)-SNP interactions and the problem of imbalanced data between cases and controls are frequently ignored. In the present study, we used an improved multifactor dimensionality reduction (MDR) approach namely MDR-ER to detect the high order SNP­SNP interaction in an imbalanced breast cancer data set containing seven SNPs of chemokine CXCL12/CXCR4 pathway genes. Most individual SNPs were not significantly associated with breast cancer. After MDR­ER analysis, six significant SNP­SNP interaction models with seven genes (highest cross­validation consistency, 10; classification error rates, 41.3­21.0; and prediction error rates, 47.4­55.3) were identified. CD4 and VEGFA genes were associated in a 2­loci interaction model (classification error rate, 41.3; prediction error rate, 47.5; odds ratio (OR), 2.069; 95% bootstrap CI, 1.40­2.90; P=1.71E­04) and it also appeared in all the best 2­7­loci models. When the loci number increased, the classification error rates and P­values decreased. The powers in 2­7­loci in all models were >0.9. The minimum classification error rate of the MDR­ER­generated model was shown with the 7­loci interaction model (classification error rate, 21.0; OR=15.282; 95% bootstrap CI, 9.54­23.87; P=4.03E­31). In the epistasis network analysis, the overall effect with breast cancer susceptibility was identified and the SNP order of impact on breast cancer was identified as follows: CD4 = VEGFA > KITLG > CXCL12 > CCR7 = MMP2 > CXCR4. In conclusion, the MDR­ER can effectively and correctly identify the best SNP­SNP interaction models in an imbalanced data set for breast cancer cases.

Comparison of clinical outcome of breast cancer patients with T1-2 tumor and one to three positive nodes with or without postmastectomy radiation therapy.

OBJECTIVE: The value of postmastectomy radiation therapy for breast cancer patients with T1-2 tumor and one to three positive nodes remains controversial. The purpose of this retrospective study was to compare the clinical outcomes of breast cancer patients with T1-2 and one to three positive nodes with and without postmastectomy radiation therapy. METHODS: Between May 1990 and June 2008, of 318 breast cancer patients with T1-2 and one to three positive nodes who had undergone modified radical mastectomy, 163 received postmastectomy radiation therapy and 155 did not. The clinico-pathologic characteristics were analyzed for clinical outcomes including loco-regional recurrence, distant metastasis, disease-free survival and overall survival. RESULTS: During the median follow-up period of 102 months, the clinical outcomes in postmastectomy radiation therapy versus no-postmastectomy radiation therapy groups were as follows: loco-regional recurrence rate (3.1 versus 11.0%, P= 0.006); distant metastasis rate (20.9 versus 27.7%, P= 0.152); 10-year disease-free survival rate (73.8 versus 61.3%, P= 0.001); and 10-year overall survival rate (82.1 versus 76.1%, P= 0.239). Through a multivariate analysis, a positive nodal ratio of ≥25% (hazard ratio= 4.571, P= 0.003) and positive lymphovascular invasion (hazard ratio= 2.738, P= 0.028) were found to be independent poor prognostic predictors of loco-regional recurrence. The reduction in loco-regional recurrence (hazard ratio= 0.208, P= 0.004) by postmastectomy radiation therapy was found to be significant. CONCLUSIONS: On the basis of our results, postmastectomy radiation therapy is highly recommended for breast cancer patients with T1-2 and one to three positive nodes, especially for high-risk subgroups with a positive nodal ratio of ≥25% and positive lymphovascular invasion, not only for reducing loco-regional recurrence but also for improving disease-free survival.

Cobalt chloride-induced hypoxia modulates the invasive potential and matrix metalloproteinases of primary and metastatic breast cancer cells.

BACKGROUND: Tumor hypoxia promotes cancer progression. Matrix metalloproteinases (MMPs) are required for breast cancer cell invasion. MATERIALS AND METHODS: The effect of cobalt chloride (CoCl(2))-stimulated hypoxia on invasion potential and the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) were investigated in four breast cancer cell lines, derived from primary sites (HCC1395 and HCC1937) and metastatic sites (MCF-7 and MDA-MB-231). RESULTS: CoCl(2)-induced hypoxia induced HIF-1alpha protein expression in all four cell lines. Hypoxia significantly increased the invasiveness of HCC1395 cells, which did not correlate with a change of any one MMP. Constitutive MMP expression was different between primary and metastatic breast cancer cells. MMP-2 and MMP-9 measured by RT-PCR and zymography were notably expressed in primary cancer cells but not apparent in metastatic ones. MMP-7 was also highly expressed in primary cancer cells. Hypoxia increased the expression of MMP-1, -10 and -13 in metastatic breast cancer cells, whereas only MMP-13 was up-regulated in primary HCC1937 cells by hypoxic stimulation. TIMPs were not altered by hypoxia, except for TIMP-4 which was down-regulated in MDA-MB-231 cells. CONCLUSION: This study demonstrated a cell line-specific effect of hypoxia on invasive potential and differential expression of constitutive MMPs in primary versus metastatic breast cancer cells, i.e. primary cancer cells expressed a wider range of MMPs, in particular MMP-2, -7 and -9, than the metastatic ones. The data suggest that MMPs play no crucial roles in hypoxia-induced tumor progression in primary breast cancer cells.

Comparison of local recurrence and distant metastases between breast cancer patients after postmastectomy radiotherapy with and without immediate TRAM flap reconstruction.

BACKGROUND: The purpose of this study was to compare the local recurrence and distant metastasis of postmastectomy radiotherapy for breast cancer patients with and without immediate transverse rectus abdominis musculocutaneous (TRAM) flap reconstruction. METHODS: Between March of 1997 and October of 2001, 191 breast cancer patients received postmastectomy radiotherapy: 82 patients had TRAM flap reconstruction (TRAM flap group) and 109 patients did not (non-TRAM flap group). The mean radiation dose to the chest wall or entire TRAM flap, axillary area, and lower neck was 50 Gy (range, 48 to 54 Gy). The median follow-up period was 40 months. RESULTS: The percentages of chest wall recurrence were 3.7 percent (three of 82) in the TRAM flap group and 1.8 percent (two of 109) in the non-TRAM flap group (p = 0.653). The percentages of distant metastases were 12.2 percent (10 of 82) in the TRAM group and 15.6 percent (17 of 109) for the non-TRAM group (p = 0.67). The percentages of acute radiation dermatitis according to Radiation Therapy Oncology Group scoring criteria (TRAM flap group versus non-TRAM flap group) were as follows: grade I, 74 of 82 (90 percent) versus 93 of 109 (85 percent); grade II, seven of 82 (9 percent) versus 13 of 109 (12 percent); grade III, one of 82 (1 percent) versus three of 109 (3 percent) (p = 0.558). In the TRAM flap group, the increased percentage of fat necrosis was 8 percent. No flap loss was detected. CONCLUSIONS: There were no significant differences in the incidences of complication, locoregional recurrence, and distant metastasis between the TRAM flap and non-TRAM flap patients. The authors' results suggest that immediate TRAM flap reconstruction can be considered a feasible treatment for breast cancer patients requiring postmastectomy radiotherapy.

Serum adiponectin and leptin levels in Taiwanese breast cancer patients.

The role of two adipocytokines, adiponectin and leptin, in Taiwanese breast cancer patients remains to be determined. In this study, we analyzed the correlations between the serum levels of adiponectin and leptin and the various clinicopathological parameters in 100 newly diagnosed, histologically confirmed breast cancer patients and 100 controls. We found serum levels were decreased significantly for adiponectin in the breast cancer patients, in comparison to controls (Student t-test, P=0.003), while serum levels were increased significantly for leptin in the breast cancer patients in comparison to controls (Student t-test, P=0.025). Leptin/adiponectin (L/A ratio) were increased significantly in the breast cancer patients, in comparison to controls (Student t-test, P=0.009). Among the clinicopathological parameters, estrogen receptor, progesterone receptor, HER2/neu, lymph node metastasis, tumor stage, and tumor grade all showed no effect on the serum levels of adiponectin and leptin. BMI was negatively and positively correlated to serum adiponectin and leptin levels, respectively (Spearman's correlation, r=-0.333 and 0.323, respectively; P<0.001 for both). Intriguingly, serum L/A ratio disclosed a positive correlation to tumor size (r=0.21, P=0.036). In summary, our results suggest that low serum adiponectin levels and high serum leptin levels are associated with an increased risk for breast cancer. Also, independent of the effect of BMI, the increased serum ratio of L/A may indicate the presence of aggressive breast cancers.

Intra-abdominal desmoplastic small round cell tumor with elevated serum CA 125: a case report.

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive tumor usually involving the peritoneum. It occurs more commonly in young males and is characterized by distinctive clinical, histologic, and immunophenotypic features. The histogenesis of DSRCT remains unknown. Coexpression of epithelial, mesenchymal, and neural antigens in the same cell provides evidence that DSRCT may arise from a primitive pluripotent stem cell with divergent differentiation. Recently, according to cytogenetic studies, some authors have proposed that the divergent differentiation of DSRCT may be the result of the fusion of Ewing's sarcoma gene and Wilms' tumor suppressor gene. Clinically, an elevated serum CA 125 concentration is found in some patients with DSRCT. We present the case of a 29-year-old man with diffuse intra-abdominal DSRCT and elevated serum CA 125 concentration and briefly review the relevant literature.