Prediction of breast cancer survival using clinical and genetic markers by tumor subtypes.

PURPOSE: To identify the genetic variants associated with breast cancer survival, a genome-wide association study (GWAS) was conducted of Korean breast cancer patients. METHODS: From the Seoul Breast Cancer Study (SEBCS), 3,226 patients with breast cancer (1,732 in the discovery and 1,494 in the replication set) were included in a two-stage GWAS on disease-free survival (DFS) by tumor subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). The associations of the re-classified combined prognostic markers through recursive partitioning analysis (RPA) of DFS for breast cancer were assessed with the Cox proportional hazard model. The prognostic predictive values of the clinical and genetic models were evaluated by Harrell's C. RESULTS: In the two-stage GWAS stratified by tumor subtypes, rs166870 and rs10825036 were consistently associated with DFS in the HR+ HER2- and HR- HER2- breast cancer subtypes, respectively (Prs166870 = 2.88 × 10(-7) and Prs10825036 = 3.54 × 10(-7) in the combined set). When patients were classified by the RPA in each subtype, genetic factors contributed significantly to differentiating the high risk group associated with DFS inbreast cancer, specifically the HR+ HER2- (P discovery=1.18 × 10(-8) and P replication = 2.08 × 10(-5)) and HR- HRE2- subtypes (P discovery = 2.35 × 10(-4) and P replication = 2.60 × 10(-2)). The inclusion of the SNPs tended to improve the performance of the prognostic models consisting of age, TNM stage and tumor subtypes based on ER, PR, and HER2 status. CONCLUSION: Combined prognostic markers that include clinical and genetic factors by tumor subtypes could improve the prediction of survival in breast cancer.

Tumor subtype-specific associations of hormone-related reproductive factors on breast cancer survival.

PURPOSE: It is inconclusive whether reproductive factors, which are known as risk factors of breast cancer, also influence survival. We investigated overall and subtype-specific associations between reproductive factors and breast cancer survival. METHODS: Among 3,430 incident breast cancer patients who enrolled in the Seoul Breast Cancer Study, 269 patients (7.8%) died and 528 patients (15.4%) recurred. The overall and subtype-specific associations of reproductive factors including age at menarche and menopause, duration of estrogen exposure, menstrual cycle, parity, age at first full-term pregnancy, number of children, age at last birth, time since the last birth, and duration of breastfeeding, on overall and disease-free survival (OS and DFS) were estimated by hazard ratios (HRs) and 95% confidence intervals (95% CIs) using a multivariate Cox proportional hazard model. RESULTS: An older age at menarche (HR for OS=1.10, 95% CI=1.03-1.19), a greater number of children (≥ 4 vs. 2, HR for DFS=1.58, 95% CI=1.11-2.26), and a shorter time since last birth (<5 vs. ≥ 20 years, HR for DFS=1.67, 95% CI=1.07-2.62) were associated with worse survival while longer duration of estrogen exposure with better survival (HR for DFS=0.97, 95% CI=0.96-0.99). In the stratified analyses by subtypes, those associations were more pronounced among women with hormone receptor and human epidermal growth factor 2 positive (HR+ HER2+) tumors. CONCLUSIONS: It is suggested that reproductive factors, specifically age at menarche, number of children, time since last birth, and duration of estrogen exposure, could influence breast tumor progression, especially in the HR+ HER2+ subtype.

Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women.

BACKGROUND: The 5-year survival rate for breast cancer among Korean women has increased steadily; however, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires an adequate supply of methyl group donors and B vitamins, may affect the prognosis of breast cancer. This aim of this study was to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis on the prognosis of breast cancer. METHODS: We assessed the dietary intake using a food frequency questionnaire with 980 women who were newly diagnosed and histopathologically confirmed to have primary breast cancer from hospitals in Korea, and 141 disease progression events occurred. Cox's proportional hazard regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) adjusting for age, education, recruitment sites, TNM stage, hormone status, nuclear grade and total calorie. RESULTS: There was no significant association between any one-carbon metabolism related nutrients (vitamin B2, B6 and folate) and the progression of breast cancer overall. However, one-carbon metabolism related nutrients were associated with disease progression in breast cancer patients stratified by subtypes. In ER + and/or PR + breast cancers, no association was observed; however, in ER-/PR- breast cancers, a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression (HR = 2.28; 95% CI, 1.20-4.35, HR = 1.84; 95% CI, 1.02-3.32, respectively) compared to a low intake. This positive association between the ER/PR status and progression of the disease was profound when the nutrient intakes were categorized in a combined score (Pinteraction = 0.018). In ER-/PR- breast cancers, high combined scores were associated with a significantly poor DFS compared to those belonging to the low score group (HR = 3.84; 95% CI, 1.70-8.71). CONCLUSIONS: In conclusion, our results suggest that one-carbon related nutrients have a role in the prognosis of breast cancer depending on the ER/PR status.

Common genetic polymorphisms of microRNA biogenesis pathway genes and breast cancer survival.

BACKGROUND: Although the role of microRNA's (miRNA's) biogenesis pathway genes in cancer development and progression has been well established, the association between genetic variants of this pathway genes and breast cancer survival is still unknown. METHODS: We used genotype data available from a previously conducted case-control study to investigate association between common genetic variations in miRNA biogenesis pathway genes and breast cancer survival. We investigated the possible associations between 41 germ-line single-nucleotide polymorphisms (SNPs) and both disease free survival (DFS) and overall survival (OS) among 488 breast cancer patients. During the median follow-up of 6.24 years, 90 cases developed disease progression and 48 cases died. RESULTS: Seven SNPs were significantly associated with breast cancer survival. Two SNPs in AGO2 (rs11786030 and rs2292779) and DICER1 rs1057035 were associated with both DFS and OS. Two SNPs in HIWI (rs4759659 and rs11060845) and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with only OS. The most significant association was observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% confidence interval (CI), 1.41-4.88) and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI, 1.52-5.69). We also found cumulative effects of SNPs on DFS and OS. Compared to the subjects carrying 0 to 2 high-risk genotypes, those carrying 3 or 4-6 high-risk genotypes had an increased risk of disease progression with a hazard ratio of 2.16 (95% CI, 1.18- 3.93) and 4.47 (95% CI, 2.45- 8.14), respectively (P for trend, 6.11E-07). CONCLUSIONS: Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer survival. Further studies in larger sample size and functional characterizations are warranted to validate these results.

The association between the preoperative serum levels of lipocalin-2 and matrix metalloproteinase-9 (MMP-9) and prognosis of breast cancer.

BACKGROUND: Although a number of experimental studies have suggested the role of lipocalin-2 (LCN2) and matrix metalloproteinase-9 (MMP-9) in breast cancer progression, limited numbers of epidemiological studies have examined the relationship between the levels of lipocalin-2 and MMP-9 and breast cancer survival. METHODS: Preoperative serum levels of lipocalin-2 and MMP-9 were measured in 303 breast cancer patients and 74 healthy controls recruited between 2004 and 2007. We examined the association between lipocalin-2 and MMP-9 levels and disease-free survival (DFS) using Cox proportional hazard regression model. RESULTS: The serum levels of lipocalin-2 and MMP-9 were not significantly different between patients and controls (P > 0.05). Elevated lipocalin-2 and MMP-9 levels were associated with reduced DFS of breast cancer ( Ptrend = 0.029 and Ptrend = 0.063, respectively). When lipocalin-2 and MMP-9 levels were categorized based on the combined risk score, patients with higher levels of both lipocalin-2 and MMP-9 exhibited poor DFS compared to patients with lower levels (Ptrend = 0.004). Furthermore, these effects were profound in patients with BMI less than 25 kg/m2 (adjusted hazard ratio (aHR), 3.17; 95% confidence intervals (CI), 1.66-6.06, Ptrend < 0.001) or lymph-node negative breast cancer (aHR, 5.36; 95% CI, 2.18-13.2, Ptrend < 0.001). CONCLUSIONS: Our study suggests that the elevated levels of lipocalin-2 and MMP-9 are associated with reduced breast cancer survival, particularly in patients with lower BMI and lymph-node negative breast cancers.

Preoperative serum levels of matrix metalloproteinase-2 (MMP-2) and survival of breast cancer among Korean women.

BACKGROUND: Matrix metalloproteinase-2 (MMP-2) has been thought of as a predictor of recurrence or metastasis risk or prognostic markers in cancer. We evaluated whether preoperative serum levels of MMP-2 work as a prognostic biomarker in breast cancer prognosis. METHODS: Preoperative serum levels of MMP-2 were measured with ELISA in 303 patients with histologically confirmed breast cancer. The median follow-up time for all patients was 4.24 years. The relationship of MMP-2 to survival was investigated using Cox proportional hazard regression model adjusted for the tumor-node-metastasis (TNM) stage and estrogen receptor (ER) status. RESULTS: In the multivariate analysis, disease-free survival (DFS) was worse among patients with the third tertile of MMP-2 level than with the first tertile of MMP-2 level [hazard ratio, 1.80; 95% confidence interval (CI), 1.04-3.11; P = 0.04]. However, when the patients were stratified by age, ER status, histologic grade, and nuclear grade, inverse correlation was shown between serum MMP-2 levels and prognostic factors, and the associations between MMP-2 and DFS were only significant among patients with poor prognostic factors (HR, 2.75; 95% CI, 1.32-5.73 in ER-negative; HR, 2.90; 95% CI, 1.42-5.92 in histologic grade III; and HR, 2.61; 95% CI, 1.26-5.39 in nuclear grade III). CONCLUSIONS: Our results suggest that the preoperative serum levels of MMP-2 were associated with the survival in patients with breast cancer in ER-negative, higher histologic grade, or higher nuclear grade breast cancers. IMPACT: Our results indicate that serum levels of MMP-2 may play a role as prognostic biomarker in breast cancer survival.

Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia.

Current evidence suggests that apoptosis and the cell cycle system play an important role in cancer development. To identify susceptible genetic markers in these mechanisms, we did an association study in 63 patients and 148 controls. A total of 304 SNPs in 31 gene regions were selected. We evaluated an association at a gene region level by computing the minimum P-value (minP) and doing the false discovery rate (FDR) test. Both SNP and gene-based analyses presented associations with the risk of childhood leukemia for 5 genes: CASP7, CASP14, CASP8AP2, MYC, and RIPK1 (P(trend)<0.05). There were statistically significant associations for CASP7 (rs12416109 and rs3814231, P(trend) = 0.002 and 0.009, respectively, minP = 0.013, FDR = 0.042) and CASP14 (rs8110862, P(trend)<0.001, minP = 0.002, FDR = 0.027). This study suggests that genetic polymorphisms in apoptosis and cell cycle related genes might play a role in childhood leukemia development.

Genetic variants in interleukin-2 and risk of lymphoma among children in Korea.

To estimate the genetic susceptibility for childhood lymphoma, we conducted an association study for 23 cases and 148 controls. Total 1536 tag single nucleotide polymorphisms (SNPs) were selected in 138 candidate gene regions related to immune responses, apoptosis, the cell cycle, and DNA repair. Twelve SNPs were significantly associated with the risk of lymphoma (P(trend)<0.05) in six genes (IL1RN, IL2, IL12RB1, JAK3, TNFRSF13B, and XRCC3). The most significant association was seen for IL2 variant rs2069762 (OR(TG+GG) vs. TT=3.43 (1.29-9.11), P(trend)=0.002, minP=0.005). These findings suggest that common genetic variants in IL2 might play a role in the pathogenesis of childhood lymphoma.

Combined genetic effect of CDK7 and ESR1 polymorphisms on breast cancer.

Breast cancer development is related to genes regulating cell cycle progression such as CCND1, CDK7, and ESR1. We conducted a hospital-based case-control study to evaluate the role of genetic polymorphisms in these genes in breast cancer development among Korean women. Questionnaire data and samples were obtained from 864 incident breast cancer cases and 723 controls recruited from 1995 to 2002. Four single nucleotide polymorphisms (SNPs) in three genes were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry [CCND1 Ex4-1G>A (rs9344), CDK7 Ex2-28C>T (rs2972388), ESR1 P325P Ex4-122G>C (rs1801132), and ESR1 T594T Ex8+229G>A (rs2228480)], and their associations with breast cancer risk were assessed. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis adjusted for age, education, age at the first full-term pregnancy, and family history of breast cancer. Women carrying the CDK7 TT genotype had increased risk of breast cancer (OR, 1.4; 95% CI, 1.1-1.7). There was no significant association between breast cancer risk and the genetic polymorphisms of CCND1 and ESR1. However, when CDK7 and ESR1 P325P were combined, women carrying both the CDK7 TT and ESR1 P325P CC genotypes showed increased breast cancer risk (OR, 1.7; 95% CI, 1.1-2.5; P for trend, <0.01). In conclusion, our findings suggest that the combined genotypes of CDK7 and ESR1 are associated with breast cancer risk among Korean women.