<p>PDF file, 148KB, The previous studies on the serum levels of MMP-2 and breast cancer.</p>

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 (P rs166870=2.88×10-7 and P rs10825036=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.

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.

Background: Recently, many studies have been conducted to identify the susceptibility loci related with breast cancer risk, but few studies have examined the genetic variations for survival. Objectives & Methods: To identify the susceptibility loci for breast cancer recurrence or all-cause of death, genome wide survival analysis were performed with 2,171 histologically confirmed incident breast cancer cases. For a genetic association study, DNA was genotyped using Affymetrix SNP Array 6.0 including about 0.9 million single nucleotide polymorphisms (SNPs). We examined the association between genetic variance and disease-free survival (DFS) and overall survival (OS) using Cox proportional hazard regression model adjusting for known prognostic factors. Results: During a median of 5.8 years of follow-up, 297 women recurred and 152 women died. Three SNPs in 2 genes (ARHGAP28 and LGI4) and four intergenic SNPs were identified for DFS (P adjusted −6 ) and five SNPs in 4 genes (CADPS, KCNH7, LGI4, and TGFBRAP1) and one intergenic SNP were associated with OS (P adjusted −6 ). Most significant associated SNP with DFS was located in ARHGAP28 (P adjusted =7.40 X 10 −7 ) and this showed decreased risk of recurrence (aHR=0.6, 95% CI=0.50-0.74). SNP of CADPS was most significantly associated with OS (P adjusted = 9.04 X 10 −7 ), and showed increased risk of all-cause of death (aHR=2.1, 95% CI=1.56-2.83). Conclusions: Our results suggest that the promising SNPs might associate with the breast cancer recurrence and survival in Korean women. We will confirm these findings in the replication stages further. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1656. doi:1538-7445.AM2012-1656

Abstract Introduction: While the incidence of breast cancer is relatively low in Korean women, the proportion of breast cancer that develops in younger age is much higher than in western countries. Family-based linkage study has focused on the identification of a region which is associated with the age at onset in familial breast cancer. However, genetic factors for onset age of breast cancer are still largely unknown. While genome-wide association studies (GWAS) have identified over 20 susceptibility loci for breast cancer, no previous study has examined the relationship between the common genetic variations and the age at onset in breast cancer. Methods: To identify genetic factors underlying onset age of breast cancer, we investigated the association between genetic variants and age at diagnosis in 2,155 breast cancer cases. Over 1.9 million SNPs either directly genotyped using Affymetrix 6.0 or imputed with HapMap 2.0 as a reference panel were evaluated after quality control. Tests of association were conducted with Plink v1.01 using the additive genetic model and Mach2qtl with allelic dosages in a linear regression model in which onset age was included as a dependent variable (continuous). The differences of mean age across genotype-groups were also compared using one-way analysis of variance. Results: The mean age at onset in breast cancer was 48.1 ± 9.31. The SNPs with p-value less than 1×10-5 obtained from linear regression were clustered into two regions: two SNPs (rs6684400 and rs6659875) are at 1q25.3 in intergenic region between ZNF648 and GLUL gene; the other two (rs669576 and rs667007) are at 11q25 in intronic region of NTM gene. Per-allele effect size was 1.4 ± 0.30 (p = 4.84E-06) for rs6684400 C allele and 3.1 ± 0.68 for rs669576 T allele (p = 7.11E-06). The mean age at onset for the rs6684400 G/G, C/G and C/C groups were found to be 47.2 ± 9.00, 48.1 ± 9.32 and 49.7 ± 9.59, respectively (p = 0.0001). As for the rs669576, the mean age at onset for G/G, G/T and T/T groups were 47.8 ± 9.15, 50.9 ± 10.38 and 54.3 ± 7.80, respectively (p < 0.0001) Conclusions: Our study suggests that the common genetic variants may be closely linked to age at onset in breast cancer. Further validation with a larger sample size is required to validate our result. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1655. doi:1538-7445.AM2012-1655

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 ( P trend = 0.029 and P trend = 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 ( P trend = 0.004). Furthermore, these effects were profound in patients with BMI less than 25 kg/m 2 (adjusted hazard ratio (aHR), 3.17; 95% confidence intervals (CI), 1.66-6.06, P trend < 0.001) or lymph-node negative breast cancer (aHR, 5.36; 95% CI, 2.18-13.2, P trend < 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.

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.

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.

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.

Abstract Objective: We evaluated whether preoperative serum levels of matrix metalloproteinase-2 (MMP-2) work as a prognostic biomarker in breast cancer prognosis. Methods: Three hundred and three women with histologically confirmed breast cancer were recruited. The follow-up time for all patients was 4.24 years. The MMP-2 levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA) using the preoperative serum. The relationship of MMP-2 to survival was investigated using Cox's proportional hazard model adjusted for the 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 compared to the first tertile of MMP-2 (hazard ratio (HR)=1.80, 95% confidence interval (CI)=1.04-3.11, P=0.04). Furthermore, when the patients were stratified by histological grade and nuclear grade, the worse DFS was predicted by high levels of MMP-2 (HR=2.90 and 95% CI=1.42-5.92 in histological grade III vs. I-II and HR=2.61 and 95% CI=1.26-5.39 in nuclear grade III vs. I-II). In ER negative patients, high levels of MMP-2 also tended to have a worse prognosis (HR=2.75 and 95% CI=1.32-5.73). Conclusions: Our results suggest that the preoperative serum levels of MMP-2 were associated with the survival of breast cancer as a potential prognostic biomarker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4494. doi:1538-7445.AM2012-4494

Abstract Age of menarche as well as height is known to be associated with breast cancer risk. Adult height is associated with age at menarche, which may explain that growth in height accelerates driven by hormone changes during adolescence. The authors evaluated associations between the age of menarche and height as the adolescent growth indicator and breast cancer risk among 3,725 cases and 3,748 controls enrolled in a multicenter, case-control study in Korea, Seoul Breast Cancer Study (2001-2007). Logistic regression models were used to estimate odds ratios (ORs) of age at menarche (<=13, 14-15, and 16+ years) and quintile of height calculated in each 10-year age group based on total participants for breast cancer risk. The associations were assessed in overall and in strata of menopausal status, birth year group (median, 1957) and hormone receptor status. Early menarche and taller height increased risk of breast cancer as expected; for both premenopausal and postmenopausal women, those starting menarche at 13 years or younger had 1.3-fold (95% CI: 1.1-1.6 for premenopausal women and 1.0-1.7 for postmenopausal women, respectively) comparing to women starting menarche at 16 years or older. In contrast, the association between height and breast cancer risk was different between menopausal status; women with 5th quintile in each age group had 2.1-fold (95% CI: 1.6-2.7) comparing to women with 1st quintile among postmenopausal women, however, associations were absent among premenopausal women. Age at menarche, height and birth year were highly correlated with each other; age at menarche and height increased as the birth year increased significantly. The associations of age at menarche and height on breast cancer in the strata of birth year group were similar with the associations in the menopausal status. Although cases with hormone receptor positive increased as the birth year increased, the ORs of age at menarche and height did not vary significantly by hormone receptor status. These findings suggest that age at menarche and adult height is associated with breast cancer overall, particularly among postmenopausal women or women born prior to 1957. This may result from the chronological changes of adolescent growth in Korea. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 640. doi:1538-7445.AM2012-640

AbstractBackground: 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. Cancer Epidemiol Biomarkers Prev; 21(8); 1371–80. ©2012 AACR.

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.

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.

Abstract Objective In a hospital-based case-control study in Korea, we evaluated the association between polymorphisms in genes involved in apoptosis and cell cycle control and brain tumor risk among children. Methods Incident brain tumor cases (n=70) and non-cancer controls (n=254) were recruited from three teaching hospitals in Seoul between May 2003 and August 2006. Information on the characteristics of children and their parents were collected by trained interviewers using structured questionnaire. Tagging single-nucleotide polymorphisms (SNPs) were selected using a pairwise linkage-disequilibrium (LD) based algorithm (n=304) were genotyped for 43 cases and 153 controls in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) for SNP genotypes were estimated using unconditional logistic regression adjusted for age and birth weight. The false discovery rate (FDR) was estimated to evaluate the probability of false positive associations; we considered FDR <0.2 as noteworthy. Results Eleven tag SNPs in six genes, AICDA, LMO2, MYC, BCL2, BCL2A1, and CASP7 were significantly associated with childhood brain tumor (Ptrend<0.05). Two SNPs (rs12306110 and rs3794318) in AICDA gene, encoding activation-induced cytidine deaminase, remained significant after adjusting of multiple tests. These SNPs were in tight LD. The most significant association with childhood brain tumor risk was for the rs12306110 (OR, 0.24; 95% CI, 0.11-0.51). ConclusionOur results suggest that genetic polymorphisms in AICDA may be associated with the risk of brain tumor in childhood. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2846.