Minkyo Song

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

BackgroundAlthough 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.MethodsPreoperative 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.ResultsThe 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).ConclusionsOur 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.

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

BackgroundAlthough 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.MethodsWe 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.ResultsSeven 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).ConclusionsOur 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.

Breast cancer prevention based on gene–environment interaction

Breast cancer, the most common cancer in women, results from combined effects of genetic and environmental factors. Although a number of preventive measures have been suggested to reduce the risk of breast cancer, only a few (e.g., regular mammogram, etc.) proved to be efficient preventive modalities. Among many potential reasons, differences in individual susceptibility factors may complicate the efficacy of the intervention. A growing body of evidence shows that the strength of association between various dietary, behavioral (exercise and obesity), and environmental exposures, and breast cancer risk may be modified by individual genetic factors. Preventive strategies against breast cancer will be discussed considering the findings of the gene–environment interaction of breast cancer. These include behavior modification for high‐risk subjects (primary prevention), early detection and extensive monitoring of genetically susceptible subjects and noninvasive treatment of early stage cancer cases (secondary prevention), and finally prophylactic and therapeutic intervention to slow the progression of diseases (tertiary prevention). The accumulating evidences of the gene–environment interactions provide a better understanding of the breast cancer development and enable us to adopt individualized preventive strategies for personalized health care.

What Are the Major Determinants in the Success of Smoking Cessation: Results from the Health Examinees Study

Understanding mechanisms underlying smoking-related factors should be prioritized in establishing smoking prevention and cessation policy. The aim of this study was to identify factors significantly associated with smoking initiation and/or smoking cessation as well as the most important determinants of successful smoking cessation in a developed non-Western setting. Based on multiple logistic regression models, the odds ratios (ORs) for smoking initiation and cessation were estimated among males (N = 24,490) who had participated in the Health Examinees (HEXA) study. The Cox proportional hazards regression model was used to assess the association between selected predictors of smoking cessation and the likelihood of reaching this goal. Finally, Kaplan–Meier curves were constructed to illustrate the distribution of time from age at smoking initiation to age at smoking cessation. We found that the ORs for successfully quitting smoking increased with age, married status, educational achievement, having a non-manual job, drinking cessation and disease morbidity. Those exposed to secondhand smoking showed less likelihood of quitting smoking. A continual decrease in the ORs for successfully quitting smoking was observed according to increased smoking duration, smoking dose per day and lifetime tobacco exposure (p trend <0.001). Among the selected predictors, lifetime tobacco exposure, educational attainment, alcohol drinking status and birth cohort were the major determinants in the success of smoking cessation. Our findings suggest that lifetime tobacco exposure, educational attainment, alcohol drinking status and birth cohort can determine success in smoking cessation. Public interventions promoting a smoke-free environment are needed to reinforce discouraging the initiation of, reducing, and quitting cigarette smoking.

Metabolic syndrome and sex-specific socio-economic disparities in childhood and adulthood: the Korea National Health and Nutrition Examination Surveys

To examine whether adulthood and/or childhood sex‐specific socio‐economic disparities are associated with metabolic syndrome and its components in a developed non‐Western setting.

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

Association of selected medical conditions with breast cancer risk in Korea.

Objectives To estimate the effect of medical conditions in the population of Korea on breast cancer risk in a case-control study. Methods The cases were 3242 women with incident, histologically confirmed breast cancer in two major hospitals interviewed between 2001 and 2007. The controls were 1818 women each admitted to either of those two hospitals for a variety of non-neoplastic conditions. Information on each disease was obtained from a standardized questionnaire by trained personnel. Odds ratios (ORs) for each disease were derived from multiple logistic regression adjusted for age, age of menarche, pregnancy, age of first pregnancy, and family history of breast cancer. Results Among all of the incident breast cancer patients, pre-existing diabetes (OR, 1.33; 95% confidence interval [CI], 0.99 to 1.78), hypertension (OR, 1.46; 95% CI, 1.18 to 1.83), thyroid diseases (OR, 1.26; 95% CI, 1.00 to 1.58), and ovarian diseases (OR, 1.70; 95% CI, 1.23 to 2.35) were associated with an increased risk of breast cancer when other factors were adjusted for. In a stratified analysis by menopausal status, pre-existing hypertension (pre-menopause OR, 0.80; 95% CI, 0.48 to 1.34 vs. post-menopause OR, 1.87; 95% CI, 1.44 to 2.43; p-heterogeneity <0.01) and ovarian disease (pre-menopause OR, 4.20; 95% CI, 1.91 to 9.24 vs. post-menopause OR, 1.39; 95% CI, 1.02 to 1.91; p-heterogeneity 0.01) showed significantly different risks of breast cancer. Conclusions Our results suggest the possibility that medical conditions such as hypertension affect breast cancer development, and that this can differ by menopausal status. Our study also indicates a possible correlation between ovarian diseases and breast cancer risk.

Asia Cohort Consortium: Challenges for Collaborative Research

In this era of chronic diseases, large studies are essential in investigating genes, environment, and gene–environment interactions as disease causes, particularly when associations are important but not strong. Moreover, to allow expansion and generalization of the results, studies should be conducted in populations outside Western countries. Here, we briefly describe the Asia Cohort Consortium (ACC), a collaborative cancer cohort research project that was first proposed in 2004 and now involves more than 1 million healthy individuals across Asia. There are approximately 50 active members from Bangladesh, China, India, Japan, Korea, Malaysia, Singapore, Taiwan, Thailand, the United States, and elsewhere. To date, the work of the ACC includes 3 articles published in 2011 on the roles of body mass index, tobacco smoking, and alcohol consumption in mortality, diabetes, and cancer of the small intestine. Many challenges remain, including data harmonization, resolution of ethical and legal issues, establishment of protocols for biologic samples and transfer agreements, and funding procurement.

Subsequent Risk of Metabolic Syndrome in Women With a History of Preeclampsia: Data From the Health Examinees Study

Background To investigate whether preeclampsia is independently associated with risk of future metabolic syndrome and whether any such primary associations are modified by different ages at first pregnancy. Methods Based on the Health Examinees Study, a cross-sectional analysis was conducted. Data of women (n = 49 780) who had experienced at least 1 pregnancy during their lifetime and had never been diagnosed with any metabolic disorder before their pregnancy were analyzed using multiple logistic regression models. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated after adjusting for age, lifestyle characteristics, and reproductive factors. A stratified analysis was also conducted to estimate the extent of the primary association between preeclampsia and future metabolic syndrome by age at first pregnancy. Results Women with a history of preeclampsia had significantly increased odds of developing metabolic syndrome (adjusted OR 1.23; 95% CI, 1.12–1.35), central obesity (adjusted OR 1.36; 95% CI, 1.25–1.47), elevated blood pressure (adjusted OR 1.53; 95% CI, 1.41–1.67), or elevated fasting glucose (adjusted OR 1.13; 95% CI, 1.03–1.25) in later life. In the stratified analysis, women who first became pregnant at ages >35 years and had preeclampsia were found to be at significantly increased likelihood of metabolic syndrome later in life (adjusted OR 4.38; 95% CI, 1.62–11.9). Conclusions Our findings suggest that preeclampsia increases the risk of metabolic syndrome in later life, and late age at first pregnancy can further exacerbate this risk.

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

BackgroundThe 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.MethodsWe 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.ResultsThere 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).ConclusionsIn conclusion, our results suggest that one-carbon related nutrients have a role in the prognosis of breast cancer depending on the ER/PR status.