Search

The incidence of breast cancer among premenopausal women has been increasing rapidly in recent decades in East Asia. This case–control study investigated whether estrogen-DNA adducts were associated with breast cancer risk in Taiwan. The control group (n = 146) comprised healthy female volunteers and women with non-proliferative breast disease. The case group (n = 221) comprised women either with proliferative benign breast disease or breast cancer. The ratios of estrogen-DNA adducts to their respective metabolites and conjugates in plasma were analyzed using ultraperformance LC/MS-MS. The SNPs of CYP1A1, CYP1B1, and COMT were genotyped. Logistic regression model was used to compare the estrogen-DNA adduct ratios between the two groups. The estrogen-DNA adduct ratio in the case group was significantly higher than that in the control group (median ratio: 58.52 vs. 29.36, P = 0.004). A multiple logistic regression model demonstrated that a unit increase in the natural log of the estrogen-DNA adduct ratio in premenopausal women was a significant predictor of breast cancer risk, with an estimated hazard ratio of 1.718 (1.444−2.046, P < 0.001). However, the CYP1A1, CYP1B1, and COMT SNPs were not associated with the estrogen-DNA adduct ratios. In conclusion, plasma estrogen-DNA adduct ratio was associated with the presence of breast cancer or proliferating benign breast disease in premenopausal women in Taiwan.Prevention Relevance:This study provides evidence that endogenous estrogen-induced genotoxicity may contribute to the carcinogenesis of breast cancer in premenopausal Asian women. This work could have important preventive implication for the emerging disease in East Asia.

Supplementary Table S2: The ratios of estrogen-DNA adduct by participant subgroups

Supplementary Methods S1 describes the statistical analysis in detail.

Supplementary Table S1: Data of demographics, estrogen-DNA adduct ratios, gene polymorphisms of the study population

The incidence of breast cancer among premenopausal women has been increasing rapidly in recent decades in East Asia. This case–control study investigated whether estrogen-DNA adducts were associated with breast cancer risk in Taiwan. The control group (n = 146) comprised healthy female volunteers and women with non-proliferative breast disease. The case group (n = 221) comprised women either with proliferative benign breast disease or breast cancer. The ratios of estrogen-DNA adducts to their respective metabolites and conjugates in plasma were analyzed using ultraperformance LC/MS-MS. The SNPs of CYP1A1, CYP1B1, and COMT were genotyped. Logistic regression model was used to compare the estrogen-DNA adduct ratios between the two groups. The estrogen-DNA adduct ratio in the case group was significantly higher than that in the control group (median ratio: 58.52 vs. 29.36, P = 0.004). A multiple logistic regression model demonstrated that a unit increase in the natural log of the estrogen-DNA adduct ratio in premenopausal women was a significant predictor of breast cancer risk, with an estimated hazard ratio of 1.718 (1.444−2.046, P < 0.001). However, the CYP1A1, CYP1B1, and COMT SNPs were not associated with the estrogen-DNA adduct ratios. In conclusion, plasma estrogen-DNA adduct ratio was associated with the presence of breast cancer or proliferating benign breast disease in premenopausal women in Taiwan.Prevention Relevance:This study provides evidence that endogenous estrogen-induced genotoxicity may contribute to the carcinogenesis of breast cancer in premenopausal Asian women. This work could have important preventive implication for the emerging disease in East Asia.

Supplementary Table S3: Correlation analyses between two variables by Pearson's and Spearman's rank correlation coefficient

Purpose:Abnormal spindle-like microcephaly associated (ASPM) plays an important role in neurogenesis and cell proliferation. This study is to elucidate its role in hepatocelllular carcinoma (HCC), particularly early tumor recurrence (ETR) and prognosis.Experimental Design: We used reverse transcription-PCR assays to measure the ASPM mRNA levels in 247 HCC and correlated with clinicopathologic and molecular features.Results:ASPM mRNA levels were high in fetal tissues but very low in most adult tissues. ASPM mRNA was overexpressed in 162 HCC (66%) but not in benign liver tumors. ASPM overexpression correlated with high α-fetoprotein (P = 1 × 10-8), high-grade (grade II-IV) HCC (P = 2 × 10-6), high-stage (stage IIIA-IV) HCC (P = 1 × 10-8), and importantly ETR (P = 1 × 10-8). ETR is the most critical unfavorable clinical prognostic factor. Among the various independent histopathologic (tumor size, tumor grade and tumor stage) and molecular factors (p53 mutation, high α-fetoprotein, and ASPM overexpression), tumor stage was the most crucial histologic factor (odds ratio, 14.7; 95% confidence interval, 6.65-33.0; P = 1 × 10-8), whereas ASPM overexpression (odds ratio, 6.49; P = 1 × 10-8) is the most important molecular factor associated with ETR. ASPM overexpression was associated with vascular invasion and ETR in both p53-mutated (all P values = 1 × 10-8) and non-p53-mutated HCC (P = 1 × 10-8 and 0.00088, respectively). Hence, patients with APSM-overexpressing HCC had lower 5-year survival (P = 0.000001) in both p53-mutated (P = 0.00008) and non-p53-mutated HCC (P = 0.0027). In low-stage (stage II) HCC, ASPM overexpression also correlated with higher ETR (P = 0.008).Conclusion:ASPM overexpression is a molecular marker predicting enhanced invasive/metastatic potential of HCC, higher risk of ETR regardless of p53 mutation status and tumor stage, and hence poor prognosis.

Supplementary Data from ASPM Is a Novel Marker for Vascular Invasion, Early Recurrence, and Poor Prognosis of Hepatocellular Carcinoma

Background: Hyperlipidemia and serum oxysterol levels are known to be associated with breast cancer risk. In murine model, altered oxysterol levels in adipose tissue were identified in obese mice. However, the significance of oxysterol levels in human adipose tissue and their association with breast cancer risk were largely unknown. In this study, we aimed to quantify the levels of different oxysterols in adipose tissue and to establish their association with breast cancer risk. Methods: The breast adipose tissue was collected from patients who underwent surgery at a tertiary medical center for benign breast disease or breast cancer. We have profiled oxysterol levels by liquid chromatography-mass spectrometry. Multivariate analysis was used to analyze the relationship of adipose tissue oxysterol levels and breast cancer risk. Result: Breast adipose tissue from 279 subjects (benign low risk, n=58; benign high risk, n=33, and breast cancer, n=188) collected between March 2009 and November 2014 were included in this analysis. Parity is a protective factor both for breast cancer in premenopausal and postmenopausal groups. Brassicasterol ≤0.28 ng/mg (OR=6.739, 95% C.I.=2.092-21.707, p=0.001) and age >40.06 years old (OR=3.774, 95% C.I.=1.328-10.722, p=0.013) in premenopausal patients; high log (7α-. hydroxycholesterol) levels (OR=6.690, 95% C.I.=1.915-23.369, p=0.003) and 24-hydroxycholesterol >0.92ng/mg (OR=4.539, 95% C.I.=1.153-17.866, p=0.030) in postmenopausal patients were associated with increased BC risk. Sitosterol ≤3.03ng/mg (OR=0.057, 95% C.I.= 0.016-0.205, p Citation Format: I-Chun Chen, Wen-Hung Kuo, Fu-Chang Hu, Ming-Yang Wang, Yen-Shen Lu, Dieter Lütjohann, Ching-Hung Lin. Oxysterol profiling in breast adipose tissue identifies brassicasterol and 24-hydroxycholesterol as breast cancer risk predictors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-09.

Purpose: Abnormal spindle-like microcephaly associated (ASPM) plays an important role in neurogenesis and cell proliferation. This study is to elucidate its role in hepatocelllular carcinoma (HCC), particularly early tumor recurrence (ETR) and prognosis. Experimental Design: We used reverse transcription-PCR assays to measure the ASPM mRNA levels in 247 HCC and correlated with clinicopathologic and molecular features. Results: ASPM mRNA levels were high in fetal tissues but very low in most adult tissues. ASPM mRNA was overexpressed in 162 HCC (66%) but not in benign liver tumors. ASPM overexpression correlated with high α-fetoprotein (P = 1 × 10-8), high-grade (grade II-IV) HCC (P = 2 × 10-6), high-stage (stage IIIA-IV) HCC (P = 1 × 10-8), and importantly ETR (P = 1 × 10-8). ETR is the most critical unfavorable clinical prognostic factor. Among the various independent histopathologic (tumor size, tumor grade and tumor stage) and molecular factors (p53 mutation, high α-fetoprotein, and ASPM overexpression), tumor stage was the most crucial histologic factor (odds ratio, 14.7; 95% confidence interval, 6.65-33.0; P = 1 × 10-8), whereas ASPM overexpression (odds ratio, 6.49; P = 1 × 10-8) is the most important molecular factor associated with ETR. ASPM overexpression was associated with vascular invasion and ETR in both p53-mutated (all P values = 1 × 10-8) and non-p53-mutated HCC (P = 1 × 10-8 and 0.00088, respectively). Hence, patients with APSM-overexpressing HCC had lower 5-year survival (P = 0.000001) in both p53-mutated (P = 0.00008) and non-p53-mutated HCC (P = 0.0027). In low-stage (stage II) HCC, ASPM overexpression also correlated with higher ETR (P = 0.008). Conclusion: ASPM overexpression is a molecular marker predicting enhanced invasive/metastatic potential of HCC, higher risk of ETR regardless of p53 mutation status and tumor stage, and hence poor prognosis.

Background: Fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) signaling play critical roles in hepatocarcinogenesis. This study explored the expression and clinical significance of FGF19/FGFR4 related signaling molecules in hepatocellular carcinoma (HCC). Method: We examined the mRNA expression of FGF19, FGFR4, klotho-beta (KLB), cyclin D1 (CCND1), and FGF4 in 151 surgically resected, primary unifocal HCC using quantitative real-time PCR analysis. The correlation of gene amplification and mRNA overexpression for FGF19 and FGF4 was investigated using a real-time PCR based copy number assay. FGF19 amplification was verified using fluorescence in situ hybridization. Univariate and multivariate analyses were performed to evaluate the prognostic value of these biomarkers for tumor recurrence and survival of patients. Results: Overexpression of FGF19, FGFR4, KLB, CCND1, and FGF4 mRNA was detected in 40%, 32%, 26%, 15%, and 35% of 151 tumors, respectively. In multivariate analyses, large tumor size (> 12.7 cm) and advanced tumor stage (stage ≥ II) independently predict worse patient survival. Using generalized additive models, we found mRNA expression of FGFR4 and KLB was significantly associated large tumor size (> 12.7 cm); mRNA expression of FGF19 and KLB was significantly associated advanced tumor stage (stage ≥ II). Furthermore, gene amplification of FGF19 and FGF4 significantly correlated to their mRNA overexpression (P = 0.006 for FGF19; P = 0.039 for FGF4). Conclusions: Overexpression of FGF19/FGFR4 related biomarkers is frequently found in HCC. Overexpression of FGF19 and FGF4 mRNA significantly correlates to their gene amplification. Expression status of FGFR4, KLB, and FGF19 may determine patient survival through their impact on tumor size (FGFR4 and KLB) and tumor stage (FGF19 and KLB). Citation Format: Zhong-Zhe Lin, Yung-Ming Jeng, Chiun Hsu, I-Lun Tsai, Kuan-Yu Chen, Fu-Chang Hu, Chih-Hung Hsu, Hey-Chi Hsu, Ann-Lii Cheng. Expression of FGF19/FGFR4 related biomarkers in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3131.

Background There is no literature for stratification of permanent implantable venous ports (Port-A) related bloodstream infection (BSI) in solid cancer patients. We conduct this study to characterize the risk factors of BSI associated with the use of Port-A (PABSI) in solid cancer patients. Methods The study is done in a teaching hospital in Taiwan. Solid cancer patients who were implanted with a Port-A for systemic anti-cancer therapies were prospectively followed for the occurrence of PABSI, defined as BSI without other identifiable infection foci. Patients with PABSI during the follow-up period constitute the case cohort (N = 58) and 174 patients were randomly selected from those without BSI as the control cohort. PABSI risk score was developed by Cox proportional hazards model. Results 416 patients were registered (Table 1). Eighty-eight PABSI episodes occurred in 58 patients, with an incidence of 1.05 per 1000 catheter-days. All but one patient had stage 4 cancer. Independent predictors of PABSI occurrence included neutropenia (HR = 3.86, 95% CI = 1.75-8.50), total parental nutrition (TPN) (HR = 3.51, 95% CI = 1.86-6.63), chronic steroid use (HR = 7.01, 95% CI = 2.78-17.65), invasive procedure (HR = 3.00, 95% CI = 1.29-6.98), postoperative antibiotics (HR = 2.61, 95% CI = 1.43-4.75), and preoperative antibiotics (HR = 0.38, 95% CI = 0.17-0.83). A PABSI risk score, with a cut-off value of 0 (sensitivity 88.5%, specificity 64.3%), was defined for stage 4 cancer patients as follows: neutropenia, +1.350; TPN, +1.256; chronic steroid use, +1.947; preoperative antibiotics, –0.970; postoperative antibiotics, +0.959; and invasive procedure, +1.098. The median PABSI-free survival was 4.47 months for patients with score β0 but not reached for patients with score < 0 (p < 0.0001). Conclusions The PABSI risk score can help define high-risk groups in solid cancer patients and may help design future preventive strategies. Presence of any risk factor would render patients as high risk. 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 2656. doi:1538-7445.AM2012-2656

Background: We previously demonstrated that Aurora B overexpression correlated well with higher histology grade and more advanced stage of hepatocellular carcinoma (HCC). In this study, we sought to analyze the association between Aurora B overexpression and vascular invasion/metastasis of HCC, as well as the potential of AZD1152, a novel and selective Aurora B kinase inhibitor in preventing vascular invasion and metastasis of HCC. Method: Aurora B mRNA levels were measured in HCC and paired non-tumorous liver tissues by reverse transcription-PCR. One hundred and sixty surgically resected, primary unifocal HCCs were selected for this study. Vascular invasion was determined by pathologic examination. All 160 patients had been followed for more than 5 years or until death. Forty-nine patients developed extrahepatic tumor metastasis. Multivariate analysis was conducted to determine the significance of Aurora B overexpression on vascular invasion and metastasis of HCC. The effects of AZD1152 on tumor invasiveness were tested in Huh-7 and HA-27T HCC cell lines by migration and invasion assays. Results: Overexpression of Aurora B was found in 98 of the 160 (61%) primary HCC. Univariate analysis showed that vascular invasion and metastasis were both associated with younger age (≤ 55 years, P = 0.027 and P = 0.003, respectively), high α-fetoprotein levels (> 200 ng/mL, P < 0.001 and P = 0.008), large tumor size (> 5 cm, P < 0.001 and P < 0.001), higher tumor grade (grade III-IV, P < 0.001 and P = 0.025), as well as Aurora B overexpression (P < 0.001 and P < 0.001). Multivariate analysis confirmed that Aurora B overexpression was an independent risk factor associated with vascular invasion (odds ratio, 2.659; P = 0.0183) and metastasis (odds ratio, 4.195; P = 0.0027). AZD1152, 5-125 nM, induced dose-dependent inhibition on migration and invasion in Huh-7 and HA-27T cells. Conclusions: Overexpression of Aurora B correlates well with vascular invasion and metastasis of HCC. Inhibition of Aurora B kinase by small molecular inhibitors may suppress invasion and metastasis of HCC. Grant support: Grant NSC96-2628-B-002-054-MY3 from the National Science Council (Taiwan), Grant DOH97-TD-B-111-001 from the Department of Health (Taiwan), and Grant NSC98-3112-B-075A-001 from the National Science Council (Taiwan). 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 3290.