Jie Ming

A Common Polymorphism near the ESR1 Gene Is Associated with Risk of Breast Cancer: Evidence from a Case-Control Study and a Meta-Analysis

Background Genome-wide association studies have reported that a polymorphism near the estrogen receptor gene (ESR1) (rs2046210) is associated with a risk of breast cancer, with the A allele conferring an increased risk. However, considering the controversial results from more recent replicated studies, we conducted a case-control study in an independent Chinese Han population and a meta-analysis to clarify the association of this polymorphism with breast cancer risk. Method and Findings A hospital-based case-control study including 461 cases and 537 controls from a Chinese Han population was conducted initially, and this study showed that the rs2046210 A allele was significantly associated with breast cancer risk, with an OR of 1.32 (95% CI  = 1.10–1.59). Subsequently, a meta-analysis integrating the current study and previous publications with a total of 53,379 cases and 55,493 controls was performed to further confirm our findings. Similarly, a significant association between this polymorphism and breast cancer risk was also observed in the overall population especially among Asians, with ORs for per A allele of 1.14 (95% CI  = 1.10–1.18) in the overall population and 1.27 (95% CI  = 1.23–1.31) in the Asian population. Conclusion Our results provide strong evidence to support that the common polymorphism near the ESR1 gene, rs2046210, is associated with an increased risk of breast cancer in Asian and European populations but not in Africans, although the biological mechanisms need to be further investigated.

A Functional Variant rs1820453 in YAP1 and Breast Cancer Risk in Chinese Population

Background To investigate the association between rs1820453 which located in the promoter region of yes-associated protein 1 (YAP1) gene and breast cancer (BC) risk. Method and Findings We conducted a hospital-based case-control study including a total of 480 BC cases and 545 cancer-free controls in Chinese population. Then the expression quantitative trait locus (e-QTL) analysis was performed to explore the possible function of rs1820453 to the YAP1 gene expression. The association between rs1820453 and BC risk was significantly identified with the odds ratio (OR) was 1.27 (95 % confidence interval (CI) =1.03-1.57) under allelic model when adjusted by age and menopausal status. In addition, the correlation analysis of rs1820453 and YAP1 expression level found that this variant was significantly associated with the gene expression in Chinese population. When compared with level of mRNA expression of the AA genotype (6.011±0.046), the mRNA expression level in CC genotype (5.903±0.026) was statistically lower (P=0.024). Conclusion The results from this study suggested that rs1820453 A>C change may affect the gene expression and contribute to the risk of developing BC in Chinese population though larger sample-size studies along with functional experiments were anticipated to warrant the results.

Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity

Background Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson’s disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown. Principle Findings Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn’t alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner. Conclusion Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.

Do patients with oxyphilic cell papillary thyroid carcinoma have a poor prognosis? Analysis of the surveillance, epidemiology, and end results database 2004-2013 with propensity score matching

The prognosis of oxyphilic cell papillary thyroid carcinoma (OCPTC) remains unclear. The aim of this study was to investigate the prognosis of OCPTC and provide a new perspective on treatment guidelines for these patients. We investigated a large cohort of DTC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013. Patient mortality was examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. In the study cohort, the rate of cancer-specific mortality per 1000 person-years for OCPTC was lower than that for classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). According to the multivariate Cox regression model, the cancer-specific and all-cause mortality rates of OCPTC were similar to that of CPTC and FTC. The cancer-specific survival rate in patients with OCPTC was higher than that in patients with FTC, but similar to patients with CPTC, after matching for influential factors using propensity score matching analysis. The unanticipated prognosis provided new implications for the treatment of patients with OCPTC.

Unanticipated prognosis of differential thyroid cancer patients with T0 stage: analysis of the SEER database 2004-2013

The prognosis of T0 stage differentiated thyroid cancer (DTC) remains unclear. This study aimed to investigate the prognosis of T0 stage DTC patients to provide a new perspective on treatment guidelines for these patients. We investigated a large cohort of DTC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013. Patient survival curves were examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. In the study cohort, the rate of cancer-specific mortality per 1000 person-years for T0 was higher than T1–T3, but lower than T4. The all-cause mortality for T0 patients was higher than all other stages (T1–T4). Multivariate Cox regression modeling showed that T0 had a significant risk for cancer-specific mortality when compared to T1 and T4, but not T2 or T3, after adjustment for other risk factors. For all-cause mortality, T0 showed a significant risk for all-cause mortality when compared to T4, but not T1–T3 stage patients. Similar results were obtained after matching for influential factors using propensity scored matching analysis. The unanticipated prognosis of T0 stage DTC patients was found to be not better than of other stage DTC patients, providing new implications for the treatment of T0 stage DTC patients.

Nuclear expression of XBP1s is correlated with breast cancer survival: a retrospective analysis based on tissue microarray

An alternatively spliced transcription factor that participates in the unfolded protein response, XBP1 is a novel protein involved in cancer progression and outcome. This study aimed to investigate the relationship of spliced XBP1 (XBP1s) with the clinicopathological characteristics and prognosis of breast cancer by using tissue-microarray analysis. A consecutive series of 170 patients with breast cancer diagnosed between 2001 and 2004 in hospitals in eastern and southern China were included. Immunohistochemical staining for XBP1s was performed, and the expression of XBP1s was separately examined in nuclei and cytoplasm. We found that a higher expression of XBP1s in nuclei strongly correlated with poorer survival (46.7% versus 75%, P=0.018); however, the expression of XBP1s in the cytoplasm had no relationship with survival. Multivariate Cox regression analysis indicated that the expression of XBP1s was not an independent prognostic factor (RR 2.074, 95% CI 0.909–4.736; P=0.083). None of the other clinicopathological characteristics – age, pathology grade, T stage, N stage, TNM stage, estrogen receptor, progesterone receptor, or HER2 status – was found to be correlated with XBP1s expression in the nuclei. In conclusion, independently of other clinicopathological factors, the nuclear expression of XBP1s is correlated with shorter breast cancer survival; however, whether nuclear XBP1s is an independent prognostic biomarker needs to be confirmed by further studies with larger samples and detailed sample stratification.

High Expression of Yes-activated Protein-1 in Papillary Thyroid Carcinoma Correlates With Poor Prognosis

Context: The Hippo signal transduction pathway is highly conserved in mammals. It plays a critical role in tissue and organ size by regulating the balance between cell proliferation and apoptosis. However, there have been few reports concerning Yes-activated protein-1 (YAP-1) elevation in papillary thyroid cancer (PTC). Objective: The objective of this study was to determine whether YAP-1 expression is a biomarker and high-risk clinicopathologic prognosticator in PTC. Design: A large series of patients of PTC with a long follow-up were investigated for YAP-1 expression. Setting: Our study was carried out in the laboratory of breast and thyroid and Department of pathology. Patients or Other Participants: Immunohistochemical staining was performed on 240 patient-derived PTC specimens to analyze the correlation of YAP-1 expression with clinicopathologic features and prognosis in patients with PTC. Intervention: The 240 PTC patients were immunohistochemically assessed for YAP-1 expression. Outcome Measures: Kaplan-Meier analysis was conducted to assess recurrence-free survival (RFS). Univariate and multivariate analyses were conducted to determine prognosticators of RFS. Results: YAP-1 expression was observed in 62.1% of PTC tumors. There were significant positive correlations between YAP-1 expression and tumor size, lymph node metastases, extrathyroidal extension, and tissue infiltration. YAP-1 expression was significantly associated with RFS. Univariate analysis revealed that YAP-1 expression significantly affects RFS. YAP-1 and extrathyroidal extension were significant independent prognosticators for RFS. Conclusions: YAP-1 expression was significantly correlated with high-risk clinicopathologic features and inferior RFS in patients with PTC.