The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families.

OBJECTIVE: Approximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families. METHODS: Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families. RESULTS: Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05). CONCLUSIONS: In addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

Drug resistance gene expression and chemotherapy sensitivity detection in Chinese women with different molecular subtypes of breast cancer.

Objective: The aim of the study was to identify specific chemosensitivity drugs for various molecular subtypes of breast tumors in Chinese women, by detecting the expression of drug resistance genes and by using the drug sensitivity test on different molecular subtypes of breast cancers. Methods: The expression of drug resistance genes including Topo II, GST-π, P-gp, LRP, and CD133 were detected with immunohistochemistry in a tissue microarray. Drug sensitivity tests included those for paclitaxel, epirubicin, carboplatin, vinorelbine, and fluorouracil and were conducted on primary cancer tissue cells and cell lines, including the T47D, BT-474, and MDA-MB-231 cells and human breast cancer xenografts in nude mice. Results: The different drug resistant genes Topo II, GST-π, P-gp, and LRP were differentially expressed among different molecular subtypes of breast cancers (P < 0.05). Positive expression of CD133 was highest in basal-like breast cancer (P < 0.05). Kaplan-Meier survival analysis showed that positive expressions of Topo II and CD133 both correlated with shorter disease-free survival (DFS) (P < 0.05) and overall survival (P < 0.05), and positive expression of LRP correlated only with shorter DFS (P < 0.05). BT-474 showed chemosensitivity to paclitaxel and epirubicin, while MDA-MB-231 showed chemosensitivities to paclitaxel, epirubicin, carboplatin, and fluorouracil (T/C ≤ 50%). The basal-like and HER2+ breast cancer primary cells showed chemosensitivities to paclitaxel and epirubicin with significant differences compared with luminal breast cancer primary cells (P < 0.05). Conclusions: The differential expression of drug resistance genes and the differential chemosensitivities of drugs in different molecular subtype of breast cancers suggested that individual treatment should be given for each type of breast cancer.

ANGPTL4 overexpression is associated with progression and poor prognosis in breast cancer.

The aim of the present study was to analyze the expression levels of angiopoietin-like 4 (ANGPTL4) in breast cancer to investigate the association between ANGPTL4 and breast cancer. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues, including 205 invasive ductal carcinoma (IDC) of no special type, 40 normal breast, 40 atypical ductal hyperplasia (ADH) and 40 ductal carcinomas in situ (DCIS) tissues. The non-parametric Kruskal-Wallis test was used to evaluate the differential expression of ANGPTL4 and clinicopathological parameters in breast cancer. Kaplan-Meier analysis and Cox regression analysis were used to evaluate the association between the expression levels of ANGPTL4 and the prognosis of breast cancer. The results revealed that ANGPTL4 expression was higher in IDC (63.4%; 130/205) compared with in normal breast tissues (17.5%; 7/40), ADH (30%; 12/40) and DCIS (37.5%; 15/40). The clinical significance of ANGPTL4 expression was analyzed in a total of 205 IDC tissues, and high expression levels of ANGPTL4 were positively associated with pathological stage (P<0.001), tumor size (P<0.001), histological grade (P<0.001), lymph node metastasis (P<0.001), distant metastasis (P<0.001) and local recurrence (P<0.001). Kaplan-Meier analysis revealed that patients with high ANGPTL4 expression had a shorter overall survival (OS; P<0.001) and disease-free survival (DFS; P<0.001) compared with patients with low ANGPTL4 expression. Multivariate Cox regression analysis revealed that ANGPTL4 was an independent prognostic factor for breast cancer OS (P=0.034) and DFS (P=0.011). The results of the present study demonstrated that ANGPLT4 was associated with malignant progression and poor prognosis of breast cancer, suggesting that ANGPLT4 may be a novel therapeutic target for breast cancer.

Microstructure and Mechanical Properties of 4Al Alumina-Forming Austenitic Steel after Cold-Rolling Deformation and Annealing.

Microstructural evolutions of the 4Al alumina-forming austenitic steel after cold rolling with different reductions from 5% to 30% and then annealing were investigated using electron backscattering diffraction (EBSD), X-ray diffraction (XRD) and transmission electron microscopy (TEM). Tensile properties and hardness were also measured. The results show that the average grain size gradually decreases with an increase in the cold-rolling reduction. The low angle grain boundaries (LAGBs) are dominant in the cold-rolled samples, but high angle grain boundaries (HAGBs) form in the annealed samples, indicating that the grains are refined under the action of dislocations. During cold rolling, high-density dislocations are initially introduced in the samples, which contributes to a large number of dislocations remaining after annealing. With the sustaining increase in cold-rolled deformation, the samples exhibit more excellent tensile strength and hardness due to the decrease in grain size and increase in dislocation density, especially for the samples subjected to 30% cold-rolling reduction. The contribution of dislocations on yield strength is more than 60%.

Precipitates and Particles Coarsening of 9Cr-1.7W-0.4Mo-Co Ferritic Heat-Resistant Steel after Isothermal Aging.

The precipitates obtained by EPE technology from the 9Cr-1.7W-0.4Mo-Co ferritic heat-resistant steel subject to isothermal aging were investigated using SEM, TEM and XRD. The particle size distribution and the coarsening kinetics of M23C6 with duration of isothermal aging were also analyzed with or without consideration of Laves phase. The results show that the isolated dislocations were detected in delta ferrite interior, and the precipitates on delta ferrite and martensite boundaries are obviously larger than other locations. Fe2W-Laves phase can only be found as duration of aging time to 2000 h, and is preferential to form adjacent to M23C6 particles. The small M23C6 particles firstly coarsen, but the large M23C6 are relatively stable during short aging. The total coarsening rate of M23C6 precipitates is 9.75 × 10-28m3s-1, and the coarsening of M23C6 depends on the formation of Laves phase.

Grape seed proanthocyanidin extract prevents DDP-induced testicular toxicity in rats.

Oxidative stress has been proven to be involved in cisplatin (DDP)-induced toxicity. The aim of the present study was to investigate a possible protective role of grape seed proanthocyanidin extract (GSPE) in DDP-induced spermiotoxicity. GSPE at 200 mg kg(-1) d(-1) and 400 mg kg(-1) d(-1) was orally administered for 15 consecutive days, starting 10 days before a single intraperitoneal dose of DDP (7 mg kg(-1)). Results revealed that testicular and epididymal weight, epididymal sperm count, motility and morphology, the activities of GSH-Px and SOD, and GSH levels were significantly decreased whereas the level of MDA was significantly increased in the DDP group rats. GSPE treatment significantly attenuated the harmful effects of DDP-induced lipid peroxidation, oxidative stress, loss of genital organ weight, as well as function of reproductive organs. These changes were restored to near normal levels by GSPE at 400 mg kg(-1) d(-1). In conclusion, GSPE has dose dependent protective effects against DDP-induced rat testicular toxicity.