Fanconi Anemia: Exploration of DNA Repair Pathways from Genetic Diseases to Cancer and Prospects for Treatment / 肿瘤防治研究

Fanconi anemia (FA) is an inheritable disorder that presents with bone marrow failure, developmental anomalies, and an increased susceptibility to cancer. The etiology of this condition stems from a genetic mutation that disrupts the proper repair of interstrand DNA cross-links (ICLs). The resultant dysregulation of the DNA damage response mechanism can induce genomic instability, thereby elevating the mutation rates and the likelihood of developing cancer. The FA pathway assumes a pivotal role in safeguarding genome stability through its involvement in the repair of DNA cross-links and the maintenance of overall genomic integrity. A mutation in the germ line of any of the genes responsible for encoding the FA protein results in the development of FA. The prevalence of aberrant FA gene expression in somatic cancer, coupled with the identification of a connection between FA pathway activation and resistance to chemotherapy, has solidified the correlation between the FA pathway and cancer. Consequently, targeted therapies that exploit FA pathway gene abnormalities are being progressively developed and implemented. This review critically examines the involvement of the FA protein in the repair of ICLs, the regulation of the FA signaling network, and its implications in cancer pathogenesis and prognosis. Additionally, it explores the potential utility of small-molecule inhibitors that target the FA pathway.

BRCA1 promoter methylation & its immunohistochemical correlation in sporadic breast cancer

Background & objectives: Studies have shown that apart from hereditary breast carcinomas, breast cancer susceptibility gene 1 (BRCA1) mutations conferring to its loss are seen in sporadic breast carcinomas (SBC) as well. The aim of the present study was to assess BRCA1 methylation in females presenting at King George’s Medical University, Lucknow, with SBC by both immunohistochemistry (IHC) and methylation PCR with respect to hormonal profile and various morphological prognostic parameters. The primary objective was to look for the association between BRCA1 protein expression and DNA promoter methylation. Methods: 81 mastectomy specimens from SBC of invasive breast carcinoma (no special type) were included in this study. After a detailed morphological assessment, formalin fixed paraffin embedded tissue from a representative tumour area was selected for BRCA1 IHC by heat-mediated antigen retrieval under high pH and DNA extraction and further bisulphate treatment. BRCA1 was studied for methylation by methylated and unmethylated PCR-specific primers. Results: BRCA1 promoter methylation was present in 42/81 (51.9%) participants, with significant BRCA1 protein loss (72.7%; P=0.002). A significant association between BRCA1 loss and hormonal profile was found (P=0.001); maximum in triple negative breast carcinoma (TNBC) (72%; 18/25). Most of the TNBC also harboured methylation (68%). Although not significant grade II and III tumours, lymph vascular invasion, ductal carcinoma in situ, and nodal metastasis (?3) were seen in a higher percentage in methylated tumours. Mortality in SBC was significantly associated with BRCA1 loss (30.3%; P=0.024). Interpretation & conclusions: Study results highlight the concept of “BRCAness” in SBC as well. Hence, we can confer that identification of BRCA1 loss in SBC can make it a perfect candidate for poly ADP- ribose polymerase inhibitors or cisplatin-based therapy like hereditary ones.

Efficacy and safety of olaparib in adjuvant therapy of BRCA1/2 mutated HER2-negative breast cancer：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of olaparib in adjuvant therapy of breast cancer susceptibility gene （BRCA） 1/2 mutated human epidermal growth factor receptor 2 （HER2）-negative breast cancer， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from CNKI， VIP， Wanfang data， PubMed， ScienceDirect， the Cochrane Library and Embase databases， randomized controlled trials about adjuvant therapy of olaparib （trial group） versus adjuvant therapy of other drugs （control group） were collected. After literature screening and data extraction， meta-analysis， publication bias analysis and sensitivity analysis were performed by using RevMan5.4 software. RESULTS A total of 5 randomized controlled trials were included， with a total of 2 633 patients， including 1 495 cases in trial group and 1 174 cases in control group. Meta-analysis showed that in terms of efficacy， compared with control group， overall survival [HR＝1.02， 95%CI （1.01，1.03）， P＝0.000 8] and progression-free survival [HR＝1.78， 95%CI（1.46，2.17）， P＜0.000 01] were longer significantly in the trial group. In terms of safety， compared with the control group， the incidence of adverse drug reactions at any level in the trial group was higher [RR＝1.41， 95%CI （1.12， 1.78）， P＝0.004]， while there was no statistically significant difference in the incidence of adverse drug reactions above level 3 between the two groups [RR＝1.75， 95%CI （0.82， 3.74）， P＝0.15]. The results of publication bias indicated that the possibility of publication bias in this study was relatively low. The results of sensitivity analysis showed that the results obtained in this study were robust. CONCLUSIONS Compared with patients without adjuvant therapy of olaparib， adjuvant therapy of olaparib can prolong overall survival and progression-free survival of patients with BRCA1/2 mutated HER2-negative breast cancer，but the risk of adverse drug reactions is relatively high.

An Investigation of the Effects of B7-H4 Gene rs10754339 and miR-125a Gene rs12976445 on Cancer Susceptibility / 生物医学与环境科学（英文）

OBJECTIVE@#To investigate the effects of the B7-H4 gene rs10754339 and miR-125a gene rs12976445 on cancer susceptibility through a case-control study and meta-analysis.@*METHODS@#A total of 1,490 cancer patients (lung/gastric/liver/: 550/460/480) and 800 controls were recruited in this case-control study. The meta-analysis was performed by pooling the data from previous related studies and the present study.@*RESULTS@#The results of this study showed that in the Hubei Han Chinese population, the rs10754339 gene was significantly associated with the risk of lung and gastric cancer but not liver cancer, and the rs12976445 gene was significantly associated with the risk of lung cancer but not liver or gastric cancer. The meta-analysis results indicated that rs10754339 and rs12976445 contributed to cancer susceptibility in the Chinese population and also revealed a significant association between rs10754339 and breast cancer risk, as well as between rs12976445 and lung cancer risk.@*CONCLUSION@#The B7-H4 gene rs10754339 and miR-125a gene rs12976445 may be the potential genetic markers for cancer susceptibility in the Chinese population, which should be validated in future studies with larger sample sizes in other ethnic populations.

Progress of hereditary breast cancer with breast cancer susceptibility gene 1/2 mutations / 肿瘤研究与临床

Hereditary breast cancer refers to malignant tumors caused by pathogenic germline mutations of breast cancer susceptibility genes (BRCA). At present, it is believed that BRCA1/2 genes are most closely related to the development of hereditary breast cancer. Mutation will lead to loss of normal function, instability of genome, and then lead to tumorigenesis. Especially for those with germline mutations, not only the risk of breast cancer will be greatly increased, but also the probability of ovarian cancer and other cancers will be increased. With the emergence and clinical application of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, BRCA1/2 genes have been regarded as new targets for the treatment of breast cancer. This article reviews the latest research of breast cancer with BRCA1/2 gene mutations.

Differential Expression of Long Non-coding RNA Cancer Susceptibility Candidate 2 and Imprinted Gene H19 in Extrahepatic Cholangiocarcinoma / 中国医学科学院学报

Objective To investigate the expression and the potential roles of long non-coding RNA(lncRNA)cancer susceptibility candidate 2(CASC2)and imprinted gene H19 in extrahepatic cholangiocarcinoma(ECC). Methods Four samples from patients with ECC were collected for high-throughput sequencing which was conducted to reveal the transcriptomic profiles of lncRNA CASC2 and H19.Bioinformatics tools were employed to predict the potential roles of the two genes.Another 22 ECC tissue samples and the cholangiocarcinoma cell lines(RBE,QBC939,HuH-28,and HuCCT1)with different degrees of differentiation were selected for validation.The para-carcinoma tissue and normal human intrahepatic biliary epithelial cell(HIBEC)were used as the control groups.The expression levels of lncRNA CASC2 and H19 in carcinoma tissue,para-carcinoma tissue,and cell lines were determined by real-time quantitative polymerase chain reaction(qRT-PCR).The correlation analysis was carried out for the clinical indicators of patients with the expression levels of the target genes. Results The two target genes showed significantly different expression between carcinoma tissue and para-carcinoma tissue(all P<0.05).Specifically,CASC2 had higher expression level in the carcinoma tissue than in the para-carcinoma tissue(t=1.262,P=0.025),whereas the expression of H19 showed an opposite trend(t=1.285,P=0.005).The expression levels of CASC2 in QBC939(t=8.114,P=0.015)and HuH-28(t=9.202,P=0.012)cells were significantly higher than that in the control group.The expression levels of H19 were significantly lower in RBE(t=-10.244,P<0.001),QBC939(t=-10.476,P<0.001),HuH-28(t=-19.798,P<0.001),and HuCCT1(t=-16.193,P=0.004)cells than in the control group.Bioinformatics analysis showed that CASC2 was mainly involved in the metabolic process and H19 in the development of multicellular organisms.Both CASC2 and H19 were related to catalytic activity.The expression level of lncRNA CASC2 was correlated with pathological differentiation(χ 2=6.222,P=0.022)and lymph node metastasis(χ2=5.455,P=0.020),and that of lncRNA H19 with pathological differentiation(χ2=1.174,P=0.029)and tumor size(χ2=-0.507,P=0.037). Conclusions In the case of ECC,lncRNA CASC2 and H19 have transcription disorders.lncRNA CASC2 is generally up-regulated in the carcinoma tissue,while H19 is down-regulated.Both genes have the potential to become new molecular markers for ECC.

Heritable genomic diversity in breast cancer driver genes and associations with risk in a Chilean population

BACKGROUND: Driver mutations are the genetic components responsible for tumor initiation and progression. These variants, which may be inherited, influence cancer risk and therefore underlie many familial cancers. The present study examines the potential association between SNPs in driver genes SF3B1 (rs4685), TBX3 (rs12366395, rs8853, and rs1061651) and MAP3K1 (rs72758040) and BC in BRCA1/2-negative Chilean families. METHODS: The SNPs were genotyped in 486 BC cases and 1258 controls by TaqMan Assay. RESULTS: Our data do not support an association between rs4685:C > T, rs8853:T > C, or rs1061651:T > C and BC risk. However, the rs12366395-G allele (A/G + G/G) was associated with risk in families with a strong history of BC (OR = 1.2 [95% CI 1.0-1.6] p = 0.02 and OR = 1.5 [95% CI 1.0-2.2] p = 0.02, respectively). Moreover, rs72758040-C was associated with increased risk in cases with a moderate-to-strong family history of BC (OR = 1.3 [95% CI 1.0-1.7] p = 0.02 and OR = 1.3 [95% CI 1.0-1.8] p = 0.03 respectively). Finally, risk was significantly higher in homozygous C/C cases from families with a moderate-to-strong BC history (OR = 1.8 [95% CI 1.0-3.1] p = 0.03 and OR = 1.9 [95% CI 1.1-3.4] p = 0.01, respectively). We also evaluated the combined impact of rs12366395-G and rs72758040-C. Familial BC risk increased in a dose-dependent manner with risk allele count, reflecting an additive effect (p-trend = 0.0002). CONCLUSIONS: Our study suggests that germline variants in driver genes TBX3 (rs12366395) and MAP3K1 (rs72758040) may influence BC risk in BRCA1/2-negative Chilean families. Moreover, the presence of rs12366395-G and rs72758040-C could increase BC risk in a Chilean population.

Correlation of BRCA1 gene polymorphism with chemosensitivity and prognosis of metastatic esophageal squamous cell carcinoma treated with cisplatin combined with capecitabine / 中国临床药理学与治疗学

AIM: To explore the effect of single nucleotide polymorphism (SNP) of breast cancer susceptibility gene 1 (BRCA1) on chemotherapy sensitivity and survival prognosis of patients with metastatic esophageal squamous cell carcinoma. METHODS: A total of 153 patients with newly treated metastatic esophageal squamous cell carcinoma who were admitted to Suzhou Science and Technology City Hospital from June 2016 to February 2020 were included and administered with cisplatin combined with capecitabine chemotherapy. Before the first chemotherapy, 5 mL of venous blood was collected to extract DNA, and the TaqMan probe method was used to detect the genotypes of the BRCA1 gene rs8176318G/T, rs799917T/C and rs1799966T/C polymorphic loci. The objective response rate (ORR) and overall survival (OS) of different genotypes were analyzed. RESULTS: Rs799917T/C polymorphism was closely related to the chemosensitivity of metastatic esophageal squamous cell carcinoma. The chemotherapy response rates of TT, TC and CC genotypes increased gradually (TT 22.5%, TC 38.6%, CC 55.3%, χ

Expressions of long non-coding RNA CASC11 and proto-oncogene c-myc in colorectal cancer and their correlation with recurrence and metastasis / 肿瘤研究与临床

Objective:To investigate the expressions of long non-coding RNA (lncRNA) CASC11 and proto-oncogene c-myc in colorectal cancer and their correlation with recurrence and metastasis.Methods:The cancer tissues and paracancerous tissues of 90 colorectal cancer patients in Tangshan Union Medical College Hospital of Hebei Province from February 2016 to July 2018 were collected. Normal colon epithelial cell lines CCD841 and colorectal cancer cell lines SW480, SW620, HCT116, HT29, DLD-1 were cultured in vitro. Separated by the average value of relative expression level of CASC11 or c-myc mRNA in cancer tissues, patients were divided into the high expression and low expression of CASC11 or c-myc. The protein expressions of CASC11 and c-myc mRNA and c-myc were detected by using real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and Western blot. Cell lines with the highest protein expressions of CASC11, c-myc mRNA and c-myc were used to do the subsequent experiments. The association of the expression levels of CASC11 and c-myc mRNA with the clinicopathological features was analyzed. Pearson correlation test was used to analyze the relationship between CASC11 and c-myc mRNA of cancer tissues. JASPAR software was used to analyze whether there were binding sites of CASC11 and c-myc gene. The wild-type and mutant-type CASC11 recombinant plasmids were constructed, and the relationship between c-myc and CASC11 was confirmed by using dual luciferase reporter gene assay. Cell lines with the highest expressions of CASC11 and c-myc were transfected with c-myc interference sequence plasmid (Sh-c-myc group) or the negative control sequence plasmid (Sh-NC group), and the conventional cultured blank control group (NC group). The proliferation of cells was detected by using methyl thiazolyl tetrazolium (MTT) method, the invasion and migration abilities of cells were detected by using Tanswell test, and the protein expressions of CASC11, c-myc mRNA and c-myc in cells of all groups were detected by using qRT-PCR and Western blot.Results:The protein expression levels of CASC11, c-myc mRNA and c-myc protein in cancer tissues were increased compared with those in paracancerous tissues, and the differences were statistically significant (all P < 0.05). Compared with CCD841 cells, the protein expression levels of CASC11, c-myc mRNA and c-myc in all colorectal cancer cell lines were increased, and the differences were statistically significant (all P < 0.05); the highest protein expressions of CASC11, c-myc mRNA and c-myc were found in SW480 cell lines which were used to do the subsequent experiments. Pearson correlation analysis showed that there was a positive correlation between CASC11 mRNA and c-myc mRNA in cancer tissues ( r = 0.494, P < 0.05). The high expression rate of CASC11 and c-myc mRNA in cancer tissues for patients with lymph node metastasis was higher than that for those without lymph node metastasis [73.7% (28/38) vs. 26.9% (14/52), 84.2% (32/38) vs. 23.1% (12/52)], the high expression rate of CASC11 and c-myc mRNA in cancer tissues for patients with TNM stage Ⅲ-Ⅳ was higher than that for those with TNM stage Ⅰ-Ⅱ [76.0% (38/50) vs. 10.0% (4/40), 72.0% (36/50) vs. 20.0% (8/40)], and the differences were statistically significant (all P < 0.05). JASPAR software showed that the binding sites were detected in CASC11 promoter region and c-myc gene; dual luciferase reporter gene assay results showed that the relative activity of SW480 cells co-transfected with Sh-c-myc and wild-type CASC11 plasmid was lower compared with that of SW480 cells co-transfected with Sh-NC and wild-type CASC11 plasmid ( P < 0.05). Compared with NC group and Sh-NC group, the expression level of CASC11 mRNA, the number of invasive and migratory cells of SW480 cells in Sh-c-myc group were decreased, while cell proliferation inhibition rate was increased, and the differences were statistically significant (all P < 0.05). Conclusions:CASC11 and c-myc mRNA are highly expressed in colorectal cancer tissues and cell lines, and binding sites can be detected in CASC11 promoter region and c-myc gene. The expressions of both have a correlation, and the down regulation of c-myc can inhibit the invasion and migration of colorectal cancer cells by inhibiting the expression of CASC11.

Advances in the treatment of ovarian cancer with BRCA gene mutation / 中国综合临床

Ovarian cancer is the most fatal malignant tumor in female reproductive system tumors.In most women, it is diagnosed in a late stage, which largely leads to the poor prognosis of ovarian cancer.Breast cancer susceptibility gene (BRCA) is an important DNA homologous repair gene, which plays a major role in the normal cellular DNA repair mechanism.Its mutation will lead to homologous recombination defects, which will affect the stability of the genome and lead to occurrence of tumors.In recent years, BRCA genetic testing has become a key step in the risk assessment, prognosis, treatment and prevention of ovarian cancer.

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

@#This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

Effect of BRCA1 on proliferation, migration and invasion of non-small cell lung cancer H1650 cells via Wnt/β-catenin pathway / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effect of breast cancer susceptibility gene 1 (BRCA1) on the proliferation, migration and invasion of non-small cell lung cancer (NSCLC) H1650 cells through Wnt/β-catenin pathway. Methods: WB and qPCR were used to detect the mRNA and protein expressions of BRCA1 in NSCLC A549, H1299, H1650 cells and normal lung epithelial BEAS-2B cell. A stable BRCA1 over-expression cell line (LV-BRCA1) was constructed in H1650 cells, and blank control group (NC), negative control group (LV-BRCA1-NC), experimental group (LV-BRCA1) and inhibitor group (LV-BRCA1+XAV-939) were set up. The proliferative activity of cells in each group was detected by MTT assay, the migration ability of cells was detected by scratch test, the invasive ability of cells was detected by Transwell method, and the protein expression levels of BRCA1, cyclin D1, β-catenin, c-Myc and Cox2 were detected by WB. Results: The mRNA and protein expression levels of BRCA1 in NSCLC cells were significantly higher than those in BEAS-2B cells (all P<0.01). Up-regulation of BRCA1 expression in H1650 cells could significantly enhance cell proliferation, migration and invasion (P<0.05 or P<0.01), and increase the protein expressions of cyclin D1, β-catenin, c-Myc, Cox2 and c-Jun (P<0.05 or P<0.01). β-catenin inhibitor XAV-939 significantly down-regulated the proliferation, migration and invasion ability of H1650 cells over-expressing BRCA1, and decreased the protein expressions of cyclin D1, β-catenin, c-Myc, Cox2 and c-Jun (P<0.05 or P<0.01). Conclusion: BRCA1 can promote the proliferation, migration and invasion of NSCLC H1650 cells by activating Wnt/β-catenin pathway, and it is expected to be a potential diagnostic biomarker and treatment target for NSCLC.

Association between Polymorphism of the BRCA2 Gene rs206115 Loci and Sporadic Breast Cancer / 中国医科大学学报

Objective To analyze the correlation between polymorphism of the BRCA2 gene rs206115 loci and sporadic breast cancer in Inner Mongolia. Methods We enrolled patients from the Affiliated Hospital of Inner Mongolia Medical University from December 2015 to December 2016 who underwent breast surgery and were confirmed by pathology, resulting in a total of 101 cases of primary sporadic breast cancer (case group) and benign breast diseases (control group). DNA was extracted from blood samples and analyzed using polymerase chain reaction (PCR) and direct sequencing methods for determining the BRCA2 gene rs206115 loci polymorphism. SPSS 17.0 was used for statistical analysis. Results In this experiment, regardless of whether the patients were Han or Mongolian, the rs206115 loci could be detected in 3 kinds of genotypes:AA, AG, and GG. The BRCA2 gene rs206115 locus gene polymorphism was not significantly different between the case and control groups (χ2=3.490, P = 0.175). The A allele frequency of the BRCA2 gene rs206115 loci in the case group was significantly increased compared to the control group (χ2=4.259, P = 0.039). Conclusion The A allele of rs206115 may be one of the susceptibility alleles in sporadic breast cancer in Mongolian and Han populations.

Enhancing effect of chidamide on the sensibility of human chronic myeloid leukemia K562/ADM cells to daunorubicin / 解剖学报

Objective: To investigate whether chidamide (CDM) could influence the sensibility of human chronic myeloid leukemia K562/ADM cells to daunorubicin (DNR) and its possible mechanism. Methods: The K562 and K562/ADM cells were cultured in vitro and treated with CDM and(or) DNR for 48 hous, and then the cell viability was measured by cell counting kit-8(CCK-8) assay. The proliferation, cell cycle and apoptosis were analyzed by flow cytometry. Western blotting was performed to measure the protein levels of histon 2AX (H2AX), γH2AX (Serl39), ataxia telangiectasia mutated gene (ATM), p-ATM (Serl981), breast cancer susceptibility protein 1(BRCAl), and p-BRCAl (Serl524). Results: DNR remarkably inhibited the cell activity of K562/ADM cells in dose-dependent manner with a half maximal inhibitory concentration(IC50) value of 11.76 μmol/L, and the resistant factor was 18.09. Co-treatment with CMD and DNR produced a synergistic effect confidence interval(GI) (CI<1) with a reversal fold of 8.11. DNR remarkably inhibited proliferation (P<0.05), induced G2/M phase arrest and apoptosis (P<0.05), these effects were enhanced under non-toxic concentration of CMD (P<0.05). K562/ADM cells had a significantly higher protein levels of ATM and BRCA1 than K562 cells (P<0.05). DNR significantly up-regulated the protein levels of γH2AX, p-ATM and p-BRCAl (P<0.05), and the protein level of γH2AX appeared higher in the combination group compared to DNR alone (P<0.05); however, the co-treatment with CMD and DNR induced a decreased expression of p-ATM and p-BRCAl than the DNR alone (P< 0.05). Conclusion: CDM may enhance the sensibility of K562/ADM cells to DNR by up-regulating the protein level of γH2AX, and down-regulating the protein levels of p-ATM and p-BRCAl.

Expression of BRCA1 in sporadic invasive breast cancer and its significance / 医学研究生学报

Objective　BRCA1 is one of the most important susceptibility genes of breast cancer. The article aimed to investigate the expression of BRCA1 and its correlation in sporadic invasive breast cancer.　Methods　The expressions of BRCA1, ER, PR, HER2 and Ki67 in 618 cases of sporadic invasive breast cancer in our hospital from January 2015 to December 2017 were detected with immunohistochemistry in order to investigate and analyze the expression of BRCA1 and its correlation with molecular classification, histological type and other related molecular markers in sporadic invasive breast cancer.　Results　The positive rate of BRCA1 was 44.2% consisting of 30.3% weak positive(+) and 13.9% strong positive(++). The positive rates of ER, PR, and HER2 are 60.8%, 54.7%,and 24.9%. The proliferation index ≤30% of Ki67 was 70.7%, >30% was 29.3%. The expression of BRCA1 in luminal type A was significantly lower than the other four types of sporadic invasive breast cancer(P<0.05). The expression of BRCA1 in breast cancer with medullary histological features was significantly lower than those of the other types of breast cancer(P<0.05). There was significant difference between the expression of BRCA1 and the expressions of ER, HER2 and Ki67 (P<0.01). The expression of BRCA1 had positive correlation with expression of HER2 in sporadic invasive breast cancer (r=0.117,P<0.01).　Conclusion　The expression of BRCA1 in sporadic invasive breast cancer with triple negative subtype and medullary histological features is down-regulated and BRCA1 may affect the development and progression of sporadic invasive breast cancer.

Effect of CASC2a on proliferation and migration of papillary thyroid carcinoma cells via NF-κB signaling pathway / 医学研究生学报

Objective There are few reports on the relationship between lncRNA cancer susceptibility candidate gene 2 (CASC2) and NF-κB signaling pathway in thyroid papillary carcinoma cells at home and abroad. This study aimed to investigate the effect of lncRNA CASC2a on the proliferation and migration of TPC-1 via NF-κB signaling pathway. Methods TPC-1 was selected and constructed into lncRNA CASC2a overexpression plasmids which were divided into plasmid group [transfection with overexpressed plasmid pcDNA3.1(+)-CASC2a], empty group [transfection with equal amount of pcDNA3.1 (+) empty plasmid], blank group (without any processing). The effect of overexpressed lncRNA CASC2a on the expression of CASC2a in each group of TPC-1 cells was examined. The cells of transfected plasmid group were randomly divided into transfection group [transfection with only overexpressed plasmid pcDNA3.1(+)-CASC2a], transfection + PMA group [transfection with overexpressed plasmid pcDNA3.1(+)- CASC2a + propylene glycol methyl ether acetate (PMA) stimulation], control group (without any processing), PMA group (only plus PMA stimulation). The effects of lncRNA CASC2a on cell proliferation and migration were verified by CCK-8 and cell scratch assays at 24, 48, 72 and 96 h. Western blot was used to detect the expression of p105/p50 and p65 in NF-κB signaling pathway. The expression of NF-κB signaling pathway-related antibody proteins p105/p50 and p65 was observed by NF-κB signaling pathway agonist PMA(propylene glycol methyl ether acetate). Results After transfection with overexpressed plasmid pcDNA3.1(+)-CASC2a, the expression of CASC2a in plasmid group was significantly higher than that in empty group (P<0.05). The cell proliferation ability (0.191±0.005) was significantly lower in transfection+PMA group than that in transfection group (0.217±0.013), PMA group (0.247±0.009), and control group (0.260±0.004), and the difference was statistically significant ( P<0.01), while the cell proliferation ability in transfection group was significantly lower than those in PMA group and control group (P<0.01). The cell migration ability of transfected + PMA group [(0.208±0.109)%] was lower than that of transfection group, PMA group, and control group [(1.775±0.061)%, (1.622±0.519)%, (2.927±0.136)%], while the cell migration ability of transfection group and PMA group was lower than that in control group (P<0.05). The relative expression of p105/p50 and p65 protein in plasmid group was significantly lower than that in blank group (P<0.05). The expression of p105/p50 and p65 protein in transfection+PMA group [(0.674±0.007), (0.713±0.014)] was significantly higher than that in transfection group [(0.581±0.003), (0.570±0.012)] (P<0.05). Conclusion lncRNA CASC2a may inhibit the proliferation and migration of thyroid papillary carcinoma cells through NF-κB signaling pathway.

Expression of cancer susceptibility candidate 2 in hepatocellular carcinoma and its influence on the prognosis of the patients / 中华肝胆外科杂志

Objective To investigate the correlations between expression of CASC2 and hepatocellular carcinoma(HCC) prognosis.Methods A total of 129 patients including 80 males and 49 females with HCC were includedin this study,ranging from 21 to 73 years in Xuanwu Hospital of Capital Medical University and Beijing You'an Hospital were retrospectively analyzed from September 2007 to January 2014.Expression of CASC2 was assessed using reverse transcription quantitative-polymerase chain reaction in HCC tissue and the adjacent normal tissue.The correlations between CASC2 mRNA level and clinicopathological parameters was investigated.The relationship between the expression of CASC2 and the prognosis of patients with HCC was analyzed by Kaplan-Meier method.A log-rank analysis was performed to identify group differences.Univariate and multivariate Cox analysis were used to analyze the variables affecting the patient's prognosis.Results In 129 HCC samples,the level of CASC2 expression (0.84 ± 0.05) was lower than (3.35 ± 0.11) adjacent normal tissue (P ＜ 0.05).There were significant differences between CASC2 expression and tumor size,histological differentiation,and tumor stage in 129 HCC speciments.The median expression level of CACS2 in HCC tissues,0.84-fold,was used as the cut-off value to divide the 129 patients into two groups:low-expression group (n =72) and high-expression group (n =57).Overall survival rate of HCC patients with high CACS2 expression was significantly higher than those of patients with low CACS2 expression(P ＜0.05).Multivariate analysis indicated that histological differentiation (HR =0.20,95％ CI:0.05 ～ 0.59),tumor stage (HR =1.71,95％ CI:1.02 ～ 2.99) and CACS2 expression (HR =O.51,95％ CI:O.08 ～0.92) were an independent predictor of overall survival.Conclusion Low expression of CACS2 might be associated with the occurrence and development of HCC.

Association between single nucleotide polymorphism at rs175048 locus of ATM gene and susceptibility to lung cancer in Han population in Hengyang, Hunan / 中国肿瘤生物治疗杂志

@# Objective: To explore the association between the single nucleotide polymorphism (SNP) of rs175048 in ataxia telangiectasia mutated (ATM) gene and lung cancer susceptibility in Han population. Methods: A total of 225 cases of blood samples from lung cancer patients treated in Hospital of Traditional Chinese Medicine of Hengyang City and the Affiliated First Hospital of Nanhua University from October 2015 to August 2016 were collected as case group, and 128 cases of blood samples from healthy people were collected as the control. The polymorphisms of ATM rs175048 of above mentioned participants were detected by using the SNP sensitive On/Off Switch technique. The genotypes and allele frequencies were analyzed to compare the distribution difference between case group and control group as well as its association to the clinical features of lung cancer. Results: The genotype frequencies of AA, AT and TT of ATM rs175048 were 24.9%, 52.9%, 22.2% in case group and 42.2%, 42.2%, 15.6% in control group, respectively (all P< 0.01). Moreover, the frequencies of alleles A and T were 51.0%, 49.0% in case group, and 63.0%, 37.0% in control group (all P<0.01). Genotype TT might increase while genotype AT might decrease the risk of lung cancer. rs175048 SNP was significantly correlated with smoking, age, sex and family history (all P<0.05). Conclusion: rs175048 SNPis significantly associated with lung cancer, and TT genotype may increase the risk of lung cancer.

Targeting DNA damage response pathway: recent progress of PARP inhibitors in cancer therapy / 中国药理学通报

Genomic instability is one of the most pervasive characteristics of cancer cells,and DNA damage response (DDR) pathway plays a crucial role in genomic stability.The DDR pathway is a complex signaling network,which involves cell DNA repair,apoptosis and cell cycle regulation.Deficiencies in these repair pathways can result in several different genetic disorders,including cancer.Targeted therapy based on inhibiting the DDR pathway in cancers offers a novel therapy strategy for patients with tumors lacking specific DDR functions.Many small-mole-cule compounds targeting DDR pathway are typically developed for solid cancer therapy.The poly (ADP-ribose) polymerase (PARP) inhibitor is a kind of DDR inhibitors which exploits the principle of synthetic lethality to selectively kill cancer cells.This review highlights the molecular mechanisms of PARP inhibitor action,the progress of PARP inhibitors in cancer therapy,drug resistance and the challenge of PARP inhibitor in the future.

Polymorphism analysis of rs16941 and rs16942 loci of BRCA1 gene Uighur and Han sporadic breast cancer / 临床与实验病理学杂志

Purpose To investigate whether there is a difference in BRCA1 gene single nucleotide polymorphisms (SNPs) in Uighurs and Han Chinese sporadic breast cancer,and to analyze the relationship between SNPs locus and tumor susceptibility.Methods 100 cases of sporadic breast cancer (Uighur and Han 50 cases each) and 100 cases of mammary gland disease (Uighur and Han 50 cases each) were collected as the research object,the BRCA1 gene rs16941 and rs16942 were sequenced.Results The distribution of AA,AG and GG genotypes of rs16941 and rs16942 between Uygur and Han breast cancer groups were statistically significant (P =0.009,P =0.017).Compared with AA genotype of rs16941,AG genotype of rs16941 could reduce the risk of breast cancer in Uighurs (OR =0.964,95％ CI:0.260-3.583,P =0.009).Compared with AA genotype of rs16942,AG genotype of rs16942 could increase the risk of breast cancer in Uighurs (OR =1.017,95％ CI:0.293-3.916,P =0.017).Compared with AA genotype of rs16941,AG genotype could reduce the risk of breast cancer in Han nationality (OR=0.824,95％ CI:0.210-3.234,P =0.044).Conclusion The distribution of AA,AG and GG genotypes of rs16941 and rs16942 in Uygur and Han breast cancer groups are statistically significant,and SNPs is correlated with tumor susceptibility.