Association of Genetic Polymorphisms in the LncRNAs with Gastric Cancer Risk in a Chinese Population.

Background: Genome-wide association studies have identified that polymorphisms in 8q24 confer susceptibility to gastric cancer. Polymorphisms in the lncRNA PRNCR1, PCAT1, and CCAT2 transcribed from the 8q24 locus have a potential risk for gastric cancer. Methods: To evaluate whether there is such an association in Chinese population, a case-control study enrolled 494 patients and 494 healthy controls was carried out. Sequenom MassARRAY platform was used for genotyping. Results: This study showed that rs16901946 G allele was associated with increased risk of gastric cancer (AG: adjusted OR = 1.33, 95% CI =1.02-1.73, p=0.033; GG: adjusted OR = 2.07; 95% CI = 1.11-3.86, p=0.023, AG/GG: adjusted OR = 1.39, 95% CI = 1.08-1.1.79, p=0.011; additive model: adjusted OR = 1.37; 95% CI = 1.10-1.70, p=0.004). Stratified analysis revealed that the increased risk was more evident in the cohort of younger subjects (adjusted OR = 1.84, 95% CI = 1.18-2.87, p=0.007), males (adjusted OR = 1.55, 95% CI = 1.15-2.08, p=0.004), positive Helicobacter pylori infection (adjusted OR = 1.44, 95% CI = 1.02-2.03, p=0.041), gastric cardia adenocarcinoma (adjusted OR = 1.61, 95% CI = 1.10-2.35, p=0.014), and tumor stage T1-T2 (adjusted OR = 1.58, 95% CI = 1.10-2.28, p=0.013). Conclusions: Our study suggested that rs16901946 G allele carriers have an increased risk of gastric cancer, and the risk could be enhanced by the interactions between the polymorphism and age, sex, Helicobacter pylori infection.

Nucleotide excision repair pathway gene polymorphisms are linked to breast cancer risk in a Chinese population.

Polymorphisms in nucleotide excision repair (NER) pathway genes are associated with the risk of breast cancer, but the relevance of these associations appeared to vary according to the ethnicity of the subjects. To systemically evaluate the potential associations between NER polymorphisms and breast cancer risk in a Chinese population, we carried out a case-control study on 450 breast cancer patients and 430 healthy controls. Sequenom MassARRAY was used for genotyping, and immunohistochemistry was performed to detect estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression in tumor tissue. Our results showed that ERCC1 rs11615 (additive model: ORadjusted: 1.36, 95% CI: 1.08-1.71, p = 0.009), XPC rs2228000 (additive model: ORadjusted: 1.39, 95% CI: 1.13-1.72, p = 0.002) and ERCC2/XPD rs50872 (additive model: ORadjusted: 1.32, 95% CI: 1.04-1.67, p = 0.021) were associated with an increased risk of breast cancer. Stratified analysis revealed three polymorphisms (rs11615, rs1800975, and rs50872) to be associated with breast cancer in menopausal females. Three polymorphisms were associated with specific breast cancer grades (rs11615 with grade 3, rs2228000 and rs50872 with grade 1-2). Two polymorphisms (rs2228001 and rs50872) were associated with the risk of breast cancer with negative lymph node involvement. rs1800975 and rs50872 were associated with the risk of ER- and PR- breast cancer, whereas rs11615 was associated with the risk of ER+ and PR+ breast cancer. We found that carriers of the T allele of ERCC1 rs11615, XPC rs2228000 and rs50872, particularly in postmenopausal females, have an increased risk of breast cancer.

Association of the DISC1 and NRG1 genetic polymorphisms with schizophrenia in a Chinese population.

Polymorphisms in Disrupted-in-Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) might be associated with schizophrenia; however, the conclusions of relevant studies were inconsistent across different ethnic populations. This population-based case-control study was carried out to determine whether polymorphisms in these two genes could be associated with schizophrenia in the Chinese population. A case-control study of 248 schizophrenia patients and 236 controls was performed with the Sequenom MassARRAY platform. The results revealed that the DISC1 rs821616 heterozygous (AT vs. AA: adjusted OR, 1.98, 95%CI: 1.30-3.02) and co-dominant (AT/TT vs. AA: adjusted OR=1.94; 95%CI: 1.29-2.92) patterns were associated with increased risk for developing schizophrenia in all participants and subgroups (stratified by sex and age at onset), respectively. Moreover, in the male subgroup, the DISC1 rs821597 genotype GA or GA/AA exhibited increased risk of schizophrenia. For NRG1 polymorphisms, in the early onset subgroup (≤25years), the rs3924999 G/G genotype was susceptible to schizophrenia. The interaction of DISC1 rs821616 T allele with the NRG1 rs3924999 A allele or that of DISC1 rs821597 A allele with NRG1 rs3924999 A allele had synergic effects on the development of schizophrenia. This study concluded that carriers of the DISC1 rs821616 T allele have increased risk for developing schizophrenia, and that the DISC1 rs821597 A allele was susceptible to schizophrenia for the male, and that there are marked interactions between the DISC1 rs821616 T and/or rs821597 A alleles and the NRG1 rs3924999 A allele for the development of schizophrenia.

Evaluation the susceptibility of five polymorphisms in microRNA-binding sites to female breast cancer risk in Chinese population.

Polymorphisms in microRNA (miRNA) binding site have been widely discussed to be associated with cancer risk; however, the associations were unclear in Chinese population. To investigate the associations of five polymorphisms (rs11097457, rs1434536, rs1970801, rs1044129, rs11169571) in miRNA binding sites with breast cancer risk, a total of 435 female patients with breast cancer and 439 age- and gender-matched tumor-free individuals were enrolled in this case-control study. Sequenom MassARRAY was applied to detect the polymorphisms, and the immunohistochemistry assay was used to measure the expression of estrogen receptor (ER) and progesterone receptor (PR) and CerbB-2. The data showed that these polymorphisms were not associated with breast cancer risk or clinical characters of breast cancer in all participants and sub-group with the exception that, in the sub-group of women with their first menstruation after 14 years old, those who carried rs1970801 T allele (genotype TT/GT) were associated with decreased breast cancer risk. In short, this case-control study provided the evidence that women with their first menstruation after 14 years old and carried rs1970801 T allele (genotype TT/GT) were associated with decreased breast cancer risk.

The involvement of Kras gene 3'-UTR polymorphisms in risk of cancer and influence on patient response to anti-EGFR therapy in metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Genetic variation of the Kras oncogene is a candidate factor for increasing susceptibility to carcinoma and modulating response of metastatic colorectal cancer (mCRC) patients treated with anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR). However, results from an increasing number of studies concerning the association of Kras gene rs712 and rs61764370 polymorphisms with risk of cancer and treatment of mCRC using anti-EGFR remain equivocal. METHODS: Risk associations were evaluated in 1,661 cases and 2,139 controls from six studies concerning rs712 and 14,796 cases and 14,985 controls from 29 studies concerning rs61764370. Response association was also examined in a subset of four studies pertaining to rs61764370 and anti-EGFR treatment in mCRC. RESULTS: Results of a meta-analysis showed that allele T (P-value of heterogeneity test [P H] =0.08, odds ratio [OR] =1.33, 95% confidence interval [CI]: 1.08-1.64) and genotype GT/TT (P H=0.14, OR =1.30, 95% CI: 1.10-1.55) in rs712 were strongly associated with cancer in Chinese subjects. No evidence of association was observed between rs712 and risk of cancer in the overall population or between rs61764370 and ovarian, breast, colorectal, or non-small-cell lung cancer risk in the Caucasian population. No significant association was found between rs61764370 and patient response to anti-EGFR therapy in mCRC. CONCLUSION: The findings not only provide further evidence that allele T of rs712 increases genetic predisposition to cancer in Chinese population, but also no significant association between rs61764370 and cancer risk in Caucasian population, and suggest that genotype GT/TT of rs61764370 may not be a biomarker for predicting clinical outcome of anti-EGFR therapy in mCRC.

Roles of E-cadherin (CDH1) genetic variations in cancer risk: a meta-analysis.

E-Cadherin (CDH1) genetic variations may be involved in invasion and metastasis of various cancers by altering gene transcriptional activity of epithelial cells. However, published studies on the association of CDH1 gene polymorphisms and cancer risk remain contradictory, owing to differences in living habits and genetic backgrounds. To derive a more better and comprehensive conclusion, the present meta-analysis was performed including 57 eligible studies of the association between polymorphisms of CDH1 gene promoter -160 C>A, -347 G>GA and 3'-UTR +54 C>T and cancer risk. Results showed that these three polymorphisms of CDH1 were significantly associated with cancer risk. For -160 C>A polymorphism, -160A allele carriers (CA and CA+AA) had an increased risk of cancer compared with the homozygotes (CC), and the similar result was discovered for the -160A allele in the overall analyses. In the subgroup analyses, obvious elevated risk was found with -160A allele carriers (AA, CA, CA+AA and A allele) for prostate cancer, while a decreased colorectal cancer risk was shown with the AA genotype. For the -347 G>GA polymorphism, the GAGA genotype was associated with increased cancer risk in the overall analysis with homozygous and recessive models. In addition, results of subgroup analysis indicated that the elevated risks were observed in colorectal cancer and Asian descendants. For +54 C>T polymorphism, a decreased risk of cancer was found in heterozygous, dominant and allele models. Moreover, +54T allele carriers (CT, CT+TT genotype and T allele) showed a potential protective factor in gastric cancer and Asian descendants.

Gene therapy for colorectal cancer by an oncolytic adenovirus that targets loss of the insulin-like growth factor 2 imprinting system.

BACKGROUND: Colorectal cancer is one of the most common malignant tumors worldwide. Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) gene is an epigenetic abnormality observed in human colorectal neoplasms. Our aim was to investigate the feasibility of using the IGF2 imprinting system for targeted gene therapy of colorectal cancer. RESULTS: We constructed a novel oncolytic adenovirus, Ad315-E1A, and a replication-deficient recombinant adenovirus, Ad315-EGFP, driven by the IGF2 imprinting system by inserting the H19 promoter, CCCTC binding factor, enhancer, human adenovirus early region 1A (E1A) and enhanced green fluorescent protein (EGFP) reporter gene into a pDC-315 shuttle plasmid. Cell lines with IGF2 LOI (HCT-8 and HT-29), which were infected with Ad315-EGFP, produced EGFP. However, no EGFP was produced in cell lines with maintenance of imprinting (HCT116 and GES-1). We found that Ad315-E1A significantly decreased cell viability and induced apoptosis only in LOI cell lines in vitro. In addition, mice bearing HCT-8-xenografted tumors, which received intratumoral administration of the oncolytic adenovirus, showed significantly reduced tumor growth and enhanced survival. CONCLUSIONS: Our recombinant oncolytic virus targeting the IGF2 LOI system inhibits LOI cell growth in vitro and in vivo, and provides a novel approach for targeted gene therapy.