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// Xunjun Yang 1, 2 , Xiuchan Guo 1, 3 , Yao Chen 4 , Guorong Chen 4 , Yin Ma 1 , Kate Huang 4 , Yuning Zhang 1 , Qiongya Zhao 1 , Cheryl A. Winkler 5 , Ping An 5 , Jianxin Lyu 1 1 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China 2 Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 3 ICF International, Atlanta, GA, USA 4 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 5 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA Correspondence to: Ping An, email: anp@mail.nih.gov Jianxin Lyu, email: ljx@wmu.edu.cn Keywords: hepatocellular carcinoma, TERT, mutation, telomerase reverse transcriptase Received: February 01, 2016 Accepted: March 28, 2016 Published: April 1, 2016 ABSTRACT Telomerase reverse transcriptase ( TERT ) promoter mutations are among the most frequent noncoding somatic mutations in multiple cancers, including hepatocellular carcinoma (HCC). The clinical and pathological implications of TERT promoter mutations in hepatitis B virus (HBV)-associated HCC have not been resolved. To investigate TERT promoter mutations, protein expression, and their clinical-pathological implications, we sequenced the TERT promoter region for hotspot mutations in HCC tissues and performed immunostaining for TERT protein expression from HBV-associated HCC in Chinese patients. Of 276 HCC tumor DNA samples sequenced, 85 (31%) carried TERT promoter mutations. TERT promoter mutations were more frequent in those with low α-fetoprotein (AFP) serum levels ( p = 0.03), advanced age ( p = 0.04), and in those lacking HCC family history ( p = 0.02), but were not correlated with HCC stages and grades. TERT protein levels were higher in HCC (n = 28) compared to normal liver tissues (n = 8) ( p =0.001), but did not differ between mutated and non-mutated tumor tissues. In conclusion, TERT promoter mutations are common somatic mutations in HCC of Han Chinese with HBV infection. Detection of TERT promoter mutations in those with low levels of AFP may aid diagnosis of HCC with atypical presentation.

Depressive and anxiety symptoms are frequently observed in breast cancer survivors. To date, few randomized controlled trials have been conducted on the efficacy of cognitive behavioural therapy (CBT) for depressive and anxiety symptoms in Chinese population. This study aims to verify the efficacy of CBT in Chinese breast cancer survivors. Women (n = 392) with breast cancer were randomly assigned to 3 groups: CBT (n = 98), self-care management (SCM, n = 98), and usual care (UC, n = 196) using the proportion 1:1:2. Women in the CBT and SCM groups received a series of nine sessions for 12 weeks, while women in the UC group received their usual medical care only. Depressive and anxiety symptoms were assessed using the Hamilton Depression Rating Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) score at baseline, 2, 4, 8, 12, 16, and 24 weeks. A significant intergroup difference was found in the HAMD and HAMA scores. Women in the CBT group showed significantly less depressive and anxiety symptoms compared with women in the SCM and UC groups over time. In conclusion, this study supports the efficacy of CBT for depressive and anxiety symptoms in Chinese breast cancer survivors.

Background: Little information is available about care before death among human immunodeficiency virus (HIV)–infected persons who die of HIV infection, compared with those who die of other causes. Objective: The objective of our study was to compare HIV care and outcome before death among persons with HIV who died of HIV-attributable versus other causes. Methods: We used National HIV Surveillance System data on CD4 T-lymphocyte counts and viral loads within 12 months before death in 2012, as well as on underlying cause of death. Deaths were classified as “HIV-attributable” if the reported underlying cause was HIV infection, an AIDS-defining disease, or immunodeficiency and as attributable to “other causes” if the cause was anything else. Persons were classified as “in continuous care” if they had ≥2 CD4 or viral load test results ≥3 months apart in those 12 months and as having “viral suppression” if their last viral load was

We have conducted a comprehensive case-control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A(*)0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A(*)0206, HLA-B(*)3802 alleles plus the A(*)0207-B(*)4601 and A(*)3303-B(*)5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 (P0.0001). HLA alleles that associate with low risk for NPC include HLA-A(*)1101, B(*)27, and B(*)55 with a combined OR of 0.42 (P0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.

To understand the role of environmental and genetic influences on nasopharyngeal carcinoma (NPC) in populations at high risk of NPC, we have performed a case-control study in Guangxi Province of Southern China in 2004-2005. NPC cases (n = 1,049) were compared with 785 NPC-free matched controls who were seropositive for IgA antibodies (IgA) to Epstein-Barr virus (EBV) capsid antigen (VCA)-a predictive marker for NPC in Chinese populations. A questionnaire was used to capture exposure and NPC family history data. Risk factors associated with NPC in a multivariant analysis model were the following: (i) a first, second or third degree relative with NPC [attributable risk (AR)= 6%, odds ratio (OR) = 3.1, 95% confidence interval (CI) = 2.0-4.9, p0.001]; (ii) consumption of salted fish 3 or more than 3 times per month (AR = 3%, OR = 1.9, 95% CI = 1.1-3.5, p = 0.035); (iii) exposure to domestic wood cooking fires for more than 10 years (AR = 69%, OR = 5.8, 95% CI = 2.5-13.6, p0.001); and (iv) exposure to occupational solvents for 10 or less years (AR = 4%, OR = 2.6, 95% CI = 1.4-4.8, p = 0.002). Consumption of preserved meats or a history of tobacco smoking were not associated with NPC (p0.05). We also assessed the contribution of EBV/IgA/VCA antibody serostatus to NPC risk-32.2% of NPC can be explained by IgA+ status. However, family history and environmental risk factors cumulatively explained only 2.7% of NPC development in NPC high risk population. These findings should have important public health implications for NPC risk reduction in endemic regions.

Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs inITGA9at 3p21.3 and 9 SNPs within the 6p21.3HLAregion were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC).Results.The reported associations betweenITGA9variants and NPC were not replicated. Multiple loci ofGABBR1,HLA-F,HLA-A, andHCG9were statistically significant in both cohorts (Pcombinedrange from 5.96 × 10−17to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China., Author Summary NPC is a deadly throat cancer in China that is dependent on EBV infection. Here, we performed a 1 M SNP genome-wide association study using a large cohort of Chinese study participants at risk for NPC. Although several putative gene regions show significant associations, the strongest statistical signals involved scores of variants within the HLA region on chromosome 6. HLA poses a formidable association-genetics challenge because of extensive linkage disequilibrium, rather low allele frequencies, and multiple physically close interacting genes of diverse function. We examined over 250 NPC-HLA associated variants detected with sequence-based nucleotide alleles and amino acid variants. The multiple associations were collapsed to implicate causal signals by multivariate logistical regression to resolve allele association interaction. One operative variant was identified as the HLA-A*11:01 allele motif, specifically in the peptide binding groove, which recognizes invading antigens; a second involved two aa sites with HLA-B tracking B*13:01 and B*55:02 alleles. We synthesize these new and previous discoveries to help resolve the important gene influences on this disease.

To study the effect of human papillomavirus (HPV) and tumour promoters spermidine (SPD and N-butyrate) on malignant transformation of human embryo cervical cells.Plasmid HPV16E6/E7 was constructed and transfected into human embryo cervical cells obtained by induced labor from pregnant women with severe heart diseases. Twenty-one scid mice were divided into 4 groups: experimental group (n = 7, incubated subcutaneously with the transfected cervical cells at the right shoulder, and then injected subcutaneously with spermidine and N-butyrate at the left shoulder three days after the incubation once a week for 12 times), virus-infected group B (n = 5, incubated subcutaneously with transfected cervical cell only), tumor promoter group (n = 5, incubated with untransfected cervical cells and SPD and N-butyrate), and control group (n = 4, incubated subcutaneously with only untransfected cervical cells). Twelve weeks after incubation, the mice were killed. Pathological reexamination was conducted to detect the existence of tumor. PCR was used to detect HPV16E6/E7 gene in tumor tissues.Tumor, diagnosed as fibrosarcoma by pathology, was found in 5 out of the 7 mice in the experimental group. The tumor-forming rate was 0 in other groups. Expression of HPV16E6/E7 gene was detected in tumour tissues by PCR.HPV16E6/E7 gene containing retrovirus infection, synergized by spermidine and N-butyrate acid, causes malignant transformation in human cervical cells.

Background Southern China is a major area for endemic nasopharyngeal carcinoma (NPC). Genetic factors as well as environmental factors play a role in development of NPC. To investigate the roles of previously described carcinogen metabolism gene variants for NPC susceptibility in a Han Chinese population, we conducted a case-control study in two independent study population groups afflicted with NPC in Guangdong and Guangxi Provinces of southern China. Methods Five single nucleotide polymorphisms (SNPs) of CYP2E1-rs2031920, CYP2E1-rs6413432, GSTP1-rs947894, MPO-rs2333227 and NQO1-rs1800566 were genotyped by PCR-based RFLP, sequencing and TaqMan assay in 358 NPC cases and 629 controls (phase I cohort). Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI). To confirm our results, sixteen tag SNPs for GSTP1, MPO, NQO1 (which 100% covered these genes), and 4 functional SNPs of CYP2E1 were genotyped in another cohort of 213 NPC cases and 230 controls (phase II cohort). Results No significant associations in NPC risk were observed for the five polymorphisms tested in the phase I cohort. In an additional stratified analysis for phase I, there was no significant association between cases and controls in NPC high risk population (EBV/IgA/VCA positive population). Analysis of 14 tagging SNPs within the same genes in an independent phase II cohort were in agreement with no SNPs significantly associated with NPC. Conclusions Our results suggest that polymorphism of CYP2E1, GSTP1, MPO and NQO1 genes does not contribute to overall NPC risk in a Han Chinese in southern China.