Qian Cui

Expression of human leukocyte antigen G is associated with prognosis in nasopharyngeal carcinoma.

Human leukocyte antigen G (HLA-G) has multiple immune regulatory functions including the induction of immune tolerance in malignancies. The roles of HLA-G have not been investigated in nasopharyngeal carcinoma (NPC). This study is aimed to evaluate the role of HLA-G as prognostic factor for NPC patients as well as its role in the immune regulation. Western assays showed high HLA-G expression in NPC cell lines, but low in the immortalized nasopharyngeal epithelial cell line NP69. HLA-G protein was further detected in 79.2% of 552 NPC specimens with immunohistochemistry (IHC), but not in normal nasopharyngeal epithelium tissue. Moreover, high expression of HLA-G predicted poor survival of NPC patients and positively correlated with tumor N classification and recurrence or metastasis. Multivariate analysis indicated that HLA-G was an independent and unfavorable prognostic factor. Furthermore, the presence of CD68+macrophages and IL-10 were also examined, which are two prognostic markers of NPC and important factors for regulating immune surveillance. The correlations of HLA-G with these two immune factors were revealed in NPC tissues. Taken together, our results suggest that HLA-G is an independent biomarker for NPC prognosis, and HLA-G might contribute to NPC progression, which might jointly regulate immune surveillance in NPC together with macrophages and IL-10.

Genome-wide association study of B cell non-Hodgkin lymphoma identifies 3q27 as a susceptibility locus in the Chinese population

To identify genetic risk factors underlying non-Hodgkin lymphomas (NHLs) from the B cell lineage, we conducted a genome-wide association study (GWAS) of 253 Chinese individuals with B cell NHL (cases) and 1,438 controls and further validation in 1,175 cases and 5,492 controls. We identified a new susceptibility locus, rs6773854, located between BCL6 (encoding B cell lymphoma protein 6) and LPP (encoding lipoma preferred partner) on oncogene-rich chromosome 3q27 that was significantly associated with increased risk of B cell NHL (meta-analysis P = 3.36 × 10−13, per-allele odds ratio (OR) = 1.44) and with diffuse large B cell lymphoma (DLBCL) in particular (meta-analysis P = 1.14 × 10−11, OR = 1.47). We found no evidence of association of rs6773854 with non–B cell NHLs (T cell and natural killer (NK) lineages) (P = 0.17, OR = 1.12) and observed significant heterogeneity between B cell and non–B cell subtypes (Phet = 0.01, I2 = 84%). Our results provide insight that germline variation in the intergenic region between BCL6 and LPP has a role in risk of B cell lymphomagenesis.

A GWAS meta-analysis and replication study identifies a novel locus within CLPTM1L/TERT associated with nasopharyngeal carcinoma in individuals of Chinese ancestry

Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied. Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case–control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed. Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10−13). Our results also provide support for associations reported from published NPC GWAS—rs6774494 (P = 1.5 × 10−12; located in the MECOM gene region), rs9510787 (P = 5.0 × 10−10; located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10−8, P = 7.0 × 10−7, and P = 8.4 × 10−7, respectively; located in the CDKN2A/B gene region). Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity. Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(1); 188–92. ©2015 AACR.

Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma

BackgroundThe correlation of S-phase kinase–associated protein 2 (Skp2) with metastasis and prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. The purpose of this study was to explore whether there was a correlation between the expression of Skp2 evaluated by immunohistochemistry and the clinical outcome of patients with operable ESCC, and to further determine the possible mechanism of the impact of Skp2 on survival.MethodsTissue microarrays that included 157 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of Skp2 expression was analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. The prognostic impact of clinicopathologic variables and Skp2 expression was evaluated using a Cox proportional hazards model. A cell proliferation assay and a colony formation assay were performed in ESCC cell lines to determine the function of Skp2 on the progression of ESCC in vitro.ResultsSkp2 expression correlated closely with the T category (p = 0.035) and the pathological tumor-node-metastasis (TNM) stage (p = 0.027). High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01). The multivariate Cox regression analysis demonstrated that pathological T category, pathological N category, cell differentiation, and negative Skp2 expression were independent factors for better overall survival. In vitro assays of ESCC cell lines demonstrated that Skp2 promoted the proliferative and colony-forming capacity of ESCCs.ConclusionsNegative Skp2 expression in primary resected ESCC is an independent factor for better survival. Skp2 may play a pro-proliferative role in ESCC cells.

Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma

Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants

Genetic susceptibility and Epstein-Barr virus (EBV) infection are important etiological factors in nasopharyngeal carcinoma (NPC). In this study, in southern China, where NPC is endemic, a single nucleotide polymorphism (SNP) in the EBV-encoded RPMS1 gene (locus 155391: G > A [G155391A]) and seven host SNPs (rs1412829, rs28421666, rs2860580, rs2894207, rs31489, rs6774494, and rs9510787) were confirmed to be significantly associated with NPC risk in 50 NPC cases versus 54 hospital-based controls with throat washing specimens and 1925 NPC cases versus 1947 hospital-based controls with buffy coat samples, respectively. We established a strategy to detect the NPC-associated EBV and host SNPs using saliva samples in a single test that is convenient, noninvasive, and cost-effective and displays good compliance. The potential utility of this strategy was tested by applying a risk prediction model integrating these EBV and host genetic variants to a population-based case-control study comprising 1026 incident NPC cases and 1148 controls. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve of the NPC risk prediction model of 0.74 (95% CI: 0.71−0.76). Net reclassification improvement (NRI) analysis showed that inclusion of the EBV SNP significantly improved the discrimination ability of the model (NRI = 0.30, P < 0.001), suggesting the promising value of EBV characteristics for identifying high-risk NPC individuals in endemic areas. Taken together, we developed a promising NPC risk prediction model via noninvasive saliva sampling. This approach might serve as a convenient and effective method for screening the population with high-risk of NPC.

Translational oncology toward benefiting cancer patients: the Sun Yat-sen University Cancer Center experience

Sun Yat-sen University Cancer Center (SYSUCC) is currently conducting many translational studies to improve cancer pa-tients’ condition through early diagnosis, discovering new treatments, improving treatment outcomes, and better classification and prognosis of cancer. SYSUCC is a leading institution for treating nasopharyngeal carcinoma (NPC) and carrying out re-search into the disease. The center has performed several large-scale studies that have produced new insights, such as a ge-nome-wide analysis study, which has allowed researchers to identify new genetic risk factors for NPC; the findings are signif-icant toward building a risk prediction model for NPC. Other researchers are using molecular biological methods to identify new biomarkers, which will allow a better classification and prognosis of this disease. Drug discovery, especially for molecular targeted therapy, is also an active field of research at SYSUCC, not only for NPC treatment, but also for, among others, can-cers of the head, neck, and liver. As an alternative to Western medicine, scientists also use derivatives of natural products from Traditional Chinese Medicine to develop new compounds. The tumor biobank at SYSUCC, one of the largest in China, play an essential role in producing clinical applications from research findings. Translational oncology is a promising field, and scien-tists and clinicians from SYSUCC will continue to work in synergy to develop new anticancer therapies.