Jiarui Yao

A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers

Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and CFLAR, three genes important for death receptor–induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (−652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer. The deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical and breast cancers, acting in an allele dose–dependent manner. These results support the hypothesis that genetic variants influencing immune status modify cancer susceptibility.

Functional Genetic Variations in Cytotoxic T-Lymphocyte Antigen 4 and Susceptibility to Multiple Types of Cancer

Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. This study examined whether genetic polymorphisms in CTLA-4 are associated with cancer susceptibility. A two-stage investigation using haplotype-tagging single nucleotide polymorphism approach and multiple independent case-control analyses was performed to assess the association between CTLA-4 genotypes and cancer risk. Functional relevance of the polymorphisms was examined by biochemical assays. We found that the 49G>A polymorphism in the CTLA-4 leading sequence causing (17)Ala to (17)Thr amino acid substitution is associated with increased susceptibility to multiple cancers, including lung, breast, esophagus, and gastric cardia cancers. Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50-2.10; P = 3.4 x 10(-7)) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4-(17)Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4-(17)Ala. T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results are consistent with our hypothesis and indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility.

Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer

Background Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaining spindle checkpoint function. This study examined the functional relevance of missense coding single nucleotide polymorphisms (SNPs) in MAD1L1 and MAD2L1 and their association with susceptibility to lung cancer. Methods SNPs in the MAD2L1 coding region were discovered by sequencing and impact of MAD1L1 and MAD2L1 variants on spindle checkpoint function was examined by flow cytometry and mitotic index assay. The associations of MAD1L1 and MAD2L1 variants with lung cancer were analysed in a case–control cohort of 1000 patients and 1000 controls. ORs and 95% CIs were estimated by logistic regression. Results A novel C-to-A SNP at codon 84 of MAD2L1 (Leu84Met substitution) was discovered. Cells expressing MAD2L1-84Met and MAD1L1-558His had impaired spindle checkpoint function, with a lower 4N-DNA content and mitotic index when treated with nocodazole. Case–control analysis showed that the MAD2L1 Leu84Met SNP was associated with increased risk of lung cancer in an allele dose dependent manner, with the ORs being 2.55 (95% CI 1.95 to 3.33) for the Leu/Met and 2.68 (95% CI 2.05 to 3.48) for the Met/Met genotype compared with the Leu/Leu genotype. The MAD1L1 558 His/His genotype was also associated with 1.4-fold elevated lung cancer risk compared with the Arg/Arg genotype. Conclusion These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1 and/or MAD2L1.

Antitumor Effects of a Novel Chromosome Region Maintenance 1 (CRM1) Inhibitor on Non-Small Cell Lung Cancer Cells In Vitro and in Mouse Tumor Xenografts

Background Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter and its inhibitor has anti-tumor activity in various cancers. This study assessed the therapeutic efficiency of the novel CRM1 inhibitor KPT-185 on non-small cell lung cancer (NSCLC). Methods NSCLC cell lines were treated with KPT-185 to assess changes in cell viability, cell cycle, apoptosis, and protein expression. NOD-SCID mice carrying NSCLC cell xenografts were orally treated with KPT-276, a clinical analog of KPT-185, to examine the efficacy and side effects of KPT-276 in vivo. Results KPT-185 significantly reduced the viability of six NSCLC cell lines in a time- and dose-dependent manner, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant H1975 and H1650GR cell lines. In addition, KPT-185 induced these NSCLC cells to arrest at G1 phase of the cell cycle and caused apoptosis in a dose-dependent manner. KPT-185 treatment also reduced CRM1 protein levels in six NSCLC cell lines, and the reduction could be completely abolished by the proteasome inhibitor bortezomib. KPT-185 activated caspase 3, 8, and 9, but inhibited survivin expression in NSCLC cells. In a mouse H1975 cell xenograft model, tumor growth was significantly inhibited by oral KPT-276 administration, and there was no significant mouse body weight loss or other side effects. Conclusions The current study demonstrated the anti-tumor effects of KPT-185 in NSCLC cells, including EGFR-TKI-resistant NSCLC cell lines. Further studies will assess anti-tumor activity of KPT-185 in a clinical trial for NSCLC patients.

Interleukin-23 receptor genetic variants contribute to susceptibility of multiple cancers

AIM Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple cancers. Several IL-23R single nucleotide polymorphisms (SNPs), especially rs6682925, rs10889677 and rs1884444 polymorphisms, are considered to have significant impacts on susceptibility of multiple cancers. A number of case-control studies have explored the role these genetic polymorphisms in development of carcinogenesis, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically investigate the associations between the three genetic variants and multiple cancer risk. METHODS A total of ten studies are eligible (12,211 patients and 14,650 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. RESULTS Significant associations between rs6682925 or rs10889677 polymorphism and cancer risk were found (OR=1.11, 95% CI=1.03-1.21, P=0.007; or OR=0.85, 95% CI=0.71-0.92, P=0.001). However, there was no such association between rs1884444 genotypes and cancer susceptibility (P>0.05). CONCLUSION These findings reveal that the IL-23R rs6682925 and rs10889677 genetic variants play a more important part in pathogenesis of multiple cancers.

Predictive factors for inadequate stem cell mobilization in Chinese patients with NHL and HL: 14-year experience of a single-center study

Background: Factors affecting progenitor cell mobilization in patients with non‐Hodgkins lymphoma (NHL) and Hodgkins lymphoma (HL) are incompletely understood. The aim of this retrospective study was to determine which factors are crucial for effective mobilization and collection of autologous peripheral blood stem cells (PBSC) prior to transplantation in Chinese patients. Patients and methods: A total of 239 patients with lymphoma (198 NHL and 41 HL patients) underwent PBSC collection after mobilization with granulocyte‐colony‐stimulating factor (G‐CSF) or G‐CSF plus chemotherapy priming. Results: Patient characteristics at diagnosis and transplant, including low Eastern Cooperative Oncology Group score (P = 0.013), lack of extranodal invasion (P = 0.034), previously administered radiotherapy regimens (P = 0.040), treatment with platinum prior to mobilization (P = 0.042), previous chemotherapy regimens (P = 0.001) and cycles (P < 0.001), and chemotherapy regimens (P < 0.001) were statistically significant for successful mobilization in multivariate analysis. Premobilization factors, including previous radiotherapy (P = 0.009), previous chemotherapy regimens (P = 0.043) and cycles (P = 0.039), low platelet count prior to mobilization (P = 0.042), and lower CD34+ cells in peripheral blood (PB) (P = 0.050) or bone marrow (BM) (P = 0.007) were considered possibly predictive of poor mobilization. We found the patients who had chemosensitive lymphoma had worse progress‐free survival (PFS) than the patients with initial treatment and high risks (P = 0.017). Conclusion: Our analysis showed that high amounts of chemotherapy, radiotherapy, low platelet count, chemosensitive recurrent patients, combination chemotherapy plus G‐CSF and low CD34+ cells in BM prior to mobilization could emerged as important predictive factors for mobilization failure in Chinese patients with NHL and HL. J. Clin. Apheresis, 2012.

Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity

Limited data are available to guide the choice of conditioning regimen before autologous hematopoietic stem cell transplantation (AHSCT) for patients with lymphoma.

Combined effect of histone deacetylase inhibitor suberoylanilide hydroxamic acid and anti-CD20 monoclonal antibody rituximab on mantle cell lymphoma cells apoptosis

Interactions between histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and anti-CD20 monoclonal antibody rituximab in mantle cell lymphoma have been examined both in vitro and in vivo. The combination of SAHA and rituximab synergistically induced apoptosis, concomitant with caspase activation and Bcl-2 downregulation. These events were associated with multiple perturbations in signal transduction pathways, including inactivation of cyto-protective nuclear factor (NF)-κB, Akt, extracellular signal-regulating kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) pathways, and activation of c-jun N-terminal kinase (JNK) when pretreated with the pan-caspase inhibitor. Moreover, the combination of SAHA and rituximab significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, SAHA had no apparent effect on the CD20 expression in the two MCL cell lines. Taken together, our results demonstrate the synergistic anti-MCL activity of SAHA and rituximab, and build the framework for clinical trials using SAHA-rituximab combining regimen in the treatment of MCL.

Risk of genome-wide association study-identified genetic variants for non-Hodgkin lymphoma in a Chinese population

Recent genome-wide association studies have identified 15 single nucleotide polymorphisms (SNPs) associated with non-Hodgkin lymphoma (NHL) and its subtypes. Because the incidence and subtype portion of NHL between the Chinese population and Caucasian populations are substantially different, we assessed the associations of these SNPs with NHL risk in a case-control study consisting of 792 cases and 1542 controls derived from the Chinese population. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. False-positive report probability was also assessed for significant findings. We found that the allele frequencies of the 15 SNPs in our study population significantly differed from those in Caucasian populations, with rs13397985, rs735665 and rs11083846 being extremely rare in Chinese. Only two variants (rs872071 in IRF4 and rs2647012 in HLA class II) were significantly associated with NHL risk in Chinese, with the ORs of 1.20 (95% CI, 1.05-1.38; P = 0.009) and 1.20 (95% CI, 1.03-1.39; P = 0.018) for per allele of rs872071 and rs2647012, respectively, calculated using an additive model. These results indicate a substantial different genetic background for susceptibility to NHL among the different ethnic populations.

Phase I study of chimeric anti-CD20 monoclonal antibody in Chinese patients with CD20-positive non-Hodgkin＇s lymphoma

Objective: This study was designed to determine the safety, pharmacokinetics and biologic effects of a human-mouse chimeric anti-CD20 monoclonal antibody (SCT400) in Chinese patients with CD20-positive B-cell non-Hodgkins lymphoma (CD20+ B-cell NHL). SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. Methods: Fifteen patients with CD20+ B-cell NHL received dose-escalating SCT400 infusions (250 mg/m2: n=3; 375 mg/m2: n=9; 500 mg/m2: n=3) once weekly for 4 consecutive weeks with a 24-week follow-up period. The data of all patients were collected for pharmacokinetics and pharmacodynamics analyses. Results: No dose-limiting toxicities were observed. Most drug-related adverse events were grade 1 or 2. Two patients had grade 3 or 4 neutropenia. Under premedication, the drug-related infusion reaction was mild. A rapid, profound and durable depletion of circulating B cells was observed in all dose groups without significant effects on T cell count, natural killer (NK) cell count or immunoglobulin levels. No patient developed anti-SCT400 antibodies during the course of the study. SCT400 serum half-life (T1/2), maximum concentration (Cmax) and area under the curve (AUC) generally increased between the first and fourth infusions (P<0.05). At the 375 mg/m2 dose, the T1/2 was 122.5±46.7 h vs. 197.0±75.0 h, respectively, and the Cmax was 200.6±20.2 g/mL vs. 339.1±71.0 g/mL, respectively. From 250 mg/m2 to 500 mg/m2, the Cmax and AUC increased significantly in a dose-dependent manner (P<0.05). Patients with a high tumor burden had markedly lower serum SCT400 concentrations compared with those without or with a low tumor burden. Of the 9 assessable patients, 1 achieved complete response and 2 achieved partial responses. Conclusions: SCT400 is well-tolerated and has encouraging preliminary efficacy in Chinese patients with CD20+ B-cell NHL.