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1.  Systemic Cytokine Levels and Subsequent Risk of Gastric Cancer in Chinese Women 
Cancer Science  2011;102(10):1911-1915.
Background
The control of the host cytokine network is known to influence gastric cancer susceptibility; the specific inflammatory responses in gastric carcinogenesis remain unclear.
Methods
We prospectively examined the relationships of plasma levels of interleukin (IL)-1β, IL6, IL8 and tumor necrosis factor (TNF)-α to gastric cancer risk within The Shanghai Women’s Health Study. Two controls were matched to each case by age, menopausal status and sample collection parameters. The associations of gastric cancer risk and tertile of cytokine levels were estimated by odds ratios (ORs) and 95 per cent confidence intervals (% CIs) from conditional logistic regression, adjusting for education.
Results
During a median follow-up period of 4 years (range: 0.1–8), 141 women developed gastric cancer and were matched to 282 cancer-free study participants. Elevated levels of plasma IL6 were associated with an increased risk of gastric cancer (Ρtrend=0.04). Risk increased 70% (OR=1.7, 95% CI, 1.0, 3.0) for women in the highest tertile (> 4 pg/mL) of IL-6 compared to those in the lowest tertile (<1.8 pg/mL). The association with IL6 was stronger after 4 years of follow-up (OR=2.6, 95% CI, 1.0, 6.7 for highest vs. lowest tertile) compared to an OR of 1.4 (0.7, 2.9) for those diagnosed within 1–4 years of follow-up. No associations were observed with the other examined pro-inflammatory cytokines, IL1β, IL8 and TNFα.
Conclusions
Systemic plasma IL6 levels may inform long-term gastric cancer risk. This novel finding awaits confirmation in future studies with sequential plasma collection.
doi:10.1111/j.1349-7006.2011.02033.x
PMCID: PMC3349461  PMID: 21740481
cytokine; gastric cancer; prediagnostic
2.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
doi:10.1097/QAD.0b013e328332d5b1
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
3.  Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk 
While germline mutations in the adenomatous polyposis coli (APC) gene cause the hereditary colon cancer syndrome (Familial Adenomatous Polyposis), the role of common germline APC variants in sporadic adenomatous polyposis remains unclear. We studied the association of eight APC SNPs, possibly associated with functional consequences, and previously identified gene-environment (dietary fat intake and hormone replacement therapy (HRT) use) interactions, in relation to advanced colorectal adenoma in 758 cases and 767 sex- and race-matched controls, randomly selected from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma of the distal colon; controls, a negative sigmoidoscopy. We did not observe an association between genotypes for any of the eight APC SNPs and advanced distal adenoma risk (Pglobal gene-based =0.92). Frequencies of identified common haplotypes did not differ between cases and controls (Pglobal haplotype test =0.97). However, the risk for advanced distal adenoma was three-fold higher for one rare haplotype (cases:2.7%;controls:1.6%) (odds ratio = 3.27; 95 percent confidence interval =1.08–9.88). The genetic association between D1822V and advanced distal adenoma was confined to persons consuming a high-fat diet (Pinteraction=0.03). Similar interactions were not observed with HRT use. In our large, nested case-control study of advanced distal adenoma and clinically-verified adenoma-free controls, we observed no association between specific APC SNPs and advanced adenoma. Fat intake modified the APC D1822V-adenoma association, but further studies are warranted.
doi:10.1016/j.ejca.2010.04.020
PMCID: PMC2924917  PMID: 20510605
adenomatous polyposis coli; SNPs; advanced adenoma
4.  C-Reactive Protein and Risk of Lung Cancer 
Journal of Clinical Oncology  2010;28(16):2719-2726.
Purpose
Chronic inflammation could play a role in lung carcinogenesis, underscoring the potential for lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP, an inflammation biomarker) and CRP single nucleotide polymorphisms (SNPs) with prospective lung cancer risk.
Patients and Methods
We conducted a nested case-control study of 592 lung cancer patients and 670 controls with available prediagnostic serum and 378 patients and 447 controls with DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 77,464). Controls were matched to patients on age, sex, entry year, follow-up time, and smoking. We measured CRP levels in baseline serum samples and genotyped five common CRP SNPs.
Results
Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR], 1.98; 95% CI, 1.35 to 2.89; P-trend < .001 for fourth quartile [Q4, ≥ 5.6 mg/L] v Q1 [< 1.0 mg/L]). The CRP association did not differ significantly by histology, follow-up time, or smoking status, but was most apparent for squamous cell carcinomas (OR, 2.92; 95% CI, 1.30 to 6.54), 2 to 5 years before lung cancer diagnosis (OR, 2.33; 95% CI, 1.24 to 4.39), and among former smokers (OR, 2.48; 95% CI, 1.53 to 4.03) and current smokers (OR, 1.90; 95% CI, 1.06 to 3.41). Although CRP SNPs and haplotypes were associated with CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels among former smokers (Q4: 2.55%; 95% CI, 1.98% to 3.27% v Q1: 1.39%; 95% CI, 1.07% to 1.81%) and current smokers (Q4: 7.37%; 95% CI, 5.81% to 9.33% v Q1: 4.03%; 95% CI, 3.01% to 5.40%).
Conclusion
Elevated CRP levels are associated with subsequently increased lung cancer risk, suggesting an etiologic role for chronic pulmonary inflammation in lung carcinogenesis.
doi:10.1200/JCO.2009.27.0454
PMCID: PMC2881850  PMID: 20421535
5.  The Major Histocompatibility Complex Conserved Extended Haplotype 8.1 in AIDS-related Non-Hodgkin’s Lymphoma 
Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA +252G, rs909253 A>G) and tumor necrosis factor (TNF −308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin’s lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with HLA-B* 08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in Caucasians most likely represents a true etiologic factor remains uncertain. We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL. SNPs in LTA and TNF and in six other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study. The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A) and rs6467 (C)) were associated with AIDS-NHL (OR=2.7, 95% CI: 1.5–4.8, p=0.0009 and OR=3.2, 95% CI: 1.6–6.6 p=0.0008; respectively). These two haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. The CEH 8.1-specific haplotype association of MHC class III variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both.
doi:10.1097/QAI.0b013e3181b017d5
PMCID: PMC3015185  PMID: 19654554
Human Leukocyte Antigen; HIV; CD4; Multicenter AIDS Cohort NHL Study

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