We are investigating the role of inflammation in the risk and molecular pathogenesis of colon and lung cancer. Colon Cancer: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer than the general population. Genome-wide association studies have identified and replicated several loci associated with risk of IBD however it is currently unknown whether these loci are also associated with colon cancer risk. We found that rs744166 in STAT3 was associated with colon cancer risk in two studies;however, the direction of the observation was reversed in TP53 mutant tumors possibly due to a nullification of the effect by mutant p53. In conclusion, these data suggest that the STAT3 locus is associated with both IBD and cancer. Understanding the function of this variant, or the identification and function of one in linkage with it, could possibly explain the role of this gene in autoimmunity and cancer. Furthermore, an analysis of this locus, specifically in the population with IBD, could help to resolve the relationship between this SNP and cancer (Ryan BM, et al., Cancer Epidemiol., In Press, 2014). We have discovered that germline variation in NCF4, and innate immunity gene, is associated with an increased risk of colorectal cancer. Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer;however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer [odds ratios (OR)=2.43;95% confidence intervals (CI): 1.73-3.39;P0.0001]. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer (Ryan et al., Int.J.Cancer, 2014). We are investigating the hypothesis that innate immunity gene polymorphisms and the risk of colorectal neoplasia. Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the PLCO Screening Trial. A total of 935 tag SNPs in 98 genes were evaluated. Sixteen SNPs were associated with colorectal neoplasia risk at P0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (OR(per T allele)=0.68;95% CI: 0.57-0.83, P=7.7 x 10(-5);adjusted P=0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was much stronger for colorectal cancer than for adenoma, but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status. Among never and former smokers, it was inversely associated with colorectal neoplasia, but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia (Chang et al., Carcinogenesis, 2014). The association between oral contraceptive (OC) use, hormone replacement therapy (HRT) and lung cancer risk in women is still debated. We performed a pooled analysis of six case-control studies contributing to the International Lung Cancer Consortium. Potential associations were investigated with multivariable unconditional logistic regression and meta-analytic models. Multinomial logistic regressions were performed to investigate lung cancer risk across histologic types. A reduced lung cancer risk was found for OC and HRT ever users. Both oestrogen only and oestrogen+progestin HRT were associated with decreased risk. No dose-response relationship was observed with years of OC/HRT use. The greatest risk reduction was seen for squamous cell carcinoma in OC users and in both adenocarcinoma and small cell carcinoma in HRT users (Pesatori et al., Br.J.Cancer, 2013). Our findings suggest that exogenous hormones can play a protective role in lung cancer etiology. Lung Cancer: The advent of LDCT for lung cancer screening will likely lead to an increase in the detection of stage I lung cancer. Presently, these patients are primarily treated with surgery alone and approximately 30% will develop recurrence and die. Biomarkers that can identify patients for whom adjuvant chemotherapy would be a benefit could significantly reduce both patient morbidity and mortality. Herein, we sought to build a prognostic inflammatory-based classifier for stage I lung cancer. We performed a retrospective analysis of 548 European American lung cancer cases prospectively enrolled in the PLCO study. CRP, IL-6, IL-8, TNFalpha and IL-1beta were measured using an ultrasensitive electrochemiluminescence immunoassay in serum samples collected at the time of study entry. IL-6 and IL-8 were each associated with significantly shorter survival. Moreover, a combined classifier of IL-6 and IL-8 were significantly associated with poor outcome in stage I lung cancer patients and in stage I patients with greater than or equal to 30 pack-years of smoking. In conclusion, These results further support the association between inflammatory markers and lung cancer outcome and suggest that a combined serum IL-6/IL-8 classifier could be a useful tool for guiding therapeutic decisions in stage I lung cancer patients (Ryan BM, et al., J Thorac.Oncology, In Press, 2014). We are also collaborating with David Schrump to investigate telomerase variants in esophageal carcinoma. Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas. Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous);A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-beta-catenin complex, markedly depleted beta-catenin, and down-regulated canonical Wnt signaling in cancer cells;these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells (Zhang Y, et al., PLoS ONE, 9:e101010, 2014).
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