Interferons (IFNs) are proteins involved in many functions including antiviral and antimicrobial response, apoptosis, cell cycle control and mediating other cytokines. IFN gamma (IFNG) is a ...proinflammatory cytokine that modulates many immune-related genes. In this study we examine genetic variation in IFNG, IFNGR1, IFNGR2 and interferon regulatory factors (IRFs) to determine associations with colon and rectal cancer and survival after diagnosis. We include data from two population-based incident studies of colon cancer (1555 cases and 1956 controls) and rectal cancer (754 cases and 959 controls). Five tagSNPs in IFNG, IRF2 and IRF3 were associated with colon cancer and eight tagSNPs in IFNGR1, IFNGR2, IRF2, IRF4, IRF6 and IRF8 were associated with rectal cancer. IRF3 rs2304204 was associated with the strongest direct association and IRF2 3775554 with the strongest inverse association for colon cancer odds ratios (ORs) 1.43, 95% confidence interval (CI) 1.12-1.82 for recessive model and 0.52, 95% CI 0.28-0.97 for unrestricted model. For rectal cancer, IFNGR1 rs3799488 was directly associated with risk (OR 2.30, 95% CI 1.04-5.09 for recessive model), whereas IRF6 rs861020 was inversely associated with risk (OR 0.57, 95% CI 0.34-0.95). Several single-nucleotide polymorphisms interacted significant with both NF-κB1 and IL6 and with aspirin/non-steroidal anti-inflammatory drugs and cigarette smoking. Using a summary score to estimate mutational load, we observed a hazard rate ratio (HRR) close to 5.00 (95% CI 2.73-8.99) for both colon and rectal (HRR 4.83, 95% CI 2.34-10.05) cancer for those in the category having the most at-risk genotypes. These data suggest the importance of IFN-signaling pathway on colon and rectal cancer risk and survival after diagnosis.
Toll‐like receptors (TLRs) are mediators of inflammation in the gut and potentially important modulators of colon and rectal cancer risk. We use data from a population‐based study of incident colon ...cancer cases (n = 1,555) and controls (n = 1,956) and rectal cancer cases (n = 754) and controls (n = 959). We evaluate genetic variation in TLR2 (six SNPs), TLR3 (four SNPs) and TLR4 (eight SNPs) with risk of developing colon or rectal cancer and survival after diagnosis. TLR3 rs11721827 was associated with rectal cancer (odds ratio OR 1.27, 95% confidence interval CI 1.02, 1.58 for AC/CC vs. AA genotype, Wald p = 0.035; adjusted p = 0.126); TLR3 rs3775292 and TLR4 rs11536898 were associated with colon cancer (OR 0.68, 95% CI 0.49, 0.95 for GG vs. CC/CG and OR 0.50. 95% CI 0.29, 0.87 for AA vs. CA/CC, respectively; Wald p = 0.023 and 0.015; adjusted p = 0.085 and 0.101, respectively). TLR2 rs7656411 and rs3804099, respectively, interacted with nonsteroidal anti‐inflammatory drug (NSAID) use and cigarette smoking to alter risk of colon cancer (adjusted p = 0.034 and 0.077); TLR3 rs11721827 interacted with NSAID use to alter risk of colon cancer (adjusted p = 0.071). TLR3 rs3775292 interacted with dietary carbohydrates to alter colon cancer risk and with dietary carbohydrates and saturated fat to alter rectal cancer risk (adjusted p = 0.064, 0.0035 and 0.025, respectively). Multiple SNPs in TLR2 and TLR4 were associated with colon cancer survival. Although few independent associations with TLR genes were observed, we observed significant interaction of TLR2 and TLR3 with hypothesized lifestyle factors. Interaction with dietary factors remained significant for rectal cancer after adjustment for multiple comparisons.
Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration, and inflammatory and anti‐inflammatory responses by the immune system. In our study, we examined ...genetic variation in genes from various anti‐inflammatory and proinflammatory interleukins to determine association with colon and rectal cancer risk and overall survival. Data from two population‐based incident studies of colon cancer (1,555 cases and 1,956 controls) and rectal cancer (754 cases and 954 controls) were used. After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk. Only SNPs from genes within the IL‐8 pathway (IL8, CXCR1 and CXCR2) showed a significant association with both colon and rectal cancer risk. Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/non‐steroidal anti‐inflammatory drug (NSAID), cigarette smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk alleles were associated with increased hazard of death from cancer; the estimated hazard of death for colon cancer for the highest category of risk alleles was 1.74 (95% confidence interval CI 1.18–2.56) and 1.96 (95% CI 1.28–2.99) for rectal cancer. These data suggest that interleukin genes play a role in risk and overall survival for colon and rectal cancer.
What's new?
This research describes the association of genetic variation in interleukin genes with risk for colon or rectal cancer, as well as with survival from these diseases. Few of these associations were modified by lifestyle factors such as obesity, smoking, or NSAID/aspirin use, although several associations were modified by current estrogen use. As a whole, the data suggest that interleukins play a role in both risk and survival for colon and rectal cancers, and set the stage for future studies of specific mechanisms involved.
Given poor use of recall in primary care practices, we compared outsourced versus office-based recall systems.
From 2011 to 2013, we enrolled 87 individual Arkansas providers in distinct practices ...treating their own patients <24 months of age which were randomized to usual care (A), office-based (B), or outsourced (C) recall groups.
At the end of study, recall activity was 19.4%, 55.0%, and 92.6% for Groups A, B, and C, respectively (B and C vs A: P < .001). Only 68 Group B patients were identified as needing immunizations versus 826 in Group C. The majority of successful contacts were made through mobile phone (41.3%) or text message (32.6%). The total cost per practice per week was significantly lower for Group C versus Group B ($39.50 and $53.00, respectively; P = .004).
With limited electronic health record use, an outsourced recall system is more sustainable and less costly than an office-based system.
The Gail and CARE models estimate breast cancer risk for white and African‐American (AA) women, respectively. The aims of this study were to compare metropolitan and nonmetropolitan women with ...respect to predicted breast cancer risks based on known risk factors, and to determine if population density was an independent risk factor for breast cancer risk. A cross‐sectional survey was completed by 15,582 women between 35 and 85 years of age with no history of breast cancer. Metropolitan and nonmetropolitan women were compared with respect to risk factors, and breast cancer risk estimates, using general linear models adjusted for age. For both white and AA women, tisk factors used to estimate breast cancer risk included age at menarche, history of breast biopsies, and family history. For white women, age at first childbirth was an additional risk factor. In comparison to their nonmetropolitan counterparts, metropolitan white women were more likely to report having a breast biopsy, have family history of breast cancer, and delay childbirth. Among white metropolitan and nonmetropolitan women, mean estimated 5‐year risks were 1.44% and 1.32% (p < 0.001), and lifetime risks of breast cancer were 10.81% and 10.01% (p < 0.001), respectively. AA metropolitan residents were more likely than those from nonmetropolitan areas to have had a breast biopsy. Among AA metropolitan and nonmetropolitan women, mean estimated 5‐year risks were 1.16% and 1.12% (p = 0.039) and lifetime risks were 8.94%, and 8.85% (p = 0.344). Metropolitan residence was associated with higher predicted breast cancer risks for white women. Among AA women, metropolitan residence was associated with a higher predicted breast cancer risk at 5 years, but not over a lifetime. Population density was not an independent risk factor for breast cancer.
: Breast cancer continues to be among the most common cancers affecting women in the United States. Researchers investigating the area are turning their attention to novel prevention, detection, and ...treatment options. Recent molecular epidemiology research has highlighted the effects of both genetic and environmental exposures on an individual’s risk of developing breast cancer and predicted response to treatment. Cohort designs are a potentially powerful tool that researchers can utilize to investigate the genetic and environmental factors affecting breast cancer risk and treatment options. This paper describes the recruitment of a community‐based cohort of women in a southern state. The Spit for the Cure Cohort (SFCC), being developed by researchers at the University of Arkansas for Medical Sciences (Little Rock, AR), is designed to be representative of the female population of the state with oversampling of women with a history of breast cancer and women of color. To date, the SFCC includes more than 14,000 women recruited from all 75 counties of Arkansas and six neighboring states. Methods used to recruit and maintain the cohort and collect both questionnaire data and genetic material are described, as are the demographic characteristics of the cohort as it currently exists. The recruitment methods utilized for the SFCC are rapidly building a breast cancer cohort and providing a large biorepository for molecular epidemiology research.
Tumor necrosis factor-α (TNF) is a promoter of inflammation. Genes in the TNF pathway include tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNF receptor-associated factor 2 ...(TRAF2), mitogen activated protein kinase 8 (MAPK8), 14 (MAPK14), and mitogen activated protein kinase kinase kinase 7 (MAP3K7), nuclear factor of activated-T-5 (NFAT5) cells and NFAT activated protein with ITAM motif 1 ﹛NFAM1). Data from population-based studies of colon cancer (cases=1,555; controls=1,956) and rectal cancer (cases=754; controls=959) were used. We observed that MAP3K7 rs13208824 was associated with reduced colon cancer risk (OR 0.83, 95% CI 0.71, 0.98 dominant model), TNF rs1800630 was associated with an increased colon cancer risk (OR 1.19 95% CI 1.03, 1.38 for CA/AAvsCC), and TNFRSF1A rs4149570 was associated with reduced risk (OR 0.79 95% CI 0.64, 0.96 TTvsGG). For rectal cancer MAPK8 rs10508901 was associated with increased risk (OR 1.45 95% CI 1.05, 1.99 AA vs CC/CA; NFAT5 (rs12447326 and rs16959025) was associated with a 40% reduced risk for the recessive model. Aspirin/NSAID interacted with MAP3K7 (colon cancer) and with MAPK14, NFAT5, and TRAF2 (rectal cancer); smoking cigarettes interacted with NFAM1 and NFAT2 (colon cancer) and MAPK8, NFAT5, and TNFRSF1A (rectal cancer); BMI interacted with NFAM1 and NFAT5 (colon cancer) and with MAPK8 and TNFRSF1A (rectal cancer). A genotype summary score showed a threefold increased risk of dying with higher mutational load. Although few independent associations were detected, aspirin/NSAID, cigarette smoking, and BMI influenced genes in this pathway. These data suggest pathways through which TNF-signaling operates.
Purpose: The serine protease stratum corneum chymotryptic enzyme (SCCE) is overexpressed by ovarian tumor cells, but is not expressed
by normal tissues, suggesting that SCCE may be an attractive ...target for immunotherapy. In this study, we tested the hypothesis
that dendritic cells loaded with SCCE peptides will induce ovarian tumor antigen–specific CD8 + CTL responses and antigen-specific CD4 + helper T cell responses.
Experimental Design: Computer algorithms were used to identify candidate HLA-A2.1-restricted CD8 + CTL epitopes and HLA-DR-binding CD4 + helper T cell epitopes within SCCE. CD8 + CTL stimulated with peptide-loaded dendritic cells were tested against targets expressing endogenous SCCE, including HLA-A2.1-matched
ovarian tumor cells. Dendritic cells were also loaded with an extended SCCE peptide, SCCE 110-139, which encompassed a defined
CD8 + CTL epitope and multiple candidate CD4 + T helper cell epitopes.
Results: CD8 + CTL specific for SCCE 123-131 lysed autologous macrophages infected with an SCCE-expressing recombinant adenovirus, and also
lysed HLA-A2.1-matched, SCCE-expressing ovarian tumor cells. Dendritic cells loaded with SCCE 5-13 peptide stimulated an HLA-A2.1-restricted
CD8 + CTL response, but with a reduced level of lysis against ovarian tumor cells. Dendritic cells loaded with SCCE 110-139 induced
antigen-specific CD4 + T cell and CD8 + T cell responses. Although SCCE 110-139-loaded dendritic cells processed and presented the 123-131 epitope, the dominant
CD8 + CTL response was directed against alternative epitopes within SCCE 110-139.
Conclusions: The 110-139 region of SCCE incorporates multiple CD8 + CTL and CD4 + helper T cell epitopes, and represents an attractive target antigen for immunotherapy of ovarian cancer.
Abstract
The purpose of our study is to increase recruitment of rural and disparate populations within the Spit for the Cure Breast Cancer Cohort. The Spit for the Cure Breast Cancer Cohort being ...established at the University of Arkansas for Medical Sciences provides a repository of information and DNA samples to study breast cancer in Southern women. Currently, over 19,000 women from Arkansas and surrounding states have been recruited into the cohort. Demographics of the cohort closely match the demographics of the state of Arkansas, though our cohort is better educated and younger on average than the state's overall female population. One of our goals is to over-sample disparate populations in rural areas, which presents many challenges; these areas tend to have sparse populations which are located in largely agricultural areas of Arkansas. Furthermore, it has been reported in literature that a lower percentage of minority populations and rural populations participate in biorepositories and cancer research. These are the same populations that suffer from limited access to health services. The assumption is that these populations are not willing to participate in cancer research; however, we hypothesize that disparate populations would enroll in research studies if given access to research opportunities. As a novel method for reaching underrepresented populations, Spit for the Cure recruiters collaborated with a mobile mammography unit, the Mammovan, based out of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences. We compared the demographics of participants recruited through community events in Southeast Arkansas, whose residents live in the rural Delta region, to recruitment from the Mammovan in that same region. Mammovan participants from Southeast Arkansas had a lower education level compared to women in that same area recruited through community events; 53.7% of Mammovan participants had no education beyond high school, compared to 25% of community participants (p-value <0.0001). Also, a greater proportion of African American women were recruited through the Mammovan (40.3%) compared to community events (31.1%) within the southeast region (p-value 0.01). Overall, the recruitment of Mammovan participants more closely reflects the actual demographics of the population of Southeast Arkansas. Interestingly, a high proportion of the Mammovan participants (81.8%) reported having had a mammogram prior to their Mammovan experience; indicating that these marginalized groups with limited access to health care facilities, are still able to leverage available resources in order to address their health needs. In conclusion, traveling with the mobile mammography unit is a valuable resource for the Spit for the Cure Breast Cancer Cohort to recruit disparate populations, who are in fact willing to participate, in order to more accurately mirror the demographics of Arkansas women.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3715. doi:10.1158/1538-7445.AM2011-3715
PDF
