<p>Background: The major histocompatibility complex class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer (CRC), but have not been examined in CRC development. Methods: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of pre-selected SNPs with sMICA and sMICB levels and CRC risk (236 CRCs, 8,609 participants) and of sMICA and sMICB levels with CRC risk (312 CRCs, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed. Results: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased CRC risk. Lower sMICA levels were associated with lower CRC risk in males (HR=0.68, 95%CI 0.49-0.96) but not in females (p-interaction=0.08). Conclusions: Rs2596542-T associated with lower sMICA levels was associated with decreased CRC risk. Lower sMICA levels were associated with lower CRC risk in males. Impact: These findings support an importance of immunosurveillance in CRC.</p>

Cancer survivors may have elevated atherosclerotic cardiovascular disease (ASCVD) risk. Therefore, we tested how accurately the American College of Cardiology/American Heart Association 2013 pooled cohort equations (PCEs) predict 10-year ASCVD risk in cancer survivors. To estimate the calibration and discrimination of&nbsp;the PCEs in cancer survivors compared to non-cancer participants in the Atherosclerosis Risk in Communities (ARIC) study. We evaluated the PCEs’ performance among 1244 cancer survivors and 3849 cancer-free participants who were free of ASCVD at the start of follow-up. Each cancer survivor was incidence-density matched with up to five controls by age, race, sex, and study center. Follow-up began at the first study visit at least 1&nbsp;year after the diagnosis date of the cancer survivor and finished at the ASCVD event, death, or end of follow-up. Calibration and discrimination were assessed and compared between cancer survivors and cancer-free participants. Cancer survivors had higher PCE-predicted risk, at 26.1%, compared with 23.1% for cancer-free participants. There were 110 ASCVD events in cancer survivors and 332 ASCVD events in cancer-free participants. The PCEs overestimated ASCVD risk in cancer survivors and cancer-free participants by 45.6% and 47.4%, respectively, with poor discrimination in both groups (C-statistic for cancer survivors = 0.623; for cancer-free participants, C = 0.671). The PCEs overestimated ASCVD risk in all participants. The performance of the PCEs was similar in cancer survivors and cancer-free participants. Our findings suggest that ASCVD risk prediction tools tailored to survivors of adult cancers may not be needed.

Purpose: The higher prevalence of cognitive impairment/ dementia among cancer survivors is likely multifactorial. Since both exposures to cytomegalovirus (CMV) and inflammation are common among elderly cancer survivors, we evaluated their contribution towards dementia. Methods: Data from 1387 cancer survivors and 7004 participants without cancer in the 2016 wave of the Health and Retirement Study (HRS) was used in this study. Two inflammatory biomarkers, C-reactive protein (CRP) and neutrophil–lymphocyte ratio (NLR), were used to create an inflammation score. We used survey logistic regression adjusted for survey design parameters. Results: CMV seropositivity was not associated with cognitive impairment among cancer survivors (p = 0.2). In addition, inflammation was associated with elevated odds of cognitive impairment (OR = 2.2, 95% CI [1.2, 4.2]). Cancer survivors who were both CMV seropositive and had increased inflammation had the highest odds of cognitive impairment compared to those who were CMV seronegative and had low inflammation (OR = 3.8, 95% CI [1.5, 9.4]). The stratified analysis among cancer survivors showed this association was seen only among cancer survivors in whom the cancer was diagnosed within three years of measurement of inflammation score and CMV serostatus (OR = 18.5; 95% CI [6.1, 56.1]). Conclusion: The CMV seropositivity and high inflammation was associated with higher cognitive impairment among cancer survivors. The stronger associations seen among cancer survivors diagnosed within the last three years suggest that strategies to reduce CMV activation and inflammation during or immediately after cancer treatment may be important in reducing the prevalence of cognitive impairment/ dementia among cancer survivors.

Abstracts: AACR Special Conference on Modernizing Population Sciences in the Digital Age; February 19-22, 2019; San Diego, CA The 10,000 Families Study (10KFS) is a family-based prospective cohort study, the goal of which is to collect information about health-related outcomes, including cancer, in multigeneration families. Since 2017, we have been conducting a pilot feasibility study to prepare for the implementation of 10KFS. At baseline, eligible participants answer a questionnaire about demographics and lifestyle factors and attend a health fair during which trained staff measure their blood pressure, vision, hearing, and several other characteristics, as well as collect blood, urine, and saliva. Also, during the heath fair participants receive easy-to-use kits that enable them to collect stool samples in the convenience of their home. The method for stool collection to characterize gut microbiome in this study was chosen based on a small pilot of three methods: (1) Omnigene Gut (DNA Genotek), (2) iSWAB-Microbiome Collection Kit (Mawi Corporation), and (3) a homemade kit including a BD culture swab and vial with RNAlater preservative. The second method (iSWAB) was unanimously chosen by the volunteers as most acceptable due to the ease of stool collection. The acceptability and reduction of the participant’s burden are of primary importance in this study, since an adult participant often collects stool samples from one or more of their children. The quality of DNA assessed by spectrophotometry (based on 260/280 and 260/230 ratios) was similar for the iSWAB and the Omnigene kits (gold standard), and the quantity using the iSWAB kit was sufficient to characterize gut microbiome. Thus, in our study, stool samples are collected by participants using iSWAB kits and then returned by mail within four days of collection to the central laboratory biorepository at the University of Minnesota – Advanced Research and Diagnostic Laboratory, where they are immediately frozen and stored at -80°C. To date, stool samples from 62 participants aged 0 to over 90 years have been returned (out of 139 kits that were given to participants). This collection method meets the requirements necessary for stool collection in large population studies: (1) it is fast and easy for participants to use; (2) a preservative in the tube allows stool samples to be kept without freezing for up to 8 weeks while maintaining intact and viable bacteria; (3) samples use little space during shipment and storage; and (4) the method is cost efficient. Citation Format: Anna Prizment, Deanna Gabrielson, DeAnn Lazovich, Sharon Minnerath, Heather H. Nelson, Jenny N. Poynter, Cavan Reilly, Michelle Roesler, Logan G. Spector, Bharat Thyagarajan. Collecting gut microbiome in the 10,000 Families Study [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A25.

Background: We field tested new-to-market portable, digital applications to assess hearing, pulmonary, and cognitive function to determine the feasibility of implementing these applications across a range of age groups in the pilot phase of the 10,000 Families Study (10KFS), a new Minnesota family-based prospective cohort study. Methods: We followed manufacturer recommended protocols for audiometry (SHOEBOX Inc), spirometry (NuvoAir) and the digital clock drawing test (dDCT) (Digital Cognition Technologies Inc). Results: These digital devices were low cost and readily implemented in a 2.5-hour health fair visit with minimal training (2-3 hours) of study staff. To date, we have performed these measurements on 197 eligible 10KFS participants during an in-person clinic visit. A total of 37 children (age 4-17 years), 107 adults (18-64 years) and 53 seniors (65+ years) were eligible to undergo hearing and pulmonary assessments. Children were less likely to successfully complete the hearing test (76%) compared to adults (86%) and seniors (89%). However, successful completion of the pulmonary assessment was high across all groups: 100% of children and seniors, 98% of adults. The dCDT was performed among those over the age of 40, and completion rates were 92% for those aged 41-64 and 94% for those 65+ years. Conclusions: Our field testing indicates these digital applications are easy and cost-effective to implement in epidemiological studies. Impact: Digital applications provide exciting opportunities to collect data in population studies. Issues related to data privacy, data access and reproducibility of measurements need to be addressed before deploying digital applications in epidemiological studies.

PURPOSE Cytomegalovirus (HCMV) is a common viral infection that shapes lifelong immunity. A history of infection with HCMV has been associated with many chronic diseases, including cancer. In addition, prospective cohort studies have established that HCMV is associated with all-cause mortality. However, there are limited data regarding HCMV and cancer mortality. METHODS Data were obtained from the National Health and Nutrition Examination Survey (NHANES) III study (1988-1994): subjects aged 18 to 98, who had HCMV serology results, did not report having cancer at baseline, and were eligible for mortality follow-up (n = 14,498). Mortality was ascertained until December 2011 using National Death Index (NDI) linkage. RESULTS The unadjusted risk of all-cancer mortality was higher in HCMV seropositive individuals (HR 2.74, 95% CI 2.05-3.64). This association was attenuated after adjusting for age (HR 1.39, 95% CI 1.02-1.92), and other covariates (age, sex, race/ethnicity, smoking status, BMI, education, and C-reactive protein (CRP); HR 1.21, 95% CI 0.91-1.81). There was a statistically significant interaction between HCMV and sex (p = 0.01): HCMV seropositivity was associated with increased cancer mortality in men (HR 1.65, 95% CI 0.99-2.73) but not in women (HR 0.95, 95% CI 0.59-1.54). CONCLUSION(S) Consistent with prior reports, HCMV seropositivity may be associated with an increased risk of cancer-related mortality but the association is partially driven by socioeconomic status and other risk factors. Future research is needed to determine whether HCMV is a risk factor for cancer, as well as identify the specific cancer types where HCMV increases mortality.

Background: Aspirin is associated with decreased risk of colorectal cancer (CRC), potentially by modulating the gut microbiome. Aims: To evaluate the effect of aspirin on the gut microbiome in a double-blinded, randomised placebo-controlled pilot trial. Methods: Healthy volunteers aged 50-75 received a standard dose of aspirin (325 mg, N = 30) or placebo (N = 20) once daily for 6 weeks and provided stool samples every 3 weeks for 12 weeks. Serial measurements of gut microbial community composition and bacterial abundance were derived from 16S rRNA sequences. Linear discriminant analysis of effect size (LEfSe) was tested for between-arm differences in bacterial abundance. Mixed-effect regression with binomial distribution estimated the effect of aspirin use on changes in the relative abundance of individual bacterial taxa via an interaction term (treatment × time). Results: Over the study period, there were differences in microbial composition in the aspirin vs placebo arm. After treatment, four taxa were differentially abundant across arms: Prevotella, Veillonella, Clostridium XlVa and Clostridium XVIII clusters. Of pre-specified bacteria associated with CRC (n = 8) or aspirin intake (n = 4) in published studies, interactions were significant for four taxa, suggesting relative increases in Akkermansia, Prevotella and Ruminococcaceae and relative decreases in Parabacteroides, Bacteroides and Dorea in the aspirin vs placebo arm. Conclusion: Compared to placebo, aspirin intake influenced several microbial taxa (Ruminococcaceae, Clostridium XlVa, Parabacteroides and Dorea) in a direction consistent with a priori hypothesis based on their association with CRC. This suggests that aspirin may influence CRC development through an effect on the gut microbiome. The findings need replication in a larger trial.

Purpose: Previous studies have reported that taller people have an increased risk of colorectal cancer (CRC). We examined the association of two height components—leg length and sitting height—with CRC risk in 14,532 individuals aged 45–64 years in the Atherosclerosis Risk in Communities study. Methods: Anthropometrics were measured at baseline (1987–1989). Incident CRC cases (n = 382) were ascertained from 1987 to 2012. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios for CRC and colon cancer across quintiles of sex-specific leg length and sitting height. Results: The highest (versus the lowest) quintile of leg length was associated with a 36% greater CRC risk (p-trend = 0.04), and 51% greater colon cancer risk (p-trend = 0.01). For the top four quintiles combined, risk was increased by 34% for CRC and by 45% for colon cancer versus the lowest quintile. Total height and sitting height were not significantly associated with CRC or colon cancer risk. A small number of cases (n = 57) limited our ability to conduct subgroup analyses for rectal cancer. Conclusions: A positive association of leg length with CRC and colon cancer risk suggests that biological mechanisms leading to greater leg length during puberty may explain the association between taller height and CRC.

Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.Methods: Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer-specific death associated with each composite score.Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38-0.75; Ptrend = 0.0004) and 0.66 (0.51-0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18-0.51; Ptrend < 0.0001) and 0.41 (0.27-0.63; Ptrend < 0.0001) for colorectal cancer-related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer-related death.Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622-31. ©2016 AACR.

The role of the innate immune response in colorectal cancer is understudied. We examined the survival of colorectal cancer patients in relation to eosinophils, innate immune cells, infiltrating the tumor. Tissue microarrays were constructed from paraffin-embedded tumor tissues collected between 1986 and 2002 from 441 post-menopausal women diagnosed with colorectal cancer in the Iowa Women's Health Study. Tissue microarrays were stained with an eosinophil peroxidase antibody. Eosinophils in epithelial and stromal tissues within the tumor (called epithelial and stromal eosinophils, hereafter) were counted and scored into three and four categories, respectively. In addition, the degree of eosinophil degranulation (across epithelial and stromal tissues combined) was quantified and similarly categorized. We used Cox regression to estimate the hazard ratios and 95% confidence interval for all-cause and colorectal cancer death during 5-year follow-up after diagnosis and during follow-up through 2011 ('total follow-up'). The hazard ratios associated with eosinophil scores were adjusted for age of diagnosis, SEER (Surveillance, Epidemiology, and End Results) stage, tumor grade, body mass, and smoking history. High tumor stromal eosinophil score was inversely correlated with age and stage, and was associated with a decreased risk for all-cause and colorectal cancer death: hazard ratios (95% confidence intervals) were 0.61 (0.36-1.02; P-trend=0.02) and 0.48 (0.24-0.93; P-trend=0.01), respectively, during the 5-year follow-up for the highest vs lowest category. The inverse associations also existed for total follow-up for all-cause and colorectal cancer death for the highest vs lowest stromal eosinophil score: hazard ratios (95% confidence intervals) were 0.72 (0.48-1.08; P-trend=0.04) and 0.61 (0.34-1.12; P-trend=0.04), respectively. Further adjustment for treatment, comorbidities, additional lifestyle factors, tumor location, or molecular markers did not markedly change the associations, while adjustment for cytotoxic T cells slightly attenuated all associations. The infiltration of tumors with eosinophils, especially in stromal tissue, may be an important prognostic factor in colorectal cancer.

BACKGROUND Serum β-2 microglobulin (B2M), a major histocompatibility complex class I molecule that is a biomarker of kidney filtration and increased cell turnover, is elevated at the time of diagnosis in hematological and some solid cancers. However, serum B2M was not examined prospectively as a marker for cancer risk. We hypothesized that in a population without a prior cancer diagnosis, serum B2M is associated with risk of cancer (n = 2,436), including colorectal (n = 255), lung (n = 298), breast (n = 424), and prostate (n = 524) cancers, and hematological (n = 176) malignancies. METHODS The analytical cohort (n = 12,300) was followed for incident cancers from 1990 through 2006. B2M (range, 0.9-57.8 mg/L) was measured in stored serum collected in 1990-1992. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals for cancer incidence and mortality in relation to quartiles of B2M. RESULTS Adjusting for age, sex, race, center, education, body mass index, smoking, aspirin, and hormone therapy (in women) and comparing highest to lowest B2M quartiles, HRs were 1.25 (1.06-1.47; Ptrend = 0.002) for total cancer risk and 2.21 (1.32-3.70; Ptrend=0.001) for colorectal cancer risk, with similar HRs for colon and rectal cancers. These associations remained after adjustment for an inflammatory biomarker, C-reactive protein, and after excluding the first three years of follow-up. Significant associations were also observed for mortality from total, lung, and hematological cancers. CONCLUSIONS These findings provide the first evidence that higher serum B2M is associated with increased colorectal cancer risk. IMPACT This study supports B2M as a potential biomarker for colorectal cancer risk. Cancer Epidemiol Biomarkers Prev; 25(4); 657-64. ©2016 AACR.