Implementing Mailed Colorectal Cancer Fecal Screening Tests in Real-World Primary Care Settings: Promising Implementation Practices and Opportunities for Improvement.

Colorectal cancer (CRC) screening reduces morbidity and mortality, but screening rates in the USA remain suboptimal. The Colorectal Cancer Control Program (CRCCP) was established in 2009 to increase screening among groups disproportionately affected. The CRCCP utilizes implementation science to support health system change as a strategy to reduce disparities in CRC screening by directing resources to primary care clinics to implement evidence-based interventions (EBIs) proven to increase CRC screening. As COVID-19 continues to impede in-person healthcare visits and compel the unpredictable redirection of clinic priorities, understanding clinics' adoption and implementation of EBIs into routine care is crucial. Mailed fecal testing is an evidence-based screening approach that offers an alternative to in-person screening tests and represents a promising approach to reduce CRC screening disparities. However, little is known about how mailed fecal testing is implemented in real-world settings. In this retrospective, cross-sectional analysis, we assessed practices around mailed fecal testing implementation in 185 clinics across 62 US health systems. We sought to (1) determine whether clinics that do and do not implement mailed fecal testing differ with respect to characteristics (e.g., type, location, and proportion of uninsured patients) and (2) identify implementation practices among clinics that offer mailed fecal testing. Our findings revealed that over half (58%) of clinics implemented mailed fecal testing. These clinics were more likely to have a CRC screening policy than clinics that did not implement mailed fecal testing (p = 0.007) and to serve a larger patient population (p = 0.004), but less likely to have a large proportion of uninsured patients (p = 0.01). Clinics that implemented mailed fecal testing offered it in combination with EBIs, including patient reminders (92%), provider reminders (94%), and other activities to reduce structural barriers (95%). However, fewer clinics reported having the leadership support (58%) or funding stability (29%) to sustain mailed fecal testing. Mailed fecal testing was widely implemented alongside other EBIs in primary care clinics participating in the CRCCP, but multiple opportunities for enhancing its implementation exist. These include increasing the proportion of community health centers/federally qualified health centers offering mailed screening; increasing the proportion that provide pre-paid return mail supplies with the screening kit; increasing the proportion of clinics monitoring both screening kit distribution and return; ensuring patients with abnormal tests can obtain colonoscopy; and increasing sustainability planning and support.

Geographic Examination of COVID-19 Test Percent Positivity and Proportional Change in Cancer Screening Volume, National Breast and Cervical Cancer Early Detection Program.

INTRODUCTION: In 2020, the COVID-19 pandemic led to significant declines in cancer screening, including among women served by the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). This study examined the spatial association between state-based COVID-19 test percent positivity and proportional change in NBCCEDP screening volume. METHODS: Using the COVID-19 Diagnostic Laboratory Testing dataset, we calculated state-based monthly COVID-19 test percent positivity from July through December 2020 and categorized rates into low, medium, and high groups. We used data from 48 NBCCEDP state awardees to calculate the state-based monthly proportional change in screening volume and compared data for July-December 2020 with the previous 5-year average for those months. We categorized changes in screening volume into large decrease, medium decrease, and minimal change and created maps of the associations between variable subgroups by using bivariate mapping in QGIS. RESULTS: Bivariate relationships between COVID-19 test percent positivity and proportional change in cancer screening volume varied over time and geography. In 5 of 6 months, 4 states had high COVID-19 test percent positivity and minimal change in breast or cervical cancer screening volume; 2 states had high COVID-19 test percent positivity and minimal change in breast and cervical cancer screening volume. CONCLUSION: Some states maintained pre-COVID-19 screening volumes despite high COVID-19 test percent positivity. Follow-up research will be conducted to determine how these states differ from those with consistent decreases in screening volume and identify factors that may have contributed to differences. This information could be useful for planning to maximize NBCCEDP awardees' ability to maintain screening volume during future public health emergencies.

Evaluating Uptake of Evidence-Based Interventions in 355 Clinics Partnering With the Colorectal Cancer Control Program, 2015-2018.

PURPOSE AND OBJECTIVES: Colorectal cancer screening rates remain suboptimal in the US. The Colorectal Cancer Control Program (CRCCP) of the Centers for Disease Control and Prevention (CDC) seeks to increase screening in health system clinics through implementation of evidence-based interventions (EBIs) and supporting activities (SAs). This program provided an opportunity to assess the uptake of EBIs and SAs in 355 clinics that participated from 2015 to 2018. INTERVENTION APPROACH: The 30 funded awardees of CRCCP partnered with clinics to implement at least 2 of 4 EBIs that CDC prioritized (patient reminders, provider reminders, reducing structural barriers, provider assessment and feedback) and 4 optional strategies that CDC identified as SAs (small media, professional development and provider education, patient navigation, and community health workers). EVALUATION METHODS: Clinics completed 3 annual surveys to report uptake, implementation, and integration and perceived sustainability of the priority EBIs and SAs. RESULTS: In our sample of 355 clinics, uptake of 4 EBIs and 2 SAs significantly increased over time. By year 3, 82% of clinics implemented patient reminder systems, 88% implemented provider reminder systems, 82% implemented provider assessment and feedback, 76% implemented activities to reduce structural barriers, 51% implemented provider education, and 84% used small media. Most clinics that implemented these strategies (>90%) considered them fully integrated into the health system or clinic operations and sustainable by year 3. Fewer clinics used patient navigation (30%) and community health workers (19%), with no increase over the years of the study. IMPLICATIONS FOR PUBLIC HEALTH: Clinics participating in the CRCCP reported high uptake and perceived sustainability of EBIs that can be integrated into electronic medical record systems but limited uptake of patient navigation and community health workers, which are uniquely suited to reduce cancer disparities. Future research should determine how to promote uptake and assess cost-effectiveness of CRCCP interventions.

Weight cycling and cancer incidence in a large prospective US cohort.

Weight cycling, which consists of repeated cycles of intentional weight loss and regain, is common among individuals who try to lose weight. Some evidence suggests that weight cycling may affect biological processes that could contribute to carcinogenesis, but whether it is associated with cancer risk is unclear. Using 62,792 men and 69,520 women enrolled in the Cancer Prevention Study II Nutrition Cohort in 1992, we examined the association between weight cycling and cancer incidence. Weight cycles were defined by using baseline questions that asked the number of times ≥10 pounds (4.54 kg) was purposely lost and later regained. Multivariable-adjusted hazard ratios and 95% confidence intervals for all cancer and 15 individual cancers were estimated by using Cox proportional hazards regression. During up to 17 years of follow-up, 15,333 men and 9,984 women developed cancer. Weight cycling was not associated with overall risk of cancer in men (hazard ratio = 0.96, 95% confidence interval: 0.83, 1.11 for ≥20 cycles vs. no weight cycles) or women (hazard ratio = 0.96, 95% confidence interval: 0.86, 1.08) in models that adjusted for body mass index and other covariates. Weight cycling was also not associated with any individual cancer investigated. These results suggest that weight cycling, independent of body weight, is unlikely to influence subsequent cancer risk.

Oophorectomy and hysterectomy and cancer incidence in the Cancer Prevention Study-II Nutrition Cohort.

OBJECTIVE: To examine associations of simple hysterectomy and hysterectomy with bilateral salpingo-oophorectomy (BSO), relative to no surgery, with total and site-specific cancer risk in the Cancer Prevention Study-II Nutrition Cohort. METHODS: We examined associations of hysterectomy with BSO and simple hysterectomy with total and site-specific cancer risk in 66,802 postmenopausal women from the Cancer Prevention Study-II Nutrition Cohort. RESULTS: During a median follow-up of 13.9 years, 8,621 cancers were diagnosed. Hysterectomy with BSO performed at any age (1,892 cases), compared with no hysterectomy (n=5,586 cases), is associated with a 10% reduction in all cancers (relative risk [RR] 0.90, 95% confidence interval [CI] 0.85-0.96). This inverse association does not hold if the surgery occurred at ages 55 years or older (583 cases; RR 1.02, 95% CI 0.94-1.12). Hysterectomy with BSO (715 cases) was associated with a 20% reduction in breast cancer performed at any age (RR 0.80, 95% CI 0.73-0.88). Hysterectomy without BSO was associated with a deceased cancer risk only if performed at age 45 years or younger (541 cases; RR 0.88, 95% CI 0.80-0.97) and overall was associated with a decreased risk of breast cancer (419 cases; RR 0.86, 95% CI 0.76-0.96). CONCLUSION: In a large prospective study, hysterectomy with BSO before age 55 years, relative to no surgery, is associated with a lower risk of total cancer. This information, particularly the lower risk in women younger than 45 years, should be considered in counseling women about ovarian management at the time of surgery. LEVEL OF EVIDENCE: II.

No association of plasma levels of adiponectin and c-peptide with risk of aggressive prostate cancer in the Cancer Prevention Study II Nutrition Cohort.

BACKGROUND: Obesity is associated with a higher risk of aggressive prostate cancer and alters circulating levels of insulin and adiponectin, two hormones that influence biologic processes implicated in carcinogenesis. Results of some studies showed associations of circulating levels of adiponectin, insulin, and c-peptide (a marker of insulin secretion) with aggressive prostate cancer, but the size of these studies was limited. METHODS: A nested case-control study of 272 aggressive prostate cancer cases [Gleason score ≥ 7 (4+3) or T3-T4] and 272 age- and race-matched controls from the Cancer Prevention Study II Nutrition Cohort was conducted to determine the associations of prediagnostic plasma levels of c-peptide and adiponectin with risk of aggressive prostate cancer. RESULTS: Neither circulating adiponectin nor c-peptide was associated with risk of aggressive prostate cancer. In analyses of the highest-risk aggressive prostate cancer (Gleason score ≥ 8 or T3-T4), the highest quartile of c-peptide, compared with the lowest, was associated with an OR of 1.41 [95% confidence interval (CI), 0.72-2.78]. CONCLUSIONS: Our findings provide no support for the hypothesis that adiponectin is associated with risk of aggressive prostate cancer but a possible association of high levels of c-peptide with particularly high-risk prostate cancer cannot be ruled out. IMPACT: These results indicate that changes in circulating levels of adiponectin and c-peptide do not play an important role in risk of aggressive prostate cancer.

Body weight in early adulthood, adult weight gain, and risk of endometrial cancer in women not using postmenopausal hormones.

PURPOSE: High body mass index (BMI) measured in middle age or later is an established risk factor for endometrial cancer. However, whether BMI measured in early adulthood and adult weight change are associated with endometrial cancer risk is less clear, particularly among nonusers of postmenopausal hormones (PMH). METHODS: These associations were investigated among women in the Cancer Prevention Study II Nutrition Cohort. Women taking PMH (n = 11,624, 12 % of all women) were excluded, and the analysis was limited to 33,057 postmenopausal women who did not take PMH. Between enrollment in 1992/1993 and 30 June 2009, 447 women were diagnosed with endometrial cancer. Cox proportional hazards regression was used to calculate hazard rate ratios (RR) and corresponding 95 % confidence intervals (CI) for the association of BMI at age 18, calculated from recalled weight, and weight change between age 18 and 1992, with endometrial cancer incidence. RESULTS: BMI at age 18 was associated with higher risk of endometrial cancer in multivariable models adjusted for other risk factors (RR 1.29, 95 % CI 1.12-1.49 per 5 BMI units). Similarly, adult weight change was associated with higher risk of endometrial cancer (RR 1.81, 95 % CI 1.66-1.98 per 5 BMI unit change) in multivariable models adjusted for other risk factors. CONCLUSIONS: High BMI at age 18 and greater adult weight gain were strongly associated with risk of endometrial cancer. These results underscore the importance of both avoiding overweight/obesity in young adulthood and preventing weight gain thereafter to minimize risk of this cancer.

Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Obesity-related markers and breast cancer in CPS-II Nutrition Cohort.

Low circulating levels of adiponectin and high levels of insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP), and C-peptide have been shown to be related to postmenopausal breast cancer risk, and to partially mediate the obesity-postmenopausal breast cancer association; however, data from prospective studies, especially those limited to non-users of postmenopausal hormones, are sparse. To further evaluate these associations, we measured these markers in a case-control study nested in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort. Plasma samples from 302 postmenopausal breast cancer cases and matched controls were analyzed. None of the women were taking postmenopausal hormones at blood draw. Multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Low levels of total adiponectin and high levels of total IGF-1 and CRP were associated with increased breast cancer risk, but associations were not statistically significant. The association with C-peptide was statistically significant (T3 vs. T1: OR=1.63, 95% CI 1.08-2.45; p-value for linear trend=0.001), but was slightly attenuated after further adjustment for BMI (T3 vs. T1: OR=1.51, 95% CI 0.99-2.31; p-value for linear trend=0.004). The association between BMI and breast cancer risk was attenuated toward the null after controlling for C-peptide (from OR=1.43 to OR=1.25 for BMI ≥30 kg/m(2) compared to <25 kg/m>(2)). The elevated risk of postmenopausal breast cancer associated with higher circulating levels of C-peptide is consistent with a role of hyperinsulinemia in breast carcinogenesis, and might account for some of the higher risk associated with obesity.

Active smoking and breast cancer risk: original cohort data and meta-analysis.

BACKGROUND: The relationship between active cigarette smoking and breast cancer risk remains controversial because of unresolved issues of confounding and dose response. METHODS: To investigate these issues further, we analyzed data from 73 388 women in the American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort. Analyses were based on 3721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from multivariable-adjusted Cox proportional hazard regression models. P values were two-sided. We also conducted meta-analyses of our results with those published from 14 other cohort studies. RESULTS: In CPS-II, incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR =1.13, 95% CI = 1.06 to 1.21) than in never smokers. Women who initiated smoking before menarche (HR = 1.61, 95% CI = 1.10 to 2.34) or after menarche but 11 or more years before first birth (HR = 1.45, 95% CI = 1.21 to 1.74) had higher risk (P trend = .03). No relationships were observed with other smoking parameters. Alcohol consumption did not confound associations with smoking status, although neither current nor former smoking were associated with risk among never drinkers (P interaction = .11). In meta-analyses, current (HR = 1.12, 95% CI = 1.08 to 1.16) and former smoking (HR = 1.09, 95% CI = 1.04 to 1.15) were weakly associated with risk; a stronger association (HR = 1.21, 95% CI = 1.14 to 1.28) was observed in women who initiated smoking before first birth. CONCLUSIONS: These results support the hypothesis that active smoking is associated with increased breast cancer risk for women who initiate smoking before first birth and suggest that smoking might play a role in breast cancer initiation.

Tubal sterilization and breast cancer incidence: results from the cancer prevention study II nutrition cohort and meta-analysis.

Tubal sterilization is a common form of contraception in the United States and is hypothesized to be associated with a lower risk of breast cancer. However, prior observational studies have reported inconsistent results. We investigated the association between tubal sterilization and breast cancer risk among 77,249 postmenopausal, cancer-free women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort, enrolled in 21 states in the United States during 1992-1993. During 15 years of follow-up through June 30, 2007, 4,084 invasive breast cancer cases were diagnosed. Multivariable Cox proportional hazard regression was used to estimate hazard ratios and 95% confidence intervals. A meta-analysis including the CPS-II Nutrition Cohort results with other published results from 4 case-control studies and 3 prospective studies was conducted to provide a summary estimate for the association between tubal sterilization and breast cancer risk. In the CPS-II Nutrition Cohort, tubal sterilization was not associated with breast cancer incidence (multivariable-adjusted hazard ratio = 1.08, 95% confidence interval: 0.97, 1.20). Associations stratified by year of tubal sterilization, age, and time since surgery were also null. The meta-analysis also found no association between tubal sterilization and breast cancer risk (odds ratio = 0.97, 95% confidence interval: 0.84, 1.09). Tubal sterilization does not appear to be associated with breast cancer risk.

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Weight cycling and risk of endometrial cancer.

BACKGROUND: Obesity, as measured by body mass index (BMI), is an established risk factor for endometrial cancer in postmenopausal women. Weight cycling, which consists of repeated cycles of weight loss followed by regain, occurs frequently in overweight and obese women. It is unclear whether weight cycling is associated with risk of endometrial cancer independent of BMI. METHODS: This analysis included 38,148 postmenopausal women enrolled in the Cancer Prevention Study II Nutrition Cohort, of whom 559 were diagnosed with endometrial cancer between enrollment in 1992 and June 30, 2007. Number of lifetime weight cycles was determined from questions on the baseline questionnaire asking how many times 10 or more pounds were intentionally lost and later regained. Multivariable-adjusted hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. RESULTS: Weight cycling was positively associated with endometrial cancer incidence (RR, 2.13; 95% CI, 1.63-2.78 for 10+ weight cycles vs. no weight cycles; P(trend) < 0.0001). However, after adjustment for BMI in 1992, this association was null (RR, 1.05; 95% CI, 0.77-1.42; P(trend) = 0.82). Weight cycling was not associated with endometrial cancer in analyses stratified by BMI or by weight change after adjustment for BMI. CONCLUSIONS: After adjustment for BMI, weight cycling was not associated with the risk of endometrial cancer. IMPACT: These findings suggest that weight loss with subsequent regain is unlikely to increase risk of endometrial cancer. Therefore, weight loss for better health should be encouraged.

Weight cycling and mortality in a large prospective US study.

Weight cycling has been associated with an increased risk of death in some studies, but few studies differentiated weight cycling initiated by intentional weight loss from that initiated by illness. The association of weight cycling with death was examined among 55,983 men and 66,655 women in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2008. A weight cycle was defined as an intentional loss of 10 or more pounds (≥4.5 kg) followed by regain of that weight, and the lifetime number of weight cycles was reported on a questionnaire administered at enrollment in 1992. A total of 15,138 men and 10,087 women died during follow-up, which ended in 2008. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression models. When the models were adjusted for age only, weight cycling was positively associated with mortality (P for trend < 0.0001). However, after adjustment for body mass index and other risk factors, low numbers of weight cycles (1-4 cycles) were associated with slightly lower mortality rates (hazard ratio (HR) = 0.93, 95% confidence interval (CI): 0.89, 0.97 in men and HR = 0.93, 95% CI: 0.89, 0.98 in women), whereas high numbers of weight cycles (≥20 cycles) were not associated with mortality (HR = 1.03, 95% CI: 0.89, 1.19 in men and HR = 0.99, 95% CI: 0.88, 1.12 in women). These results do not support an increased risk of mortality associated with weight cycling.

Prospective studies of body mass index with head and neck cancer incidence and mortality.

BACKGROUND: Results of a pooled analysis of case-control studies show a higher risk of head and neck cancer (HNC) associated with a low body mass index (BMI) and a lower risk associated with being overweight or obese compared with being normal weight. However, these results are prone to bias due to residual confounding by smoking, a strong risk factor, and possible weight loss prior to diagnosis. Using prospectively collected data from the Cancer Prevention Study-II cohort and the Nutrition cohort, we examined the association of BMI with HNC mortality and incidence, overall and by smoking status. METHODS: Mortality analyses included 1,383 cases among 1,059,153 participants; incidence analyses included 340 cases among 150,262 participants. Multivariable Cox proportional hazard models were used to estimate HRs and 95% confidence intervals (CI) for the association of BMI with HNC incidence and mortality. RESULTS: Overall, compared with the category of BMI 22.5-24.9 kg/m(2), the categories of BMI 25.0-29.9 kg/m(2) and ≥ 30.0 kg/m(2) were associated with a lower risk of HNC mortality but not incidence. In never smokers, there were no associations of BMI with HNC incidence or mortality. In smokers, BMI < 22.5 kg/m(2) was associated with a higher risk of HNC mortality (HR = 1.42, 95% CI, 1.20-1.67). CONCLUSIONS: In this prospective cohort, there was no association between BMI and HNC incidence, although BMI was inversely associated with HNC mortality in smokers. IMPACT: These suggest that there is no etiologic relationship between BMI and HNC.

High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer.

BACKGROUND & AIMS: Folate intake has been inversely associated with colorectal cancer risk in several prospective epidemiologic studies. However, no study fully assessed the influence of the high levels of folate that are frequently consumed in the United States as a result of mandatory folate fortification, which was fully implemented in 1998, and the recent increase in use of folate-containing supplements. There is evidence that consumption of high levels of folic acid, the form of folate used for fortification and in supplements, has different effects on biochemical pathways than natural folates and might promote carcinogenesis. METHODS: We investigated the association between folate intake and colorectal cancer among 43,512 men and 56,011 women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort; 1023 were diagnosed with colorectal cancer between 1999 and 2007, a period entirely after folate fortification began. Cox proportional hazards regression was used to calculate multivariate hazards ratios (RR) and 95% confidence interval (CI). RESULTS: Intake of high levels of natural folate (RRQ5vsQ1=0.86; 95% CI: 0.70-1.06; P trend=.12) or folic acid (RRQ5vsQ1=0.84; 95% CI: 0.68-1.03; P trend=.06) were not significantly associated with risk of colorectal cancer. Total folate intake was significantly associated with lower risk (RRQ5vsQ1=0.81; 95% CI: 0.66-0.99; P trend=.047). CONCLUSIONS: Intake of high levels of total folate reduces risk of colorectal cancer; there is no evidence that dietary fortification or supplementation with this vitamin increases colorectal cancer risk.

Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

Folate and other one-carbon metabolism-related nutrients and risk of postmenopausal breast cancer in the Cancer Prevention Study II Nutrition Cohort.

BACKGROUND: Epidemiologic studies of the association of folate intake with breast cancer risk have been inconclusive, and few have investigated how related nutrients modify this association. OBJECTIVE: We investigated the association of dietary (food folate plus folic acid from fortification) and total folate (food folate, folic acid from fortification, and folic acid from supplements), vitamin B-6, vitamin B-12, methionine, and alcohol intakes with postmenopausal breast cancer among women in the Cancer Prevention Study II Nutrition Cohort. The modification of the folate associations by the other nutrients was also investigated. DESIGN: This prospective cohort study included 70,656 postmenopausal women for whom dietary information was collected in 1992. Of these, 3898 developed breast cancer between enrollment in 1992 and June 2005. Cox proportional hazards modeling was used to calculate multivariate-adjusted hazard rate ratios and 95% CIs. RESULTS: Compared with the lowest quintile, the highest quintile of dietary folate intake was associated with a higher risk of breast cancer (rate ratio: 1.12; 95% CI: 1.01, 1.24). However, the test for trend was not significant (P for trend = 0.15). No association was found for total folate, vitamin B-6, or vitamin B-12, but methionine was inversely associated with breast cancer risk (P for trend = 0.04). The association of dietary folate with breast cancer was not modified by other nutrients or alcohol. CONCLUSIONS: This study suggests that dietary folate intake may be positively associated with postmenopausal breast cancer. However, no dose-response relation was observed. The extent to which increased supplement use and folate fortification contributes to breast cancer risk warrants further research.

HNF1B and JAZF1 genes, diabetes, and prostate cancer risk.

BACKGROUND: Epidemiologic studies have shown that men with type II diabetes have a lower risk of prostate cancer than non-diabetic men. Recently, common variants in two genes, HNF1B and JAZF1, were found to be associated with both of these diseases. METHODS: We examined whether the relationship between HNF1B and JAZF1 variants and decreased prostate cancer risk may potentially be mediated through diabetes in two large prospective studies, the Cancer Prevention Study II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. RESULTS: Three HNF1B SNPS, rs11649743, rs4430796, and rs7501939, were associated with decreased risk of prostate cancer and were also associated, with marginal statistical significance, with increased risk of diabetes. The JAZF1 SNPs rs6968704 and rs10486567 were associated with decreased risk of prostate cancer but were not associated with diabetes. All five SNP-prostate cancer relationships did not substantially differ when the analyses were stratified by diabetic status or when diabetic status was controlled for in the model. Furthermore, the association of diabetes with prostate cancer was not altered when the SNPs were included in the logistic model. CONCLUSIONS: These findings indicate that the HNF1B variants are directly associated with both diabetes and prostate cancer, that diabetes does not mediate these gene variant-prostate cancer relationships, and the relationship between these diseases is not mediated through these gene variants.

No association of single nucleotide polymorphisms in one-carbon metabolism genes with prostate cancer risk.

One-carbon metabolism mediates the interconversion of folates for the synthesis of precursors used in DNA synthesis, repair, and methylation. Inadequate folate nutrition or compromised metabolism can disrupt these processes and facilitate carcinogenesis. In this study, we investigated associations of 39 candidate single nucleotide polymorphisms (SNP) in 9 one-carbon metabolism genes with risk of prostate cancer using 1,144 cases and 1,144 controls from the Cancer Prevention Study-II Nutrition Cohort. None of these SNPs were significantly associated with prostate cancer risk, either overall or in cases with advanced prostate cancer. Thus, our findings do not support the hypothesis that common genetic variation in one-carbon metabolism genes influences prostate cancer risk.