Metabolic dysregulation and cancer risk program (MeDOC): a transdisciplinary approach to Obesity-Associated cancers.

With the escalating prevalence of obesity, the association between obesity and cancer is a growing public health concern. Obesity will soon surpass tobacco smoking as the most important preventable cause of cancer. Obesity-driven mechanisms can alter cell functions to induce metabolic changes, chronic inflammation, and insulin resistance that are believed to contribute to cancer risk and development; yet the specific underlying biological mechanisms of obesity-related cancer development are largely unknown. The Metabolic Dysregulation and Obesity Cancer Risk (MeDOC) Program is a trans-NCI research program supported by the Division of Cancer Control and Population Sciences, the Division of Cancer Biology, the Division of Cancer Prevention, and the Center to Reduce Cancer Health Disparities. The overall purpose of the MeDOC Program is to advance our understanding of the underlying mechanisms that connect obesity, metabolic dysregulation, and increased obesity cancer risk, as well as identify markers that will enhance cancer risk prediction, improve screening for high-risk individuals, and identify targets for preventive and therapeutic interventions for cancer interception or treatment. This report describes the funded research projects, the Coordinating Center, and the goals of the MeDOC Program.

Opportunities for Examining Child Health Impacts of Early-Life Nutrition in the ECHO Program: Maternal and Child Dietary Intake Data from Pregnancy to Adolescence.

Background: Longitudinal measures of diet spanning pregnancy through adolescence are needed from a large, diverse sample to advance research on the effect of early-life nutrition on child health. The Environmental influences on Child Health Outcomes (ECHO) Program, which includes 69 cohorts, >33,000 pregnancies, and >31,000 children in its first 7-y cycle, provides such data, now publicly available. Objectives: This study aimed to describe dietary intake data available in the ECHO Program as of 31 August, 2022 (end of year 6 of Cycle 1) from pregnancy through adolescence, including estimated sample sizes, and to highlight the potential for future analyses of nutrition and child health. Methods: We identified and categorized ECHO Program dietary intake data, by assessment method, participant (pregnant person or child), and life stage of data collection. We calculated the number of maternal-child dyads with dietary data and the number of participants with repeated measures. We identified diet-related variables derived from raw dietary intake data and nutrient biomarkers measured from biospecimens. Results: Overall, 66 cohorts (26,941 pregnancies, 27,103 children, including 22,712 dyads) across 34 US states/territories provided dietary intake data. Dietary intake assessments included 24-h recalls (1548 pregnancies and 1457 children), food frequency questionnaires (4902 and 4117), dietary screeners (8816 and 23,626), and dietary supplement use questionnaires (24,798 and 26,513). Repeated measures were available for ∼70%, ∼30%, and ∼15% of participants with 24-h recalls, food frequency questionnaires, and dietary screeners, respectively. The available diet-related variables describe nutrient and food intake, diet patterns, and breastfeeding practices. Overall, 17% of participants with dietary intake data had measured nutrient biomarkers. Conclusions: ECHO cohorts have collected longitudinal dietary intake data spanning pregnancy through adolescence from a geographically, socioeconomically, and ethnically diverse US sample. As data collection continues in Cycle 2, these data present an opportunity to advance the field of nutrition and child health.

Cancer Epidemiology in Hispanic Populations: An Analysis of Funded Observational Research at the National Cancer Institute.

BACKGROUND: More than 62 million people self-identified as Hispanic/Latino (H/L) in the 2020 United States census. The U.S. H/L population has higher burden of certain cancers compared with their non-Hispanic White counterparts. METHODS: Key term search using the NIH Query/View/Report (QVR) system, along with Research, Condition, and Disease Categorization codes identified cancer epidemiology research grants in H/L populations funded by the NCI as a primary or secondary funder from fiscal years 2016 through 2021. Three reviewers identified eligible grants based on specified inclusion/exclusion criteria and a codebook for consistency extracting key characteristics. RESULTS: A total of 450 grants were identified through the QVR system using key words related to H/Ls; 41 cancer epidemiology grants remained after applying exclusion criteria. These grants contained specific aims focused on H/Ls (32%) or included H/Ls as part of a racial/ethnic comparison (68%). NCI was the primary funder of the majority of the grants (85%), and most of the research grants focused on cancer etiology (44%) and/or survivorship (49%). Few grants (10%) investigated environmental exposures. CONCLUSIONS: This article provides an overview of NCI-funded cancer epidemiology research in H/L populations from 2016 to 2021. Future cancer epidemiology research should reflect the changing dynamics of the U.S. demography with diverse, representative populations and well-characterized ethnicity. IMPACT: Research that carefully measures the relevant biological, environmental, behavioral, psychologic, sociocultural, and clinical risk factors will be critical to better understanding the nuanced patterns influencing cancer-related outcomes in the heterogenous H/L population.

Regional and sociodemographic differences in average BMI among US children in the ECHO program.

OBJECTIVE: The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region. METHODS: This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome. RESULTS: The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (ß = -0.12, 95% CI: -0.19 to -0.05) and West (ß = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (ß = 0.09, 95% CI: 0.05 to 0.14) and lower in the South (ß = -0.12, 95% CI: -0.16 to -0.08) and West (ß = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight. CONCLUSIONS: Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.

Understanding childhood obesity in the US: the NIH environmental influences on child health outcomes (ECHO) program.

BACKGROUND: Few resources exist for prospective, longitudinal analysis of the relationships between early life environment and later obesity in large diverse samples of children in the United States (US). In 2016, the National Institutes of Health launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate influences of environmental exposures on child health and development. We describe demographics and overweight and obesity prevalence in ECHO, and ECHO's potential as a resource for understanding how early life environmental factors affect obesity risk. METHODS: In this cross-sectional study of 70 extant US and Puerto Rico cohorts, 2003-2017, we examined age, race/ethnicity, and sex in children with body mass index (BMI) data, including 28,507 full-term post-birth to <2 years and 38,332 aged 2-18 years. Main outcomes included high BMI for age <2 years, and at 2-18 years overweight (BMI 85th to <95th percentile), obesity (BMI ≥ 95th percentile), and severe obesity (BMI ≥ 120% of 95th percentile). RESULTS: The study population had diverse race/ethnicity and maternal demographics. Each outcome was more common with increasing age and varied with race/ethnicity. High BMI prevalence (95% CI) was 4.7% (3.5, 6.0) <1 year, and 10.6% (7.4, 13.7) for 1 to <2 years; overweight prevalence increased from 13.9% (12.4, 15.9) at 2-3 years to 19.9% (11.7, 28.2) at 12 to <18 years. ECHO has the statistical power to detect relative risks for 'high' BMI ranging from 1.2 to 2.2 for a wide range of exposure prevalences (1-50%) within each age group. CONCLUSIONS: ECHO is a powerful resource for understanding influences of chemical, biological, social, natural, and built environments on onset and trajectories of obesity in US children. The large sample size of ECHO cohorts adopting a standardized protocol for new data collection of varied exposures along with longitudinal assessments will allow refined analyses to identify drivers of childhood obesity.

The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers.

BACKGROUND: Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case-control studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre-diagnostic exposure assessments and biological samples. METHODS: Eligibility criteria, follow-up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses. RESULTS: Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388 120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother-child pairs within 5 years. Harmonised data currently includes over 20 "core" variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades. CONCLUSIONS: The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case-control studies offer the potential for breakthroughs in paediatric cancer aetiologic research.

Next steps in studying the human microbiome and health in prospective studies, Bethesda, MD, May 16-17, 2017.

The National Cancer Institute (NCI) sponsored a 2-day workshop, "Next Steps in Studying the Human Microbiome and Health in Prospective Studies," in Bethesda, Maryland, May 16-17, 2017. The workshop brought together researchers in the field to discuss the challenges of conducting microbiome studies, including study design, collection and processing of samples, bioinformatics and statistical methods, publishing results, and ensuring reproducibility of published results. The presenters emphasized the great potential of microbiome research in understanding the etiology of cancer. This report summarizes the workshop and presents practical suggestions for conducting microbiome studies, from workshop presenters, moderators, and participants.

Research Strategies for Nutritional and Physical Activity Epidemiology and Cancer Prevention.

Very large international and ethnic differences in cancer rates exist, are minimally explained by genetic factors, and show the huge potential for cancer prevention. A substantial portion of the differences in cancer rates can be explained by modifiable factors, and many important relationships have been documented between diet, physical activity, and obesity, and incidence of important cancers. Other related factors, such as the microbiome and the metabolome, are emerging as important intermediary components in cancer prevention. It is possible with the incorporation of newer technologies and studies including long follow-up and evaluation of effects across the life cycle, additional convincing results will be produced. However, several challenges exist for cancer researchers; for example, measurement of diet and physical activity, and lack of standardization of samples for microbiome collection, and validation of metabolomic studies. The United States National Cancer Institute convened the Research Strategies for Nutritional and Physical Activity Epidemiology and Cancer Prevention Workshop on June 28-29, 2016, in Rockville, Maryland, during which the experts addressed the state of the science and areas of emphasis. This current paper reflects the state of the science and priorities for future research. Cancer Epidemiol Biomarkers Prev; 27(3); 233-44. ©2017 AACR.

Effects of low-to-moderate alcohol supplementation on urinary estrogen metabolites in postmenopausal women in a controlled feeding study.

Heavy alcohol drinking is associated with increased breast cancer risk, but associations with low-to-moderate alcohol consumption are less clear and the biological mechanisms are not well defined. The objective of this study was to evaluate the effects of 8 weeks of low (15 g/d) and moderate (30 g/d) alcohol ingestion on concentrations of 15 urinary estrogen metabolites (EMs) in postmenopausal women (n = 51) in a controlled feeding study with a randomized crossover design. Compared to no alcohol, 15 g/day for 8 weeks had no effect on urinary EMs. However, compared to no alcohol, 30 g/day for 8 weeks decreased urinary 2-hydroestrone (2-OHE1) by 3.3% (P = 0.055) and increased 16-epiestriol (16-EpiE3) by 26.6% (P = 0.037). Trends for reduced urinary 2-OHE1 (P = 0.045), reduced ratio of 2-OH:16OH pathways (P = 0.008), and increased 16-EpiE3 (P = 0.035) were observed as alcohol ingestion increased from 0 g to 15 g to 30 g/d. Moderate alcohol consumption for 8 weeks had modest effects on urinary concentrations of 2-OHE1 and 16-EpiE3 among postmenopausal women in a carefully controlled feeding study.

Early-life exposures to infectious agents and later cancer development.

There is a growing understanding that several infectious agents are acquired in early life and this is the reason why available vaccines target the new born, infants, and adolescents. Infectious agents are associated with cancer development and it is estimated that about 20% of the world's cancer burden is attributed to infectious agents. There is a growing evidence that certain infectious agents acquired in early life can give rise to cancer development, but estimates of the cancer burden from this early-life acquisition is unknown. In this article, we have selected five cancers (cervical, liver, Burkitt's lymphoma-leukemia, nasopharyngeal carcinoma, and adult T-cell leukemia-lymphoma) and examine their links to infectious agents (HPV, HBV, HCV, EBV, and HTLV-1) acquired in early life. For these agents, the acquisition in early life is from mother-to-child transmission, perinatal contact (with genital tract secretions, amniotic fluids, blood, and breast milk), saliva, sexual intercourse, and blood transfusion. We also discuss prevention strategies, address future directions, and propose mechanisms of action after a long latency period from the time of acquisition of the infectious agent in early life to cancer development.

Association between diet during preadolescence and adolescence and risk for breast cancer during adulthood.

It is increasingly evident that diet during preadolescence and adolescence has important consequences for breast cancer during adulthood. However, only a few epidemiologic studies have been conducted on the relationship between diet during preadolescence and adolescence, and cancer during adulthood. This situation is partly because of methodological challenges such as the long latency period, the complexity of breast cancer, the lack of validated diet assessment tools, and the large number of subjects that must be followed, all of which increase costs. In addition, funding opportunities are few for such studies. Results from the small number of epidemiologic studies are inconsistent, but evidence is emerging that specific aspects of the diet during preadolescence and adolescence are important. For example, during preadolescence and adolescence, severe calorie restriction with poor food quality, high total fat intake, and alcohol intake tend to increase risk, whereas high soy intake decreases risk. Research on preadolescent and adolescent diet is a paradigm shift in breast cancer investigations. This research paradigm has the potential to produce transformative knowledge to inform breast cancer prevention strategies through dietary intervention during preadolescence and adolescence, rather than later in life, as is current practice, when it is perhaps less effective. Methodological challenges that have plagued the field might now be overcome by leveraging several existing large-scale cohort studies in the U.S. and around the world to investigate the role of diet during preadolescence and adolescence in risk for adult breast cancer.

Challenges and opportunities in research on early-life events/exposures and cancer development later in life.

It is becoming increasingly evident that early-life events and exposures have important consequences for cancer development later in life. However, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges such as the long latency period, the distinctiveness of each cancer, and large number of subjects that must be studied, all likely to increase costs. These traditional hurdles might be mitigated by leveraging several existing large-scale prospective studies in the United States (US) and globally, as well as birth databases and birth cohorts, in order to launch both association and mechanistic studies of early-life exposures and cancer development later in life. Dedicated research funding will be needed to advance this paradigm shift in cancer research, and it seems justified by its potential to produce transformative understanding of how cancer develops over the life-course. This in turn has the potential to transform cancer prevention strategies through interventions in early-life rather than later in life, as is the current practice, where it is perhaps less effective.

Epigenetic Contributions to the Relationship between Cancer and Dietary Intake of Nutrients, Bioactive Food Components, and Environmental Toxicants.

Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence. Cancer is a multistep process derived from combinational crosstalk between genetic alterations and epigenetic influences through various environmental factors. The observation that epigenetic changes are reversible makes them an attractive target for cancer prevention. Until recently, there have been difficulties studying epigenetic mechanisms in interactions between dietary factors and environmental toxicants. The development of the field of cancer epigenetics during the past decade has been advanced rapidly by genome-wide technologies - which initially employed microarrays but increasingly are using high-throughput sequencing - which helped to improve the quality of the analysis, increase the capacity of sample throughput, and reduce the cost of assays. It is particularly true for applications of cancer epigenetics in epidemiologic studies that examine the relationship among diet, epigenetics, and cancer because of the issues of tissue heterogeneity, the often limiting amount of DNA samples, and the significant cost of the analyses. This review offers an overview of the state of the science in nutrition, environmental toxicants, epigenetics, and cancer to stimulate further exploration of this important and developing area of science. Additional epidemiologic research is needed to clarify the relationship between these complex epigenetic mechanisms and cancer.

Mineral intake and lung cancer risk in the NIH-American Association of Retired Persons Diet and Health study.

BACKGROUND: Using data from a case-control study, we previously reported that low dietary intakes of magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), but not selenium (Se) and calcium (Ca), were associated with increased lung cancer risk. Due to dietary recall bias in case-control studies, our objective was to assess whether these findings hold in a prospective cohort study. METHODS: We analyzed data from the NIH-American Association of Retired Persons Diet and Health study of 482,875 subjects (288,257 men and 194,618 women) who were cancer-free and completed a food frequency questionnaire at enrollment between 1995 and 2003. Cox proportional hazards models were computed to estimate the relative risk adjusted for potential confounders. RESULTS: During a mean follow-up of 7 years, 7,052 lung cancer cases were identified. For all subjects, we observed no significant associations between total (diet + supplement) Ca, Mg, Fe, Cu, Se, and Zn intakes and lung cancer risk. Total Ca intake was protective (P trend < 0.05) for current smokers and subjects with adenocarcinomas. Total Mg intake increased risk (P trend < 0.05) in men and current smokers. Total Fe intake was inversely associated with risk in women (P trend < 0.01). For dietary minerals, Mg increased risk (P trend < 0.05) in all subjects, among men and current smokers. Increased dietary Ca intake reduced risk in women (P trend = 0.05). Dietary Fe decreased risk in all subjects and among women (P trend < 0.05). Mineral intake from supplements did not affect lung cancer risk. CONCLUSIONS: Dietary minerals are risk factors for lung cancer. IMPACT: Dietary mineral consumption may influence lung cancer risk, but the associations differ by type of mineral and population subgroups.

Pooling dietary data using questionnaires with open-ended and predefined responses: implications for comparing mean intake or estimating odds ratios.

In the current era of diet-gene analyses, large sample sizes are required to uncover the etiology of complex diseases. As such, consortia form and often combine available data. Food frequency questionnaires, which commonly use 2 different types of responses about the frequency of intake (predefined responses and open-ended responses), may be pooled to achieve the desired sample size. The common practice is to categorize open-ended responses into the predefined response categories. A problem arises when the predefined categories are noncontiguous: possible open-ended responses may fall in gaps between the predefined categories. Using simulated data modeled from frequency of intake among 1,664 controls in a lung cancer case-control study at The University of Texas M. D. Anderson Cancer Center (Houston, Texas, 2000-2005), the authors describe the effect of different categories of open-ended responses that fall in between noncontiguous, predefined response sets on estimates of the mean difference in intake and the odds ratios. A significant inflation of false positives appears when comparing mean differences of intake, while the bias in estimating odds ratios may be acceptably small. Therefore, if pooling data cannot be restricted to the same type of response, inferences should focus on odds ratio estimation to minimize bias.

Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with operable breast cancer.

PURPOSE: To understand the mechanism through which obesity in breast cancer patients is associated with poorer outcome, we evaluated body mass index (BMI) and response to neoadjuvant chemotherapy (NC) in women with operable breast cancer. PATIENTS AND METHODS: From May 1990 to July 2004, 1,169 patients were diagnosed with invasive breast cancer at M. D. Anderson Cancer Center and received NC before surgery. Patients were categorized as obese (BMI >or= 30 kg/m(2)), overweight (BMI of 25 to < 30 kg/m(2)), or normal/underweight (BMI < 25 kg/m(2)). Logistic regression was used to examine associations between BMI and pathologic complete response (pCR). Breast cancer-specific, progression-free, and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. All statistical tests were two-sided. RESULTS: Median age was 50 years; 30% of patients were obese, 32% were overweight, and 38% were normal or underweight. In multivariate analysis, there was no significant difference in pCR for obese compared with normal weight patients (odds ratio [OR] = 0.78; 95% CI, 0.49 to 1.26). Overweight and the combination of overweight and obese patients were significantly less likely to have a pCR (OR = 0.59; 95% CI, 0.37 to 0.95; and OR = 0.67; 95% CI, 0.45 to 0.99, respectively). Obese patients were more likely to have hormone-negative tumors (P < .01), stage III tumors (P < .01), and worse overall survival (P = .006) at a median follow-up time of 4.1 years. CONCLUSION: Higher BMI was associated with worse pCR to NC. In addition, its association with worse overall survival suggests that greater attention should be focused on this risk factor to optimize the care of breast cancer patients.

Dietary alpha-, beta-, gamma- and delta-tocopherols in lung cancer risk.

Studies of vitamin E and cancer have focused on the alpha-tocopherol form of the vitamin. However, other forms of vitamin E, in particular gamma-tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, we studied the associations between 4 tocopherols (alpha-, beta-, gamma-, and delta-tocopherol) in the diet and lung cancer risk. Using multiple logistic regression analysis, the adjusted odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for increasing quartiles of dietary alpha-tocopherol intake were 1.0, 0.63 (0.50-0.79), 0.58 (0.44-0.76) and 0.39 (0.28-0.53), respectively (p-trend < 0.0001). For dietary intake of beta-tocopherol, the OR and 95% CI for all subjects were: 1.0, 0.79 (0.63-0.98), 0.59 (0.45-0.78) and 0.56 (0.42-0.74), respectively (p-trend < 0.0001). Similar results for dietary gamma-tocopherol intake were observed: 1.0, 0.84 (0.67-1.06), 0.76 (0.59-0.97) and 0.56 (0.42-0.75), respectively (p- trend = 0.0002). No significant association between delta-tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When we entered the other tocopherols in our model, only the association with dietary alpha-tocopherol intake remained significant; i.e., increasing intake of dietary alpha-tocopherol accounted for 34-53% reductions in lung cancer risk. To the best of our knowledge, this is the first report of the independent associations of the 4 forms of dietary tocopherol (alpha-, beta-, gamma- and delta-tocohperol) on lung cancer risk. Given the limitations with case-control studies, these findings need to be confirmed in further investigations.

Dietary magnesium and DNA repair capacity as risk factors for lung cancer.

Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case-control study, we identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. After adjustment for potential confounding factors including DRC, the odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer with increasing quartiles of dietary Mg intake were 1.0, 0.83 (0.66-1.05), 0.64 (0.50-0.83) and 0.47 (0.36-0.61), respectively, for all subjects (P-trend < 0.0001). Similar results were observed by histology and clinical stage of lung cancer. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83-3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing results need to be confirmed in prospective studies.

Joint effects of dietary trace metals and DNA repair capacity in lung cancer risk.

In a large case-control study, we previously reported that dietary intakes of zinc (Zn) and copper (Cu), but not selenium (Se), were inversely associated with lung cancer risk. Because Zn, Cu, Se, iron (Fe), and calcium (Ca) are important for maintaining DNA stability, we examined their associations with DNA repair capacity (DRC) measured by the lymphocyte host-cell reactivation assay in 1,139 cases and 1,210 of the controls. Dietary intake was reported in a food frequency questionnaire. In multivariate analyses, compared to those with high dietary Cu + proficient DRC, the odds ratio (95% confidence interval) [OR (95% CI)] for lung cancer for low Cu + suboptimal DRC was 2.54 (1.97-3.27). Similar results were observed for men and women. These effects were more pronounced in older and lean subjects, those with late-stage disease, and those with a family history of cancer in first-degree relatives. Compared to subjects with high Zn + proficient DRC, the OR for lung cancer for low Zn + suboptimal DRC was 1.82 (95% CI, 1.41-2.34), with pronounced effects in men, current smokers, subjects with longer duration of smoking, those with late-stage disease, or those with a family history of cancer. An OR of 1.94 (95% CI, 1.51-2.48) was observed for low Fe + suboptimal DRC compared with high Fe + proficient DRC, and pronounced effects appeared in older, lean subjects, those with longer duration of smoking, are heavier smokers, those with a late-stage disease, and those with a family history of cancer. No significant joint associations were seen for Se or Ca and DRC. Our joint associations between Cu-DRC, Zn-DRC and Fe-DRC and lung cancer risk require confirmation in prospective studies.