Blood DNA methylation and liver cancer in American Indians: evidence from the Strong Heart Study.

PURPOSE: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. METHODS: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. RESULTS: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). CONCLUSIONS: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.

Financial hardship screening among Native American patients with cancer: a qualitative analysis.

BACKGROUND: Cancer-related financial hardship is an increasingly recognized concern for patients, families, and caregivers. Many Native American (NA) patients are at increased risk for cancer-related financial hardship due to high prevalence of low income, medical comorbidity, and lack of private health insurance. However, financial hardship screening (FHS) implementation for NA patients with cancer has not been reported. The objective of this study is to explore facilitators and barriers to FHS implementation for NA patients. METHODS: We conducted key informant interviews with NA patients with cancer and with clinical staff at an academic cancer center. Included patients had a confirmed diagnosis of cancer and were referred to the cancer center through the Indian Health Service, Tribal health program, or Urban Indian health program. Interviews included questions regarding current financial hardship, experiences in discussing financial hardship with the cancer care and primary care teams, and acceptability of completing a financial hardship screening tool at the cancer center. Clinical staff included physicians, advanced practice providers, and social workers. Interviews focused on confidence, comfort, and experience in discussing financial hardship with patients. Recorded interviews were transcribed and thematically analyzed using MAXQDA® software. RESULTS: We interviewed seven patients and four clinical staff. Themes from the interviews included: 1) existing resources and support services; 2) challenges, gaps in services, and barriers to care; 3) nuances of NA cancer care; and 4) opportunities for improved care and resources. Patients identified financial challenges to receiving cancer care including transportation, lodging, food insecurity, and utility expenses. Patients were willing to complete a FHS tool, but indicated this tool should be short and not intrusive of the patient's financial information. Clinical staff described discomfort in discussing financial hardship with patients, primarily due to a lack of training and knowledge about resources to support patients. Having designated staff familiar with I/T/U systems was helpful, but perspectives differed regarding who should administer FHS. CONCLUSIONS: We identified facilitators and barriers to implementing FHS for NA patients with cancer at both the patient and clinician levels. Findings suggest clear organizational structures and processes are needed for financial hardship to be addressed effectively.

Identifying Priorities and Strategies for Improving Colorectal Cancer Screening in Tribal Clinics.

BACKGROUND: Colorectal cancer (CRC) is the 3rd most frequently diagnosed cancer and the 2nd leading cause of cancer death in the United States (US), and incidence and mortality rates in Oklahoma are higher for many American Indian (AI) populations than other populations. The AI CRC Screening Consortium addresses major regional CRC screening disparities among AIs with shared objectives to increase CRC screening delivery and uptake in AIs aged 50 to 75 years at average risk for CRC and to assess the effectiveness of implementations of the interventions. This manuscript reports environmental scan findings related to current practices and multi-stakeholder experiences with CRC screening in two Oklahoma Indian health care systems. METHOD: We conducted a mixed methods environmental scan across five clinical sites and with multiple stakeholders to determine the scope and scale of colorectal cancer screening in two separate AI health care delivery systems in Oklahoma. Data collection consisted of a mixture of individual interviews and group discussions at an urban site, and four clinical care sites within a tribal health system. RESULTS: Sixty-two individuals completed interviews. Data from these interviews will inform the development of evidence-based intervention strategies to increase provider delivery, community access to, and community priority for CRC screening in diverse AI health care delivery systems. Conversations with patients, providers, and clinical leadership point to individual and system-level opportunities for improvement at each site, shaped in part by differences in the delivery of services, structure of the health care system, and capacity to implement new intervention strategies. The thematic areas most central to the process of evidenced-based intervention development included: current practices, needs and recommendations, and CRC site priorities. CONCLUSION: Environmental scan data indicated clear opportunities for individual and system-level interventions to enhance CRC screening and was critical for understanding readiness for EBI implementation at each site.

Impact of e-cigarette use among a cohort of American Indian cigarette smokers: associations with cigarette smoking cessation and cigarette consumption.

INTRODUCTION: Despite American Indian/Alaska Native (AI/AN) people having the highest prevalence of cigarette smoking nationwide, few studies have evaluated e-cigarette use among AI/AN adults who smoke. The primary objective of this observational pilot cohort study was to determine if e-cigarette use is associated with cigarette smoking cessation or reduction among adult AI individuals who smoke. METHODS: In 2016, we collected baseline survey and biomarker data among AI adults who smoke. The survey included questions about cigarette consumption and use of e-cigarettes and biomarkers, such as salivary cotinine markers and exhaled carbon monoxide. After 18 months, we repeated data collection, and asked about changes in cigarette smoking status and cigarettes per day (CPD). Comparisons between groups were performed using the χ2 test, Fisher's exact test or Wilcoxon rank-sum test. RESULTS: Of 375 baseline participants, 214 (57.07%) returned for follow-up and were included in analyses. Of these, 20 (9.3%) reported having stopped cigarette smoking and had biochemical verification of cigarette smoking abstinence. Among those who quit smoking, 15% were baseline e-cigarette users; while among those who continued to smoke at follow-up, about 11% were baseline e-cigarette users. This difference was not statistically significant (p=0.48). Among all those who continued to smoke at follow-up, there was no overall decrease in CPD, nor a significant difference in change in CPD between baseline e-cigarette users and non-users (p=0.98). CONCLUSIONS: E-cigarette use at baseline was not associated with smoking cessation or a change in CPD in this cohort of AI adults who smoke after an 18-month follow-up period.

Vaping patterns, nicotine dependence and reasons for vaping among American Indian dual users of cigarettes and electronic cigarettes.

BACKGROUND: The American Cancer Society discourages the dual use of electronic cigarettes (ECs) and cigarettes because such use has not resulted in reduced exposures to the harmful effects of smoking. American Indian (AI) people have the highest prevalence of smoking and of EC use in the United States, but very little is known about dual EC and cigarette use in AI communities. METHODS: In 2016, 375 adult AI in Oklahoma who smoked cigarettes completed a survey about EC use (vaping). We describe vaping patterns, nicotine dependence, and reasons for EC use among the subset of 44 (12%) current dual EC users. To differentiate habitual EC users from occasional or merely curious users, we defined dual use as using ECs on some days or every day in the past 30 days. RESULTS: About one-third of dual users vaped ten or more times daily. About two-thirds used a tank product. Eleven percent used ECs without nicotine and another 9% were unsure of the nicotine content. A minority (40%) enjoyed vaping more than smoking, and most (76%) would smoke first on days they did both. Thirty-one percent vaped within 5 min of waking and another 24% within 30 min. Although the two-item heaviness of use index did not differ significantly between smoking and vaping, the ten-item Penn State Dependence Index (PSDI) suggested greater dependence on smoking than vaping (11.02 vs. 6.42, respectively; p < .0001). The most common reasons for vaping were to reduce smoking (79%), enjoyment of flavors (78%), and ability to vape where smoking is not allowed (73%). Perceptions of less harm to others (69%) or to self were the next most common (65%). Fewer than half used ECs to reduce stress, for affordability, or because others used them. CONCLUSIONS: Nearly 20% of dual users used ECs either without nicotine or without knowing if the product contained nicotine. The PSDI indicated greater dependence on smoking than vaping. Reasons for vaping were nearly equal between smoking reduction and enjoying flavors. Understanding patterns of dual use will inform future efforts to address nicotine dependence for AI communities with high prevalence of smoking.

Perceptions of Smoking and Vaping on Weight Control Among Adult American Indians Who Smoke.

Interest in electronic cigarette (EC) use, or vaping, to help control weight is increasing. Many American Indian (AI) populations have a high prevalence of smoking, obesity, and EC use, but their perceptions of EC use for weight control are unknown. In Oklahoma in 2016, 375 AI adults who smoke completed a survey including perceptions about smoking and EC effects on weight control. Only 24% believed that smoking helps control weight, and 8% believed that vaping helps control weight. Perceptions differed by EC use, with ever users more often than never users perceiving that smoking (30% vs 12%, respectively; p < .01) and vaping (10% vs 5%; p = .04) help to control weight. Sex, age group (18-44 years vs 45 + years), education (high school graduate/equivalent vs less than high school), smoking cessation attempt in past year, and likelihood to quit in 6 months were not associated with weight control perceptions for either smoking or vaping. Uncertainty regarding EC effects on weight control was less common among EC ever users compared to never users (41% vs 53%, respectively; p = .04). Most people who did not believe or were uncertain that smoking controls weight also did not believe or were uncertain that vaping controls weight. However, only a minority (29%) of people who believed smoking controls weight also believed that vaping controls weight. Among adult AI who smoke, both smoking and vaping were infrequently perceived as helping to control weight, but such perceptions were reported more frequently among those who ever used ECs.

Association of diabetes and cancer mortality in American Indians: the Strong Heart Study.

PURPOSE: The metabolic abnormalities that accompany diabetes mellitus are associated with an increased risk of many cancers. These associations, however, have not been well studied in American Indian populations, which experience a high prevalence of diabetes. The Strong Heart Study is a population-based, prospective cohort study with extensive characterization of diabetes status. METHODS: Among a total cohort of 4,419 participants who were followed for up to 20 years, 430 cancer deaths were identified. RESULTS: After adjusting for sex, age, education, smoking status, drinking status, and body mass index, participants with diabetes at baseline showed an increased risk of gastric (HR 4.09; 95% CI 1.42-11.79), hepatocellular (HR 2.94; 95% CI 1.17-7.40), and prostate cancer mortality (HR 3.10; 95% CI 1.22-7.94). Further adjustment for arsenic exposure showed a significantly increased risk of all-cause cancer mortality with diabetes (HR 1.27; 95% CI 1.03-1.58). Insulin resistance among participants without diabetes at baseline was associated with hepatocellular cancer mortality (HR 4.70; 95% CI 1.55-14.26). CONCLUSIONS: Diabetes mellitus, and/or insulin resistance among those without diabetes, is a risk factor for gastric, hepatocellular, and prostate cancer in these American Indian communities, although relatively small sample size suggests cautious interpretation. Additional research is needed to evaluate the role of diabetes and obesity on cancer incidence in American Indian communities as well as the importance of diabetes prevention and control in reducing the burden of cancer incidence and mortality in the study population.

The public health foundation of health services for American Indians & Alaska Natives.

The integration of public health practices with federal health care for American Indians and Alaska Natives (AI/ANs) largely derives from three major factors: the sovereign nature of AI/AN tribes, the sociocultural characteristics exhibited by the tribes, and that AI/ANs are distinct populations residing in defined geographic areas. The earliest services consisted of smallpox vaccination to a few AI/AN groups, a purely public health endeavor. Later, emphasis on public health was codified in the Snyder Act of 1921, which provided for, among other things, conservation of the health of AI/AN persons. Attention to the community was greatly expanded with the 1955 transfer of the Indian Health Service from the US Department of the Interior to the Public Health Service and has continued with the assumption of program operations by many tribes themselves. We trace developments in integration of community and public health practices in the provision of federal health care services for AI/AN persons and discuss recent trends.

A national study of social networks and perceptions of health among urban American Indian/Alaska Natives and non-Hispanic Whites.

Using data from The National Epidemiologic Survey on Alcohol and Related Conditions, the strength of social networks and the association of self-reported health among American Indians and Alaska Natives (AI/AN) and non-Hispanic Whites (NHW) were compared. Differences in social network-health relationships between AI/ANs and NHWs were also examined. For both groups, those with fewer network members were more likely to report fair or poor health than those with average or more network members, and persons with the fewest types of relationships had worse self-reported health than those with the average or very diverse types of relationships. Furthermore, small social networks were associated with much worse self-reported health in AI/ANs than in NHWs.

Asthma and Obstructive Sleep Apnea Overlap in a Sample of Older American Indian Adults: The Strong Heart Study.

Study Objectives: Our study aimed to investigate the association between asthma and obstructive sleep apnea (OSA) in American Indian communities, a historically underrepresented population in clinical research with a high prevalence of asthma and OSA risk factors like smoking and obesity. Methods: This cross-sectional study used data retrieved from the Strong Heart Study cohort. Participants who attended both the Asthma Sub-study and the Sleep Heart Health Study around the same time were compared for active asthma diagnosis, OSA diagnosis, and potential risk factors for asthma and OSA. The association between asthma and OSA was then evaluated. Results: Among the 2480 participants who attended the Strong Heart Study Phase III exam, 123 participated in both the Asthma Sub-study and the Sleep Heart Health Study. Of these, 13 were diagnosed with OSA, with 4 having moderate to severe OSA. There was no statistically significant difference in OSA prevalence between the active asthma group and the non-active asthma group (former asthma or no asthma) (9.6% vs. 12.5%, p = 0.63). Additionally, body mass index did not differ significantly between participants with both active asthma and OSA and those without active asthma, OSA, or both. OSA diagnosis was significantly associated with male sex (Odds Ratio [OR] 9.2 [1.85-45.87], p = 0.007) and body mass index (OR 1.1 [1.02-1.26], p = 0.016) but not with age or a diagnosis of active asthma. Conclusions: In this American Indian cohort, no significant difference in OSA prevalence was observed between participants with and without active asthma, contradicting previous studies. Further research is needed to explore the underlying reasons for this discrepancy.

Multicohort Epigenome-Wide Association Study of All-Cause Cardiovascular Disease and Cancer Incidence: A Cardio-Oncology Approach.

Background: Emerging evidence reveals a complex relationship between cardiovascular disease (CVD) and cancer, which share common risk factors and biological pathways. Objectives: The aim of this study was to evaluate common epigenetic signatures for CVD and cancer incidence in 3 ethnically diverse cohorts: Native Americans from the SHS (Strong Heart Study), European Americans from the FHS (Framingham Heart Study), and European Americans and African Americans from the ARIC (Atherosclerosis Risk In Communities) study. Methods: A 2-stage strategy was used that included first conducting untargeted epigenome-wide association studies for each cohort and then running targeted models in the union set of identified differentially methylated positions (DMPs). We also explored potential molecular pathways by conducting a bioinformatics analysis. Results: Common DMPs were identified across all populations. In a subsequent meta-analysis, 3 and 1 of those DMPs were statistically significant for CVD only and both cancer and CVD, respectively. No meta-analyzed DMPs were statistically significant for cancer only. The enrichment analysis pointed to interconnected biological pathways involved in cancer and CVD. In the DrugBank database, elements related to 1-carbon metabolism and cancer and CVD medications were identified as potential drugs for target gene products. In an additional analysis restricted to the 950 SHS participants who developed incident CVD, the C index for incident cancer increased from 0.618 (95% CI: 0.570-0.672) to 0.971 (95% CI: 0.963-0.978) when adjusting the models for the combined cancer and CVD DMPs identified in the other cohorts. Conclusions: These results point to molecular pathways and potential treatments for precision prevention of CVD and cancer. Screening based on common epigenetic signatures of incident CVD and cancer may help identify patients with newly diagnosed CVD at increased cancer risk.

Analysis of Geographic Accessibility of Breast, Lung, and Colorectal Cancer Screening Centers Among American Indian and Alaskan Native Tribes.

PURPOSE: To evaluate geographic accessibility of ACR mammographic screening (MS), lung cancer screening (LCS), and CT colorectal cancer screening (CTCS) centers among US federally recognized American Indian and Alaskan Native (AI/AN) tribes. METHODS: Distances from AI/AN tribes' ZIP codes to their closest ACR-accredited LCS and CTCS centers were recorded using tools from the ACR website. The FDA's database was used for MS. Persistent adult poverty (PPC-A), persistent child poverty (PPC-C), and rurality indexes (rural-urban continuum codes) were from the US Department of Agriculture. Logistic and linear regression analyses were used to assess distances to screening centers and relationships among rurality, PPC-A, and PPC-C. RESULTS: Five hundred ninety-four federally recognized AI/AN tribes met the inclusion criteria. Among all closest MS, LCS, or CTCS center to AI/AN tribes, 77.8% (1,387 of 1,782) were located within 200 miles, with a mean distance of 53.6 ± 53.0 miles. Most tribes (93.6% [557 of 594]) had MS centers within 200 miles, 76.4% (454 of 594) had LCS centers within 200 miles, and 63.5% (376 of 594) had CTCS centers within 200 miles. Counties with PPC-A (odds ratio [OR], 0.47; P < .001) and PPC-C (OR, 0.19; P < .001) were significantly associated with decreased odds of having a cancer screening center within 200 miles. PPC-C was associated with decreased likelihood of having an LCS center (OR, 0.24; P < .001) and an CTCS center (OR, 0.52; P < .001) within the same state as the tribe's location. No significant association was found between PPC-A and PPC-C and MS centers. CONCLUSIONS: AI/AN tribes experience distance barriers to ACR-accredited screening centers, resulting in cancer screening deserts. Programs are needed to increase equity in screening access among AI/AN tribes.

Smoking, blood DNA methylation sites and lung cancer risk.

Altered DNA methylation (DNAm) might be a biological intermediary in the pathway from smoking to lung cancer. In this study, we investigated the contribution of differential blood DNAm to explain the association between smoking and lung cancer incidence. Blood DNAm was measured in 2321 Strong Heart Study (SHS) participants. Incident lung cancer was assessed as time to event diagnoses. We conducted mediation analysis, including validation with DNAm and paired gene expression data from the Framingham Heart Study (FHS). In the SHS, current versus never smoking and pack-years single-mediator models showed, respectively, 29 and 21 differentially methylated positions (DMPs) for lung cancer with statistically significant mediated effects (14 of 20 available, and five of 14 available, positions, replicated, respectively, in FHS). In FHS, replicated DMPs showed gene expression downregulation largely in trans, and were related to biological pathways in cancer. The multimediator model identified that DMPs annotated to the genes AHRR and IER3 jointly explained a substantial proportion of lung cancer. Thus, the association of smoking with lung cancer was partly explained by differences in baseline blood DNAm at few relevant sites. Experimental studies are needed to confirm the biological role of identified eQTMs and to evaluate potential implications for early detection and control of lung cancer.

Health Disparities in Cancer Among American Indians and Alaska Natives.

American Indians and Alaska Natives (AI/AN) are underserved populations who suffer from several health disparities, 1 of which is cancer. Malignancies, especially cancers of the breast, liver, and lung, are common causes of death in this population. Health care disparities in this population include more limited access to diagnostic radiology because of geographic and/or health system limitations. Early detection of these cancers may be enabled by improving patient and physician access to medical imaging. Awareness by the radiology community of the cancer disparities among this population is needed to support research targeted to this specific ethnic group and to support outreach efforts to provide more imaging opportunities. Providing greater access to imaging facilities will also improve patient compliance with screening recommendations, ultimately improving mortality in these populations.

Disparities in Hospitalized Chronic Obstructive Pulmonary Disease Exacerbations Between American Indians and Non-Hispanic Whites.

BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is high in American Indian (AI) populations, as are diabetes and obesity, which are common COPD comorbidities. However, COPD research among AI populations is limited. STUDY DESIGN AND METHODS: We conducted a retrospective study to investigate potential health disparities and risk factors among AI and non-Hispanic White (NHW) patients with COPD exacerbations hospitalized at the University of Oklahoma Medical Center between July 2001 and June 2020. Demographics, clinical variables, and outcomes were collected. RESULTS: A total of 76 AI patients and 304 NHW patients were included. AI patients had more comorbidities than did NHW patients (4.3 versus.3.1, p<0.001). In multiple variable analyses, AI race was associated with higher odds of needing intensive care unit (ICU) care ( odds ratio [OR], 2.37, 95% confidence interval [CI], 1.36--4.16, p=0.002) and invasive mechanical ventilator use (OR, 2.75, 95% CI, 1.42-5.29, p=0.002). AI race was also associated with longer ICU stays compared with NHWs (OR, 1.43, 95% CI, 1.18--1.73, p<0.001). The average number of days on mechanical ventilator support increased by 137.3% for an AI patient compared to an NHW patient (p<0.001). AI race was not associated with discharge to other health facilities (OR, 0.98, 95% CI, 0.52-1.83, p=0.944). INTERPRETATION: AI patients were more likely than NHW patients to need ICU care and ventilator support, have longer ICU stays, and more days on mechanical ventilator support. More studies are needed to identify reasons for these disparities and effective interventions to reduce them.

Native American Patients with Chronic Obstructive Pulmonary Disease Exacerbations in a Tertiary Academic Medical Center - A Pilot Study.

PURPOSE: The prevalence of chronic obstructive pulmonary disease (COPD) and comorbidities (eg diabetes and obesity) among Native American (NA) population are higher than among the general US population. However, studies of COPD in NAs are scarce. Oklahoma has the largest NA population affiliated with federally recognized tribes in the country and is an ideal location for such research. A pilot study was designed to investigate the characteristics of NA patients with COPD exacerbations in a tertiary academic medical center. PATIENTS AND METHODS: We conducted a retrospective exploratory study of NA adults with COPD exacerbation hospitalizations and/or emergency department visits at the University of Oklahoma Medical Center between July 2001 and June 2020. Medical records were reviewed to confirm COPD exacerbation and outcomes, including death, mechanical ventilation, intensive care unit (ICU) stay, home oxygen, and 30-day readmission. Additional collected data included socio-demographics, body mass index, diabetes, other COPD comorbidities and clinical variables. RESULTS: Of 630 encounters reviewed, 159 met the inclusion criteria, representing 91 patients. Most patients were female (64%), obese or overweight (68%), and had diabetes (42%) or hypertension (71%). Mean age was 60 years old, but women were 5 years younger than men. Among the 76 patients with COPD hospitalizations, 31 patients (41%) had an intensive care unit (ICU) stay and 19 (25%) were intubated in their last hospitalization. Among 9 patients (10%) with 30-day readmissions, 8 were female. Medicare, Indian Health Service, Tribal health service, or Medicaid were the most frequently used payment sources. Sex, diabetes, and obesity were not associated with hospital length of stay, 30-day readmission or supplemental O2 use. CONCLUSION: Hospitalized NA COPD patients at this tertiary care center had multiple comorbidities. Many required ICU care and intubation. Larger studies of the risk and mitigating factors for COPD health outcomes in NA patients are needed.

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

BACKGROUND: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed. METHODS: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010. RESULTS: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71). CONCLUSIONS: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.

DNA methylation and cancer incidence: lymphatic-hematopoietic versus solid cancers in the Strong Heart Study.

BACKGROUND: Epigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic-hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic-hematopoietic cancers. METHODS: Blood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic-hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms. RESULTS: Over a follow-up of up to 28 years (mean 15), we identified 41 lymphatic-hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic-hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic-hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic-hematopoietic cancers. CONCLUSIONS: This study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic-hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic-hematopoietic cancers.

Use of Potentially Reduced Exposure Tobacco Products Among American Indian Smokeless Tobacco Users: Associations With Cessation Behaviors and Cotinine Levels.

OBJECTIVES: American Indian/Alaska Native (AI/AN) adults use smokeless tobacco products (eg, chewing and dip tobacco) more often than other racial/ethnic groups do. Although US adults increasingly use potentially reduced exposure tobacco products (PREPs), such as electronic cigarettes and snus, no studies have examined the use of PREPs among AI/AN smokeless tobacco users. We examined associations between current PREPs use and smokeless tobacco-related measures, including cessation attempts and cotinine levels, in a sample of American Indian adults who currently use smokeless tobacco. METHODS: We collected survey and tobacco biomarker data from 299 adult American Indian smokeless tobacco users at Cherokee Nation health care facilities and events in 2016 and 2017. We used multivariable analyses to determine associations between current PREPs use and smokeless tobacco-related characteristics. RESULTS: Current PREPs users were younger, less likely to be married or living with a partner, less likely to report a chronic medical condition, and more likely to report other tobacco use than PREPs nonusers. Among participants with annual household incomes ≤$30 000, current PREPs users were less likely than PREPs nonusers to report a definite desire to quit smokeless tobacco (P = .02). PREPs use was not associated with planning to quit smokeless tobacco, past 12-month smokeless tobacco quit attempts, amount of smokeless tobacco used per week, cotinine levels, or scores on the Fagerström Test for Nicotine Dependence-Smokeless Tobacco. CONCLUSIONS: Our study suggests that American Indian smokeless tobacco users may not be using PREPs as a smokeless tobacco cessation aid. Future studies should take this finding into consideration when evaluating the role of PREPs use in smokeless tobacco cessation and in total tobacco cessation in this population.

Telomere length and cancer mortality in American Indians: the Strong Heart Study.

The objective of this study was to investigate whether leukocyte telomere length (LTL) predicts the risk for cancer mortality among American Indians participating in the Strong Heart Study (1989-1991). Participants (aged 45-74 years) were followed annually until December 2015 to collect information on morbidity/mortality. LTL was measured by qPCR using genomic DNA isolated from peripheral blood. The association between LTL and risk for cancer mortality was examined using a multivariable Cox proportional hazard model, adjusting for age, gender, education, study site, smoking, alcohol use, physical activity, systolic blood pressure, fasting blood glucose, obesity, and low- and high-density lipoprotein. Of 1945 participants (mean age 56.10 ± 8.17 at baseline, 57% women) followed for an average 20.5 years, 220 died of cancer. Results showed that longer LTL at baseline significantly predicts an increased risk of cancer death among females (HR 1.57, 95% CI 1.08-2.30), but not males (HR 0.74, 95% CI 0.49-1.12) (p for interaction 0.009). Specifically, compared with the women with the longest LTL (fourth quartile), those in the third, second, and first quartiles showed 53%, 41%, and 44% reduced risk for cancer death, respectively. The findings highlight the importance of sex-specific analysis in future telomere research.