Polymorphisms in the beta-2-adrenergic receptor (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, risk factors that have received increased attention in relation to breast cancer. We evaluated the hypothesis that ADRB2 variants (rs 1042713, rs1042714) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case–control study conducted in the southwestern United States.
Data on lifestyle and medical history, and blood samples, were collected during in-person interviews for incident primary breast cancer cases (1,244 NHW, 606 H) and controls (1,330 NHW, 728 H). ADRB2 genotypes for rs1042713(G/A) and rs1042714(G/C) were determined using TaqMan assays. The associations of each variant and corresponding haplotypes with breast cancer were estimated using multivariable logistic regression.
Two copies compared to one or zero copies of the ADRB2 G–G haplotype were associated with increased breast cancer risk for NHW women [odds ratio (OR), 1.95; 95 % confidence interval (95 % CI), 1.26–3.01], but with reduced risk for H women [OR, 0.74; 95 % CI, 0.50–1.09]. Effect estimates were strengthened for women with a body mass index (BMI) ≥25 kg/m2 [H: OR, 0.50; 95 % CI, 0.31–0.82; NHW: OR, 3.85; 95 % CI, 1.88–7.88] and for H women with a history of diabetes [H: OR, 0.32; 95 % CI, 0.12–0.89].
These data suggest that ethnicity modifies the association between the ADRB2 G–G haplotype and breast cancer risk, and being overweight or obese enhances the divergence of risk between H and NHW women.
Breast cancer; Hispanic; Beta-2-adrenergic receptor; Haplotypes; Obesity; Diabetes
Insulin resistance is thought to mediate the association between obesity and colorectal neoplasia, but no prior studies have assessed stimulated insulin sensitivity as a risk factor for colorectal neoplasia. This prospective study examined the association between insulin sensitivity measured directly using the frequently sampled intravenous glucose tolerance test (FSIGT) and later risk of colorectal adenomas. Among participants with a range of glucose tolerance levels enrolled in the Insulin Resistance Atherosclerosis Study, colonoscopies were conducted on 600 participants ages ≥ 50 yr, regardless of symptoms, about 10 yr after the first FSIGT and 5 yr after the second. Multiple logistic regression analyses were used. Within this cohort, diabetes was not associated with colorectal adenoma risk [~10 yr prior to colonoscopy adjusted odds ratio (ORadj) 1.00; 95% confidence interval (CI), 0.62–1.62 or ~5 yr prior to colonoscopy ORadj 0.96; 95% CI, 0.62–1.50]. Among non-diabetic participants, insulin sensitivity was not associated with colorectal adenoma risk at either prior study visit [lowest vs. highest insulin sensitivity, ~10 yr prior to colonoscopy ORadj 0.93; 95% CI 0.50–1.71 and ~5 yr prior to colonscopy ORadj 0.74; 95% CI, 0.38–1.46]. These results suggest that factors other than insulin sensitivity mediate the relationship between obesity and colorectal neoplasia.
Gene promoter hypermethylation is now regarded as a promising biomarker for the risk and progression of lung cancer. The one-carbon metabolism pathway is postulated to affect deoxyribonucleic acid (DNA) methylation because it is responsible for the generation of S-adenosylmethionine (SAM), the methyl donor for cellular methylation reactions. This study investigated the association of single nucleotide polymorphisms (SNPs) in six one-carbon metabolism-related genes with promoter hypermethylation in sputum DNA from non-Hispanic white smokers in the Lovelace Smokers Cohort (LSC) (n = 907). Logistic regression was used to assess the association of SNPs with hypermethylation using a high/low methylation cutoff. SNPs in the cystathionine beta synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were significantly associated with high methylation in males [CBS rs2850146 (-8283G > C),
OR = 4.9; 95% CI: 1.98, 12.2, P = 0.0006] and low methylation in females [MTRR rs3776467 (7068A > G), OR = 0.57, 95% CI: 0.42, 0.77, P = 0.0003]. The variant allele of rs2850146 was associated with reduced gene expression and increased plasma homocysteine (Hcy) concentrations. Three plasma metabolites, Hcy, methionine and dimethylglycine, were associated with increased risk for gene methylation. These studies suggest that SNPs in CBS and MTRR have sex-specific associations with aberrant methylation in the lung epithelium of smokers that could be mediated by the affected one-carbon metabolism and transsulfuration in the cells.
Abbreviations:CBScystathionine beta synthaseDNAdeoxyribonucleic acidHBEChuman bronchial epithelial cellHcyhomocysteineLD, linkage disequilibrium; LSClovelace Smokers CohortMAFminor allele frequencyMTHFRmethylenetetrahydrofolate reductaseMTRRmethyltransferase reductaseSNPsingle nucleotide polymorphismsSAHS-adenosylhomocysteineSAMS-adenosylmethionine
High levels of circulating insulin-like growth factor-1 (IGF-1) have been associated with increased risk of several cancers. Regarding colorectal cancer, these associations are generally weak. We hypothesized that an increase in IGF-1 over time would be a stronger risk factor for cancer-related outcomes than the actual levels. In this analysis we utilized existing data from the Insulin Resistance and Atherosclerosis Study (IRAS). Circulating IGF-1 levels and molar ratios of IGF-1 to IGF binding protein 3 (IGFBP-3) were measured at three time points, within a 10-year follow-up period. We examined the associations of increase of the two variables with the presence of colorectal adenoma at the end of follow-up among participants with normal glucose tolerance at baseline. This included 143 individuals, from which 24 were diagnosed with adenomatous polyps. Although the mean levels of IGF-1 and IGF-1/IGFBP-3 decline with age, approximately 30% of the participants showed an increase of at least fifteen percent (“ever increase”) in one or both of these variables, compared to baseline. We found a positive association between “ever increase” in IGF-1 o r IGF-1/IGFBP-3 and the presence of colorectal adenoma: ORs were 3.81 (95% CI: 1.30-10.8) and 2.83 (95% CI: 1.00-8.22), respectively. No association was found when analyzing the actual levels of both variables at any time point. Our data suggest that an increase in circulating IGF-1 or IGF-1/IGFBP-3 may represent a disturbed GH/IGF1 homeostasis, which could favor the development of precancerous lesions, such as colorectal adenoma.
IGF-1; colorectal adenoma; biomarkers
Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low five-year survival rate. Screening may reduce the risk of death from lung cancer.
A multi-society collaborative initiative (involving the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network) was undertaken to conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low dose computed tomography (LDCT), in order to create the foundation for development of an evidence-based clinical guideline.
MEDLINE (OVID: 1996 to April 2012), EMBASE (OVID: 1996 to April 2012), and the Cochrane Library (April 2012).
Of 591 citations identified and reviewed, eight randomized controlled trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation.
Critical appraisal using pre-defined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus.
Three randomized studies provided evidence on the impact of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer-specific mortality, 247 vs 309 events per 100,000 person-years for LDCT and control groups, respectively; Relative Risk [RR] = 0.80, 95% Confidence Interval [CI] 0.73–0.93; Absolute Risk Reduction [ARR] = 0.33%, P=0.004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, about 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and the percent of surgical procedures performed in those with benign lesions. Major complications in those with benign conditions were rare.
LDCT screening may benefit individuals at an elevated risk for lung cancer, but uncertainty exists about potential harms and the generalizability of results.
To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado Cohort and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic Stage I lung cancer patients from New Mexico.
Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling.
Seventeen genes with odds ratios of 1.4 – 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (odds ratios, 3.2 – 4.2) seen for the PAX5α, GATA5, and SULF2 genes. ROC curves generated from seven gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel.
These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomography screening for early detection of lung cancer.
gene methylation; sputum; lung cancer; biomarker
Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.
No studies of dietary vitamin D intake and vitamin D receptor (VDR) have been conducted comparing breast risk among Hispanic women and non-Hispanic white (NHW) women. We investigated the association between vitamin D intake and breast cancer in a population-based case–control study of 1,527 NHW and 791 Hispanic breast cancer cases diagnosed in 1999–2004 in Arizona, New Mexico, Utah, and Colorado, and 1,599 NHW and 922 Hispanic age-matched controls. Vitamin D intake was assessed using food frequency questionnaires, and associations with breast cancer were adjusted for age, ethnicity, state, education, body mass index, smoking, age at menarche, age at first birth, parity, hormone exposure, height, and physical activity using logistic regression. BsmI, Poly A and FokI vitamin D receptor (VDR) genotypes were also measured. Dietary vitamin D intake was positively associated with breast cancer (highest vs. lowest quartile (Q4 vs. Q1): odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15–1.60; Ptrend = 0.003), whereas vitamin D supplement use was inversely associated with breast cancer (10+ µg/day vs. none: OR = 0.79, 95% CI = 0.65–0.96, Ptrend = 0.01). Similar patterns in risk were observed by ethnicity and menopausal status. Positive associations with dietary vitamin D intake and inverse associations with supplement use were observed for ER+/PR+ and ER−/PR− breast cancers, but not for ER+/PR−disease. BsmI genotype significantly modified the association between dietary vitamin D and breast cancer overall. Future research is needed to better understand potential differences in breast cancer risk by vitamin D source and hormone receptor status.
Breast cancer; Vitamin D; Vitamin D receptor; Hispanics; Diet
Low dietary folate intake is associated with several neoplasias, but reports are inconsistent for breast cancer. Additionally, the association of folate with breast cancer estrogen receptor (ER) status is not well established.
To determine if dietary intakes of folate, B-vitamins (B2, B6, B12) and methionine are associated with breast cancer risk and ER status in Hispanic, and non-Hispanic White women in the southwestern US.
Materials and Methods
Primary breast cancer cases (n = 2,325) in the 4-Corners region (Arizona, Colorado, New Mexico and Utah), diagnosed between October 1999 and May 2004, were identified through state cancer registries. Controls (n = 2,525) were frequency-matched by ethnicity and age (±5 years). Dietary intake, physical activity and other exposures were assessed using in-person interviews. Risk was assessed through multivariable and multinomial logistic regression with adjustment for relevant covariates.
While there was no overall association with breast cancer, the highest quartile of folate intake was marginally inversely associated with ER− breast cancer (Odds Ratio (OR) = 0.50, 95%CI 0.25–1.00, p for trend = 0.07). Vitamin B12 intake was inversely associated with breast cancer also (OR = 0.73, 95%CI 0.53–1.00, p for trend = 0.06), particularly for the highest quartile of ER+ breast cancer (OR = 0.67, 95%CI 0.46–0.99, p for trend = 0.06), among NHW women (OR = 0.49, 95%CI 0.29–0.81, p for trend = 0.01) and invasive breast cancer (OR = 0.63; 95%CI: 0.42, 0.93, Ptrend = 0.01). Methionine intake was also inversely associated with ER+ breast cancer (OR for 4th quartile = 0.83, 95%CI 0.66–1.03, p for trend = 0.04), primarily among Hispanic women (OR = 0.71, 95%CI 0.47–1.06, and P for trend = 0.02).
Higher intake of folate is marginally associated with a lower risk for ER− breast cancer, and higher intakes of vitamin B-12 and methionine are marginally associated with a lower risk of ER+ breast cancer.
Hispanics are more likely to be diagnosed with breast cancer at a younger age, with more advanced stage at diagnosis, hormone receptor-negative tumors, and worse prognosis than non-Hispanic whites (NHW). Little is known regarding the association between behavioral risk factors and breast tumor characteristics and whether these associations vary by race/ethnicity. We evaluated the association between several behavioral risk factors and tumor phenotype in a population-based study of Hispanics and NHWs. Participants are cases (846 Hispanic and 1,625 NHW women) diagnosed with breast cancer between 1999 and 2004 in Arizona, Colorado, New Mexico, or Utah. The association between breast cancer characteristics and obesity, physical activity, smoking, alcohol intake, and reproductive factors was examined. Logistic regression was used to compute the ethnic-specific odds ratios for the association between these risk factors and estrogen receptor (ER) status, tumor size, and histologic grade. Hispanics had more ER-negative tumors (28 vs. 20%), tumors >2 cm (39 vs. 27%), and poorly differentiated tumors (84 vs. 77%) than NHW. Among premenopausal women, obesity was associated with more ER-negative cancers among NHW [OR = 2.47 (95% CI: 1.08, 5.67)] but less ER-negative cancers among Hispanics [OR = 0.29 (0.13, 0.66)]. Obesity was associated with larger tumors among NHW [OR = 1.58 (1.09, 2.29)], but not among Hispanics. Never using mammography was associated with larger tumors in both ethnic groups. Moderate alcohol drinking and moderate and vigorous physical activity were weakly associated with smaller tumors in both ethnic groups. Our findings suggest that the association of obesity and other behavioral risk factors with breast cancer characteristics differ by ethnicity. We observed a divergent pattern between Hispanic and NHW cases in the association between obesity and ER status and tumor size. These observations suggest that a complex set of metabolic and hormonal factors related to estrogen and insulin pathways influence tumor characteristics.
Breast cancer; Tumor phenotype; Behavioral risk factors; Ethnicity; Obesity
Hispanic women are at a lower risk of getting breast cancer than non-Hispanic white (NHW) women, yet they experience a higher risk of mortality after diagnosis. There is some evidence to suggest differences in tumor pathology; however, very limited research has been published on Hispanic women. This represents one of the first studies to evaluate the prevalence of tumor markers and phenotypic subtypes that are associated with poorer prognosis (human epidermal growth factor receptor 2 [HER2], triple negative and basal-like tumors) among Hispanic women.
We reviewed pathology reports, obtained paraffin blocks of breast cancer tissue, and established tissue microarrays from NHW (n=119) and Hispanic women (n=69) who were Colorado participants in the 4-Corners Breast Cancer Study. We evaluated ethnic differences in the prevalence of tumor markers and phenotypic subtypes and assessed the contribution of risk factors in explaining the observed differences.
Consistent with other studies, Hispanic women had a higher prevalence of estrogen receptor-negative tumors compared with NHWs (36.2% vs. 22.7%, p=0.05). Hispanics also had an unexpectedly higher proportion of HER2-positive tumors compared with NHWs (31.9% vs. 14.3%, p<0.01). Independent of other prognostic factors, Hispanics were 2.8 times more likely to have a HER2-positive tumor (95% confidence interval [CI] 0.98-7.86). Hispanics were less likely to have the more favorable luminal A subtype, but no significant differences were observed for the less favorable basal-like or triple negative subtypes. However, there were suggestive differences when considering menopausal status.
These findings provide evidence that breast cancers among Hispanic women comprise a distinct spectrum of tumor subtypes when compared with NHW women.
Genome-wide association studies (GWAS) have identified several loci as being associated with breast cancer in mostly European populations. We focus on TNRC9 rs3803662, FGFR2 rs1219648 and rs2981582, MAP3K1 rs889312, and 2q35 rs13387042, to replicate in the 4-Corner’s Breast Cancer Study of Hispanic (N = 565 cases and 714 controls) and non-Hispanic white (NHW) women (N = 1177 cases and 1330 controls). We evaluate associations by ethnicity, menopausal status, and tumor ER/PR status after adjusting for genetic admixture. TNRC9 AA genotype was associated with significant increased risk among NHW women (OR 1.54, 95% CI 1.14, 2.08; P trend 0.003). Both polymorphisms of FGFR2 were associated with statistically significant increased risk for NHW and Hispanic women; MAP3K1 was not associated with risk among either ethnic group. The polymorphism on 2q35 was associated with a statistically significant increased risk among Hispanic women (OR 1.53, 95% CI 1.08, 2.15 for the AA genotype; P trend = 0.004). Associations were significantly different among pre/peri-menopausal women for TNRC9 (P heterogeneity 0.008) and for 2q35 (P heterogeneity 0.08) for NHW and Hispanic women. Both FGFR2 polymorphisms reduced risk of ER−/PR− tumors in the presence of the minor allele among NHW women. Among Hispanic women, polymorphisms of the FGFR2 gene were associated with almost a twofold increase risk of an ER+/PR+ tumor, while non-significantly inversely associated with ER−/PR− tumors. Our data replicated some of the previously reported GWAS findings. Differences in associations were detected for NHW and Hispanic women by menopausal status and by ER/PR status of tumors.
Breast cancer; Hispanic; TNRC9; MAP3K1; FGFR2; 2q35
Previous studies have shown that summary measures of comorbid conditions are associated with decreased overall survival in breast cancer patients. However, less is known about associations between specific comorbid conditions on the survival of breast cancer patients.
The Surveillance, Epidemiology, and End Results–Medicare database was used to identify primary breast cancers diagnosed from 1992 to 2000 among women aged 66 years or older. Inpatient, outpatient, and physician visits within the Medicare system were searched to determine the presence of 13 comorbid conditions present at the time of diagnosis. Overall survival was estimated using age-specific Kaplan–Meier curves, and mortality was estimated using Cox proportional hazards models adjusted for age, race and/or ethnicity, tumor stage, cancer prognostic markers, and treatment. All statistical tests were two-sided.
The study population included 64 034 patients with breast cancer diagnosed at a median age of 75 years. None of the selected comorbid conditions were identified in 37 306 (58%) of the 64 034 patients in the study population. Each of the 13 comorbid conditions examined was associated with decreased overall survival and increased mortality (from prior myocardial infarction, adjusted hazard ratio [HR] of death = 1.11, 95% CI = 1.03 to 1.19, P = .006; to liver disease, adjusted HR of death = 2.32, 95% CI = 1.97 to 2.73, P < .001). When patients of age 66–74 years were stratified by stage and individual comorbidity status, patients with each comorbid condition and a stage I tumor had similar or poorer overall survival compared with patients who had no comorbid conditions and stage II tumors.
In a US population of older breast cancer patients, 13 individual comorbid conditions were associated with decreased overall survival and increased mortality.
We assessed the hypothesis that community affluence modifies the association between individual socioeconomic status (SES) and 6 cardiovascular disease (CVD) risk factors: diabetes, hypertension, physical inactivity, obesity, smoking, and poor nutrition. We stratified data from the Colorado Behavioral Risk Factor Surveillance System for 2007 and 2008 by individual SES and 3 categories of community affluence (median household income of county). People who had a low SES seemed to benefit from residing in high-affluence communities. Living in high-affluence communities may mitigate the effect of poverty on CVD risk factors; our findings support the value of interventions that address social determinants of health.
Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal. We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer. Germline TP53 mutation status was assessed by DNA sequencing, screening for heterozygous single-nucleotide polymorphisms, and Multiplex Ligation-Dependent Probe Amplification analyses. From an Australian population-based series of invasive breast cancers, we studied (a) 52 women diagnosed before age 30 years unselected for family history [very early-onset (VEO)] and (b) 42 women diagnosed in their 30s with two or more first- or second-degree relatives with breast or ovarian cancer [early-onset family history (EO-FH)]. Of the VEO group, two (4%) had a mutation: G13203A (exon 6 missense) in a 24-year-old and a large 5,338-bp genomic deletion in a 26-year-old. Neither had a family cancer history that met Li-Fraumeni criteria. Of the EO-FH group, three (7%) had a mutation: T13240G (a known intron 5 splicing mutation) in a 36-year-old from a classic Li-Fraumeni family; G12299A (exon 4 missense) in a 33-year-old from a Li-Fraumeni–like family; and 14058delG (exon 7 frame-shift) in a 39-year-old with a family cancer history that did not meet Li-Fraumeni criteria. Germline TP53 mutations play a larger role in early-onset breast cancer than previously thought, and in this context, can be evident outside clinically defined Li-Fraumeni families. ©2010 AACR.
Hispanic and non-Hispanic white (NHW) populations within the United States have different breast cancer incidence rates, yet there is limited research on how ethnic differences in the prevalence of established risk factors and their associations with breast cancer contribute to the observed differences.
Odds ratios and population attributable risk estimates for breast cancer were determined for Hispanic and NHW women in the population-based, case-control 4-Corners Breast Cancer Study.
When comparing NHW and Hispanic women, we observed differences in the prevalence of certain risk factors, as well as the magnitude and direction of their associations with breast cancer. Hispanic women were more likely to have characteristics associated with lower breast cancer risk, such as earlier age at first birth, having more children, shorter height, less hormone use, and less alcohol consumption. Among premenopausal women, ethnic differences in risk were observed with taller height and positive family history, which were not associated with breast cancer among Hispanic women. Among postmenopausal women, associations for certain risk factors were either weaker or not observed in Hispanics, such as recent estrogen plus progestin hormone therapy use and younger age at menarche. Among NHW women, an estimated 62-75% of breast cancer cases were attributed to the evaluated risk factors, as compared with 7-36% in Hispanic women.
Breast cancer risk factors established in NHW populations had less influence on breast cancer risk in Hispanic women. These findings reflect the need to further evaluate breast cancer risk factors among different ethnic and racial populations.
Hispanic; breast cancer; risk factors; prevalence; association; 4-Corners Breast Cancer Study
Many women who survive breast cancer die of causes unrelated to their cancer diagnosis. This study was undertaken to assess factors that are related to breast cancer mortality versus mortality from other causes and to describe the leading causes of death among older women diagnosed with breast cancer.
Women diagnosed with breast cancer at age 66 or older between 1992 and 2000 were identified in the Surveillance, Epidemiology and End Results-Medicare linked database and followed through the end of 2005.
A total of 63,566 women diagnosed with breast cancer met the inclusion criteria and were followed for a median of approximately nine years. Almost one-half (48.7%) were alive at the end of follow-up. Ages and comorbidities at the time of diagnosis had the largest effects on mortality from other causes, while tumor stage, tumor grade, estrogen receptor status, age and comorbidities at the time of diagnosis all had effects on breast cancer-specific mortality. Fully adjusted relative hazards of the effects of comorbidities on breast cancer-specific mortality were 1.24 (95% confidence interval (95% CI) 1.13 to 1.26) for cardiovascular disease, 1.13 (95% CI 1.13 to 1.26) for previous cancer, 1.13 (95% CI 1.05 to 1.22) for chronic obstructive pulmonary disease and 1.10 (95% CI 1.03 to 1.16) for diabetes. Among the total study population, cardiovascular disease was the primary cause of death in the study population (15.9% (95% CI 15.6 to 16.2)), followed closely by breast cancer (15.1% (95% CI 14.8 to 15.4)).
Comorbid conditions contribute importantly to both total mortality and breast cancer-specific mortality among breast cancer survivors. Attention to reducing the risk of cardiovascular disease should be a priority for the long-term care of women following the diagnosis and treatment of breast cancer.
The detection of gene promoter hypermethylation in sputum is a promising molecular marker for early lung cancer detection. Epidemiologic studies suggest that dietary fruits and vegetables and the micronutrients they contain may reduce risk of lung cancer. This investigation evaluated whether diet and multi-vitamin use influence the prevalence for gene methylation in the cells exfoliated from the aerodigestive tract of current and former smokers. Members (n = 1101) of the Lovelace Smokers Cohort completed the Harvard Food Frequency Questionnaire and provided a sputum sample that was assessed for promoter methylation of eight genes commonly silenced in lung cancer and associated with risk for this disease. Methylation status was categorized as low (< 2 genes methylated) or high (≥2 genes methylated). Logistic regression models were used to identify associations between methylation status and 21 dietary variables hypothesized to affect the acquisition of gene methylation. Significant protection against methylation was observed for leafy green vegetables (OR = 0.83 per 12 monthly servings, CI: 0.74, 0.93) and folate (OR = 0.84 per 750 mcg/day, CI: 0.72, 0.99). Protection against gene methylation was also seen with current use of multi-vitamins (OR = 0.57, CI: 0.40, 0.83). This is the first cohort-based study to identify dietary factors associated with reduced promoter methylation in cells exfoliated from the airway epithelium of smokers. Novel interventions to prevent lung cancer should be developed based on the ability of diet and dietary supplements to affect reprogramming of the epigenome.
gene methylation; folate; multi-vitamins; green vegetables; smokers
Lung cancer is usually disseminated at diagnosis making prognosis poor. Smokers are at high risk for lung cancer and are targets for prevention and early detection strategies. Sputum is a potential source for lung cancer biomarkers, but no test is currently available with sufficient sensitivity and specificity for clinical screening utility. Chromosomal aneusomy (CA) was measured in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls matched on age, gender, and date of collection. The CA-FISH assay was performed using a four-target DNA FISH probe including EGFR, MYC, 5p15 and CEP6. Sensitivity for a positive CA-FISH assay (abnormal for ≥ 2 of the 4 markers) was substantially higher for samples collected within 18 months (76%) than >18 months before lung cancer diagnosis (31%). Specificity for a positive FISH by this same definition was 85%. Among subjects providing sputum sample within 18 months before diagnosis, sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). The adjusted odds ratios for specimens collected within 18 months of cancer diagnosis were higher using the CA-FISH assay (OR=27.2, 95% CI 7.8 to 94.1) than previous studies assessing cytologic atypia (OR=2.3, CI 0.8 to 6.4) or gene promoter methylation (OR=6.5; CI 1.2 to 35.5). In conclusion, chromosomal aneusomy in sputum is a promising biomarker for prediction of lung cancer risk. Evaluation of the 4-DNA targets was more effective than any single marker and had highest sensitivity for samples collected ≤ 18 months to lung cancer diagnosis and patients diagnosed with squamous cell carcinoma.
Sputum; Lung Cancer; FISH; biomarker; Chromosomal Abnormality
Sun exposure and high prevalence of melanocytic nevi are major risk factors for melanoma, but the relationship between them is not well understood. This study examines the relationship between sun exposure (detailed by anatomic location and history of site-specific sunburns) and the presence of melanocytic nevi on 743 White children in Denver, Colorado. Parental reports of site-specific sunburns were collected annually for 2 years starting at ages 5 to 6 years. In the third year, nevi were counted and mapped by anatomic location. Nevus density was higher for boys (36.0 nevi/m2) than for girls (31.0 nevi/m2; P = 0.04). Nevus density was highest on the face, neck, and lateral forearms and was significantly higher in chronically versus intermittently sun-exposed areas (P < 0.0001). Compared with girls, boys had higher nevus density on the face, neck, and trunk, and lower nevus density on the upper arms and thighs (P < 0.01). In 2 years of reports, most subjects (69%) received at least one sunburn. The face, shoulders, and back were the most frequently sunburned areas of the body. When adjusted for host factors, total number of sunburns was significantly associated with higher total nevus prevalence (P = 0.01 for one burn). Site-specific sunburns were significantly associated with nevus prevalence on the back (P = 0.03 for three or more sunburns), but not on the face, arms, or legs. In this high-risk population, there is evidence for two pathways to nevus accumulation: by chronic sun exposure and by intermittent exposure related to sunburns.
The nature of the relationship between nevus development in childhood and later development of melanoma is unclear. Data on melanoma diagnoses by histologic type and anatomic site were obtained for 2351 white, non-Hispanics in Colorado from the Colorado Central Cancer Registry between 2000 and 2004. Nevus size and body site were ascertained during skin exams conducted in the summer of 2007 on 717 white, non-Hispanic children aged 8–9 years. Chi-square goodness-of-fit analysis was used to assess the association between the anatomic site distributions of nevi versus melanoma. Superficial spreading melanoma was the most frequent histology, followed by lentigo maligna melanoma. Nodular melanoma was the least common histology. For males, there was no significant difference between the distribution of medium-sized (≥2mm) nevi and the distribution of both superficial spreading and nodular melanomas. For females, there was no significant difference between the anatomic distribution of small-sized (< 2mm) nevi and the distribution of nodular melanoma, and there was marginal evidence for a difference between the distribution of medium-sized (≥2mm) nevi and the distribution of nodular melanoma. There was evidence for a difference between all of the nevus distributions and the distributions of superficial spreading and lentigo maligna melanoma in females. The similarities between the nevus and melanoma distributions are interesting findings, but it is difficult to interpret the significance of these findings based on the current state of knowledge of melanoma etiology.
anatomic distribution; epidemiology; malignant melanoma; melanocytic nevi
This study explores whether certain population characteristics are associated with adherence to mammography screening guidelines among Hispanic and non-Hispanic white (NHW) women living in the southwestern United States.
Participants in a population-based study (4-Corners' Breast Cancer Study) included in this analysis were 790 Hispanic women and 1441 NHW women. Multivariate logistic regression was used to compute the ethnic-specific adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of the outcome variable (adherent vs. nonadherent) and its correlates. Women were adherent if they had obtained their first mammogram between 41 and 50 years of age and had received at least one mammogram per 2 years or less.
Ethnic-specific associations were observed with certain population characteristics and mammography adherence. Specifically, characteristics that were significantly associated with adherence among Hispanic women were younger age (50–59 years), having a family history of breast cancer, nulliparity, hormone replacement therapy (HRT) use, nonsteroidal anti-inflammatory drug (NSAID) use, and performing regular breast self-examinations (BSE). Among NHW women, younger age (50–59 years), family history of breast cancer, obesity, consuming moderate amounts of alcohol, and taking HRT were associated with mammography adherence. When adjusting for the evaluated population characteristics, the relationship between ethnicity and mammography adherence was no longer apparent.
Ethnic-specific characteristics appear to explain differences in mammography adherence among Hispanic and NHW women. Disparities in screening rates, late-stage disease and breast cancer mortality that impact Hispanic women could potentially be addressed more effectively by interventions that specifically target the unique characteristics of the Hispanic population.
To examine the relationship between tanning and nevus development in very-light-skinned children.
Prospective cohort nested within a randomized controlled trial. Skin examinations in 3 consecutive years (2004, 2005, and 2006) included full-body counts of nevi, skin color and tanning measurement using colorimetry, and hair and eye color evaluation by comparison with charts. Telephone interviews of parents provided sun exposure, sun protection, and sunburn history.
Large managed-care organization and private pediatric offices in the Denver, Colorado, metropolitan area.
A total of 131 very-light-skinned white children without red hair and 444 darker-skinned white children without red hair born in Colorado in 1998.
Main Outcome Measures
Full-body nevus counts at ages 6 to 8 years.
Among very-light-skinned white children, geometric mean numbers of nevi for minimally tanned children were 14.8 at age 6 years; 18.8 at age 7 years; and 22.3 at age 8 years. Mean numbers of nevi for tanned children were 21.2 at age 6 years; 27.9 at age 7 years; and 31.9 at age 8 years. Differences in nevus counts between untanned and tanned children were statistically significant at all ages (P < .05 for all comparisons). The relationship between tanning and number of nevi was independent of the child’s hair and eye color, parent-reported sun exposure, and skin phototype. Among darker-skinned white children, there was no relationship between tanning and nevi.
Very-light-skinned children who tan (based on objective measurement) develop more nevi than children who do not tan. These results suggest that light-skinned children who develop tans may be increasing their risk for developing melanoma later in life.
Physical activity may influence breast cancer risk through multiple mechanisms and at different periods in life. In this study we evaluate breast cancer risk associated with total and vigorous physical activity at ages 15, 30, and 50 years and the referent year prior to diagnosis/selection. Participants were non-Hispanic white (NHW) (1527 cases and 1601 control subjects) and Hispanic/American Indian (HAI) (798 cases and 924 controls) women. Both total and vigorous activity reduced risk of breast cancer in a dose-response manner. Among premenopausal women, only high total metabolic equivalent of the task (MET) hours of activity during the referent year was associated with reduced breast cancer risk in NHW women (odds ratio [OR] 0.62; 95% confidence interval [CI] 0.43, 0.91). Among postmenopausal women, physical activity had the greatest influence among women not recently exposed to hormones. Among these women, high total lifetime activity reduced risk of breast cancer for both NHW (OR 0.60; 95% CI 0.36, 1.02; p trend 0.01) and HAI women (OR 0.52; 95% CI 0.23, 1.16; p trend 0.07). Additionally, high total MET hours of activity at age 30 years (OR 0.56; 95% CI 0.37, 0.85) and at age 15 years (OR 0.57; 95% CI 0.38, 0.88) reduced breast cancer risk among postmenopausal NHW women not recently exposed to hormones. Among HAI women, more recent activity performed during the referent year and at age 50 appeared to have the greatest influence on breast cancer risk. Among postmenopausal NHW women. there was a significant interaction between physical activity and hormone replacement therapy (p value, 0.01), while among postmenopausal HAI women, physical activity interacted with body mass index (p value, 0.04). These data suggest that physical activity is important in reducing risk of breast cancer in both NHW and HAI women.
BMI; Breast Cancer; Physical Activity; Hispanic; Hormones
The association between obesity and breast cancer risk is complex. We examined whether the association between body size and breast cancer risk is modified by interleukin-6 (IL6) genotype.
Methods and Procedures
Five polymorphisms in the IL-6 gene (rs1800797/-596A>G, rs1800796/-572G>C, rs1800795/-174G>C, rs2069832/IVS2G>A, and rs2069849 exon 5 C>T) were studied. We investigated IL6 genotypes and haplotypes with indicators of body size among non-Hispanic white (NHW) and Hispanic/American Indian (AI) breast cancer cases and controls living in the Southwestern United States.
We observed lower mean levels of BMI among NHW women who carried one or two copies of the GGCAC haplotype (in order: rs1800797, rs1800796, rs1800795, rs2069832, and rs2069849; P trend 0.02). This haplotype, with an estimated frequency of 43% in NHW study controls, was considerably less common in Hispanic/AI controls (19%). We did not detect significant interactions between IL6 genotypes or haplotypes and BMI categorized as low/normal (<25), overweight (25 to <30), or obese (≥30) and breast cancer risk in either NHW or Hispanic/AI women. However, we detected consistent and significant interactions between waist-to-hip ratio (WHR) and IL6 rs1800795/-174 G>C genotype for breast cancer risk. These associations were restricted to postmenopausal NHW women. Among women without recent hormone exposure, those with a WHR >0.9 and the rs1800795 GG genotype had a greater than threefold increased risk of breast cancer (odds ratios (ORs) 3.22, 95% confidence intervals (CIs) 1.27, 817) when compared with women with a WHR <0.8 and the rs1800795 GG genotype (P interaction 0.01).
These data suggest that IL-6 genotypes may influence breast cancer risk in conjunction with central adiposity.