Because the colonic mucosa is in direct contact with digesta, luminal exposure to potentially carcinogenic or chemopreventive agents may be important in colorectal carcinogenesis, independently of the effects of systemic exposure through the circulation. To date, few biomarkers for luminal exposure have been identified, and isolation of reasonably good quality fecal human RNA remains difficult. In this study, we assessed the yield and quality of RNA extracted from 10 human stool samples after storage with several commercially available preservatives compared with stool samples immediately frozen in liquid nitrogen. This study shows that careful design of primer pairs which amplify a short length of DNA is key to obtaining interpretable and reproducible results. Moreover, the use of commercially available RNA preservation kits enables investigators to collect usable fecal samples from large populations. Of all the preservative methods tested, RNAlater had the best performance in terms of overall quality, quantity, and level of genomic DNA contamination, and thus deserves further investigation.
Several studies have reported a positive relation of baseline body mass index (BMI) with multiple myeloma, but data on other correlates of energy balance are limited. We undertook the present analyses to further examine the role of energy balance in multiple myeloma etiology in two large prospective cohorts with biennially updated exposure data. We followed members of the Nurses’ Health Study and Health Professionals Follow-up Study cohorts from baseline until multiple myeloma diagnosis, death, or 2002. Adult height and current weight were reported at enrollment, and weight every 2 years thereafter. Physical activity was queried at baseline and updated every 2-4 years. We computed age-adjusted relative risks (RR) of multiple myeloma for categories of BMI and physical activity using Cox proportional hazards regression. We conducted analyses on each cohort separately and on both cohorts combined. We confirmed 215 incident cases of multiple myeloma in the combined cohort of 136,623 individuals (>2.1 million person-years at risk). BMI was positively associated with multiple myeloma in all analyses. The association was strongest in men with BMI ≥30 kg/m2 (v. BMI <22.0 kg/m2; RR=2.4, 95% confidence interval (CI)=1.0-6.0) and modest in overweight (BMI 25-29.9 kg/m2) and obese (BMI ≥30 kg/m2) women (v. BMI <22.0 kg/m2; RR (95% CI)=1.6 (1.0-2.7) and 1.2 (0.7-2.2), respectively). Physical activity was not significantly related to multiple myeloma risk, although an inverse association was suggested in women. In conclusion, obesity appears to have an etiologic role in multiple myeloma, but the role of other correlates of energy balance remains uncertain.
multiple myeloma; risk factors; body mass index; physical activity; epidemiology
Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting.
We combined data from two case–cohort studies based in the Women’s Health Initiative- Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model.
A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2–76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9–68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6–273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8–161.1) for BMI when restricted to estrogen receptor positive (ER+) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8–284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER+ breast cancers.
The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin.
The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.
Helicobacter pylori is the leading risk factor for gastric cancer, yet only a fraction of infected individuals ever develop neoplasia.
To identify potential predictive biomarkers, we assessed the association of 15 antibodies to Helicobacter pylori proteins and gastric cancer in a nested case-control study. Blood levels of antibodies were assessed using multiplex serology for 226 incident cases and 451 matched controls from the Shanghai Men’s Health Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.
Sero-positivity to four (Omp, HP0305, HyuA, and HpaA) proteins were associated with a one-and-a-half to three-fold increased risk for gastric cancer. When excluding cases diagnosed within two years of study enrollment, sero-positivity to two additional proteins (CagA and VacA) showed significant associations with risk. Compared to individuals with ≤3 sero-positive results to the six virulent proteins identified in this population, individuals with 4–5 sero-posit ive results were at a two-fold increased risk (OR=2.08, 95% CI: 1.31–3.30) and individuals sero-positive to all 6 proteins had a three-and-a-half-fold increase in risk (OR=3.49, 95% CI: 2.00–6.11) for gastric cancer. Among individuals diagnosed at least two years after study enrollment, these associations were even stronger (OR=2.79 and OR=4.16, respectively).
Increasing number of sero-positives to six H. pylori proteins may be a risk marker for distal gastric cancer in China.
In a population with a 90% prevalence of CagA-positive H. pylori infection, assessment of additional virulent H. pylori proteins might better identify individuals at high risk for gastric cancer.
Helicobacter pylori; biomarkers; gastric cancer; epidemiology
We propose a two-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.
First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N=281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N=74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are re-estimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.
Using the best fitting segregation models in model-based multipoint linkage analysis, we identified two separate peaks on chromosome 17; the first agreed with a region identified by Shete et al. who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD).
Our approach has the advantage of not requiring markers to be in linkage equilibrium unless the minor allele frequency is small (markers which tend to be uninformative for linkage), and of using more of the available information for LOD-based linkage analysis.
Glioma; model-based linkage; segregation; age of onset; prevalence constraint
Lesbian and bisexual women may be at greater risk of breast cancer than heterosexual women during the premenopausal period due to disparities in risk factors.
With 16 years of prospective data from a large cohort of U.S. women ages 25–58 years, we conducted a breast cancer risk assessment for 87,392 premenopausal women by applying the Rosner-Colditz biomathematical risk-prediction model to estimate breast cancer risk based on known risk factors. Based on each woman’s comprehensive risk factor profile, we calculated the predicted one-year incidence rate (IR) per 100,000 person-years and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) for lesbian and bisexual women compared to heterosexual women.
87,392 premenopausal women provided 1,091,871 person-years of data included in analyses. Mean predicted one-year breast cancer IRs per 100,000 person-years for each sexual orientation group were: heterosexual 122.55, lesbian 131.61, and bisexual 131.72. IRs were significantly elevated in both lesbian (IRR 1.06; 95 CI 1.06, 1.06) and bisexual (IRR 1.10; 95% CI 1.10, 1.10) women compared to heterosexual women.
Our findings suggest both lesbian and bisexual women have slightly elevated predicted breast cancer incidence compared to heterosexual women throughout the premenopausal period.
Health professionals must ensure that breast cancer prevention efforts are reaching these women. As more health systems around the country collect data on patient sexual orientation, the National Cancer Institute’s SEER cancer registry should add this information to its data system to monitor progress in reducing sexual orientation-related disparities in cancer incidence and mortality.
breast cancer; risk model; sexual orientation; bisexual; lesbian; premenopausal
Appalachia is a geographic region with high cervical cancer incidence and mortality rates, yet little is known about human papillomavirus (HPV) vaccination in this region. We determined HPV vaccine coverage among adolescent females from Appalachia, made comparisons to non-Appalachian females, and examined how coverage differs across subregions within Appalachia.
We analyzed 2008–2010 data from the National Immunization Survey-Teen (NIS-Teen) for adolescent females ages 13–17 (n=1,951 Appalachian females and n=25,468 non-Appalachian females). We examined HPV vaccine initiation (receipt of at least one dose), completion (receipt of at least three doses), and follow-through (completion among initiators). Analyses used weighted logistic regression.
HPV vaccine initiation (Appalachian=40.8% vs. non-Appalachian=43.6%; OR=0.92, 95% CI: 0.79–1.07) and completion (Appalachian=27.7% vs. non-Appalachian=25.3%; OR=1.12, 95% CI: 0.95–1.32) were similar between Appalachian and non-Appalachian females. HPV vaccine follow-through was higher among Appalachian females than non-Appalachian females (67.8% vs. 58.1%; OR=1.36, 95% CI: 1.07–1.72). Vaccination outcomes tended to be higher in the Northern (completion and follow-through) and South Central (follow-through) subregions of Appalachia compared to non-Appalachian U.S. Conversely, vaccination outcomes tended to be lower in the Central (initiation and completion) and Southern (initiation and completion) subregions.
In general, HPV vaccination in Appalachia is mostly similar to the rest of the U.S. However, vaccination is lagging in regions of Appalachia where cervical cancer incidence and mortality rates are highest.
Current cervical cancer disparities could potentially worsen if HPV vaccine coverage is not improved in regions of Appalachia with low HPV vaccine coverage.
Human papillomavirus; HPV vaccine; Appalachia; Cancer; Adolescent
Exposure to arsenic (As) is associated with an increased risk of several cancers, as well as, cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and post-translational histone modifications (PTHMs) in vitro.
Water and urinary As concentrations, as well as, global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 trimethylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac) and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMCs) from a subset of participants (N=40) of a folate clinical trial in Bangladesh (FACT study).
Total urinary As (uAs) was positively correlated with H3K9me2 (r=0.36, p=0.02) and inversely with H3K9ac (r= -0.47, p=0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 (r=0.45, p=0.05) and H3K27me3 (r=0.50, p=0.03) among females and negatively correlated among males (H3K4me3: r= -0.44, p=0.05; H3K27me3: r= -0.34, p=0.14). Conversely, wAs was inversely associated with H3K27ac among females (r= -0.44, p=0.05) and positively associated among males (r=0.29, p=0.21). A similar pattern was observed for H3K18ac (females: r= -0.22, p=0.36; males: r=0.27, p=0.24).
Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks.
These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity.
Arsenic; epigenetics; histone modifications; Bangladesh; gender difference
Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single nucleotide polymorphisms (SNPs).
We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P-trends.
Nine out of 10 top-ranking SNPs (Ptrend<0.01) were located in the FTO (fat mass and obesity associated) gene region, while the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.
single nucleotide polymorphisms; case-control study; obesity; body mass index; thyroid neoplasms
Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation and altered levels of adipose derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight and weight change are associated with CBC risk.
Variants in twenty genes (182 single nucleotide polymorphisms) involved in adipose tissue metabolism, energy balance, insulin resistance and inflammation, as well as those identified through genome-wide association studies of BMI and type II diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants (643 cases with CBC and 1,271 controls with unilateral breast cancer) in the population-based Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression.
After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor status did not alter these findings.
Among women with early onset disease who survive a first breast cancer diagnosis there was no association between variation in obesity-related genes and risk of CBC.
Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.
genetic variation; obesity; weight; weight change; contralateral breast cancer
Leukemia is a common cancer among United States adults but there are few established risk factors. If leukemia risks are substantially influenced by exposures that vary in prevalence across generations, then population incidence rates should vary significantly by birth cohort. However, prior studies have not examined leukemia birth cohort effects using contemporary data and methods.
We used incidence data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program from 1992 through 2009 for adults 25 – 84 years old and age-period-cohort models to estimate incidence rate ratios according to birth cohort for acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL).
Leukemia incidence varied significantly between birth cohorts for each major leukemia type in men and women except female AML; changes on the order of 1% per birth year or 20% per generation were observed. The most significant birth cohort signatures were observed for CLL and AML in men, which were decreasing and increasing, respectively, in cohorts born since 1946.
Our results support the hypothesis that adult leukemia risks are significantly modulated by environmental and lifestyle exposures.
A number of well-established (smoking, certain chemicals, radiation) and newly-recognized (obesity) leukemia risk factors are modifiable; ultimately, efforts to promote healthy lifestyles might also help reduce incidence rates of adult leukemia.
Leukemia; Incidence; Age Factors; Sex Factors; United States/Epidemiology
Bladder cancer (BCa) is among the five most common malignancies world-wide, and due to high rates of recurrence, one of the most prevalent. Improvements in non-invasive urine-based assays to detect BCa would benefit both patients and healthcare systems. In this study, the goal was to identify urothelial cell transcriptomic signatures associated with BCa.
Gene expression profiling (Affymetrix U133 Plus 2.0 arrays) was applied to exfoliated urothelia obtained from a cohort of 92 subjects with known bladder disease status. Computational analyses identified candidate biomarkers of BCa and an optimal predictive model was derived. Selected targets from the profiling analyses were monitored in an independent cohort of 81 subjects using quantitative real-time PCR (RT-PCR),
Transcriptome profiling data analysis identified 52 genes associated with BCa (p≤0.001), and gene models that optimally predicted class label were derived. RT-PCR analysis of 48 selected targets in an independent cohort identified a 14-gene diagnostic signature that predicted the presence of BCa with high accuracy.
Exfoliated urothelia sampling provides a robust analyte for the evaluation of patients with suspected BCa. The refinement and validation of the multi-gene urothelial cell signatures identified in this preliminary study may lead to accurate, non-invasive assays for the detection of BCa.
The development of an accurate, non-invasive BCa detection assay would benefit both the patient and healthcare systems through better detection, monitoring and control of disease.
Genomic profiling; Bladder cancer; Urinalysis; Non-invasive detection
Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.
miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR-based analyses, we compared the expression of miRs (n=198) between lung cancer cases consuming high-versus-low quercetin-rich food intake using multivariate ANOVA tests. In family-miR-based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miRs families. We accounted for multiple testing using 10,000 global permutations (significance at p-valueglobal <0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).
Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (p-valueFCS<0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (p-valuesFCS<0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest-and-lowest quercetin-rich food consumers (23 expected by chance; p-valueglobal = 0.047).
We observed differential expression of key biologically functional miRNAs between high-versus-low consumers of quercetin-rich foods in adenocarcinoma cases.
Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis.
Sexually transmitted carcinogenic Human Papillomavirus (HPV) infections are extraordinarily prevalent worldwide. However, most incident HPV infections clear within a few years, whereas a small minority persists to invasive cancer. Recent studies indicate that detection of methylated viral DNA may distinguish women with cervical intraepithelial neoplasia grade 2+ (CIN2+) from those with a carcinogenic HPV type infection that shows no evidence of CIN2+. Several studies have reported a positive association between methylation of CpG sites in the L1 gene and CIN2+, while there are inconclusive results regarding methylation of CpG sites in the Upstream Regulatory Region (URR). In this review, we summarize the current state of knowledge on HPV DNA methylation in cervical carcinogenesis, and discuss the merits of different methods used to measure HPV DNA methylation. To follow the promising leads, we suggest future studies to validate the use of methylated carcinogenic HPV DNA as a predictive and/or diagnostic biomarker for risk of cervical cancer among HPV-positive women.
human papillomavirus; methylation; cervical cancer; biomarker; epigenetics
Participant accrual to research studies is a challenge, and oftentimes advertisements are used to supplement cases ascertained through clinic caseloads and cancer registries. It is unknown however, if cases ascertained through these two sources differ. In this study, we compare self-referred (n=209) versus cancer registry-ascertained participants (n=334) enrolled in FRESH START, a randomized controlled trial promoting a healthy diet and increased exercise among breast and prostate cancer survivors. The two groups were compared on baseline characteristics, adherence, attrition, and outcomes by study arm. Compared to participants enrolled from registries, self-referrals were significantly younger (54.1±10.4 vs. 58.7±10.7 years), more likely to have later-staged disease and to have received chemotherapy (40% vs. 19%), and more likely to report “fighting spirit” coping styles (50% vs. 30%), lower quality-of-life (88.2+15.1 vs. 92.0+12.9), fewer co-morbid conditions (1.87±1.60 vs. 2.24±1.78), and lower consumption of 5 or more daily servings of fruits and vegetables (35% vs. 45%)(p-values <.05). While no differences in behavior change were observed between self-referred and registry-ascertained cases assigned to the tailored intervention arm, this was not the case within the attention control arm. Among those who received the attention control intervention of standardized materials in the public domain, self-referred versus registry-ascertained participants demonstrated significantly greater increases in exercise at 1-year follow-up, and significantly greater increases in fruit and vegetable consumption at both 1- and 2-year follow-up (p-values <.05). Several differences exist between self-referred versus registry-ascertained participants, including motivation to respond to standardized educational materials which appears significantly greater in self-referred populations.
patient selection; registries; neoplasms; advertising
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death in females and leading gynecologic cause of cancer death. Despite the identification of a number of serum biomarkers, methods to identify early stage disease and predict prognosis remain scarce. We have evaluated two biologically connected serum biomarkers, serum leukocyte protease inhibitor (SLPI) and progranulin (PGRN).
200 frozen plasma samples were acquired from the Mayo Clinic Biospecimen Repository for Ovarian Cancer Research. Samples were obtained from 50 patients with benign conditions, 50 with AJCC stage I and II EOC, and 100 with AJCC stage III and IV EOC patients. Samples were obtained prior to surgical resection of a mass and were analyzed for absolute levels of SLPI and PGRN using enzyme-linked immunosorbent (ELISA) assays. Receiver-operator characteristic curves were generated for SLPI and PGRN. Median follow-up was 48 months.
Absolute levels of SLPI were significantly elevated in patients with EOC compared to benign disease and predicted the presence of EOC (AUC of 0.812. P = 0.04); SLPI remained elevated in the subset of patients with normal CA-125, PGRN levels were not significantly increased in early stage or late stage EOC patients as a whole, but an increase in PGRN levels was associated with decreased overall survival in advanced EOC.
SLPI levels are elevated in epithelial ovarian cancer, and SLPI shows promise as a diagnostic biomarker for patients with both elevated and normal CA-125 levels. An increase in PGRN is associated with decreased overall survival.
SLPI is elevated in EOC and warrants investigation in a screening study in women at risk for EOC.
Ovarian neoplasms; GRN protein, human; SLPI protein, human; Biological Markers; Prognosis
To determine whether exposure to smoking imagery in films predicts smoking onset among never-smoking Mexican adolescents.
The analytic sample was comprised of 11- to 14-year old secondary school students who reported never having tried smoking at baseline, 83% (1741/2093) of whom were successfully followed up after one year. Exposure to 42 popular films that contained smoking was assessed at baseline, whereas smoking behavior and risk factors were assessed at baseline and follow up. Logistic regression was used to estimate bivariate and adjusted relative risks of trying smoking and current smoking at follow up.
At follow up, 36% reported having tried smoking and 8% reported having smoked in the previous month. Students who were successfully followed up were exposed to an average of 43.8 minutes of smoking in the films they reported viewing at baseline. Adjusted relative risks (ARRs) indicated that students in the two highest levels of exposure to film smoking were more than twice as likely to have smoked in the previous 30 days at follow up (ARR3v1=2.44, 95%CI 1.31, 4.55; ARR4v1=2.23, 95% CI 1.19, 4.17). The adjusted relative risk of having tried smoking by follow up reached statistical significance only when comparing the 3rd highest to the lowest exposure group (ARR3v1=1.54, 95%CI 1.01, 2.64). Having a parent or best friend who smoked at baseline were the only other variables that independently predicted both outcomes.
Exposure to movie smoking is a risk factor for smoking onset among Mexican youth.
Media; tobacco; smoking; longitudinal; adolescents
Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in one-carbon metabolism, may alter DNA methylation levels, and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata defined by promoter methylation status for each of three genes, E- cadherin, p16, and RAR-β2 in breast cancer; in addition, we evaluated case-case comparisons of likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real time methylation-specific PCRs for 803 paraffin embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios (OR) and 95% confidence intervals (CI). We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, ER status, folate intake and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E- cadherin, p16, and RAR-β2 genes in breast cancer.
promoter methylation; MTHFR; MTR; breast cancer; epidemiology; genetic polymorphisms
Whether to return individual research results from cancer genetics studies is widely debated, but little is known about how participants respond to results disclosure or about its time and cost burdens on investigators.
We recontacted participants at one site of a multicenter genetic epidemiologic study regarding their CDKN2A gene test results and implications for melanoma risk. Interested participants were disclosed their results by telephone and followed for 3 months.
Among 39 patients approached, 27 were successfully contacted, and 19 (70% uptake) sought results, including three with mutations. Prior to disclosure, participants endorsed numerous benefits of receiving results (mean = 7.7 of 9 posed), including gaining information relevant to their children’s disease risk. Mean psychological well-being scores did not change from baseline, and no decreases to melanoma prevention behaviors were noted. Fifty-nine percent of participants reported that disclosure made participation in future research more likely. Preparation for disclosure required 40 minutes and $611 per recontact attempt. An additional 78 minutes and $68 was needed to disclose results.
Cancer epidemiology research participants who received their individual genetic research results showed no evidence of psychological harm or false reassurance from disclosure and expressed strong trust in the accuracy of results. Burdens to our investigators were high, but protocols may differ in their demands and disclosure may increase participants’ willingness to enroll in future studies.
Providing individual study results to cancer genetics research participants poses potential challenges for investigators, but many participants desire and respond positively to this information.
One plausible mechanism for the environment to alter cancer susceptibility is through DNA methylation. Alterations in DNA methylation can lead to genomic instability and altered gene transcription. Genomic DNA methylation levels have been inversely associated with age suggesting that factors throughout life may be associated with declines in DNA methylation. Using information from a multi-ethnic New York City birth cohort (born between 1959 and 1963), we examined whether genomic DNA methylation, measured in peripheral blood mononuclear cells, was associated with smoking exposure and other epidemiologic risk factors across the lifecourse. Information on prenatal and childhood exposures was collected prospectively through 1971; and information on adult exposures and blood specimens were collected in adulthood from 2001-2007. Methylation levels of leukocyte DNA were determined using a [3H]-methyl acceptance assay where higher values of DPM/μg DNA indicate less DNA methylation. Genomic methylation of leukocyte DNA differed by ethnicity (66% of blacks, 48% of whites, and 29% of Hispanics were above the median level of DPM/μg DNA) (p = 0.03). In multivariable modeling, DNA methylation was statistically significantly associated with maternal smoking during pregnancy, longer birth length, later age at menarche, nulliparity, and later age at first birth. These data, if replicated in larger samples, suggest that risk factors across the lifecourse may be associated with DNA methylation in adulthood. Larger studies and studies that measure within-individual changes in DNA methylation over time are a necessary next step.
There is growing evidence linking genetic variations to non–Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes.
We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case–control study. Gene-level summary of associations were obtained by computing the minimum P value (“minP test”) on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP.
Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05).
Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis.
Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region
We used a composite variable comprised of insurance status, income, and race/ethnicity to investigate access-enhancing programs as a possible reason for “reversals of association” (RAs), and large percent changes (LPCs), between race/ethnicity and cancer screening, when comparing the unadjusted and adjusted odds ratios.
Data were from women aged 40-64, using the combined 2008 and 2010 Behavioral Risk Factor Surveillance System surveys. Recent mammography was within the past two years, and recent Pap testing was within the past three years. Initial analyses using all variables singly, were followed by analyses that used the composite variable with the remaining covariates.
Analyses with race/ethnicity singly indicated reversals of association for Hispanic women and higher estimated screening for Black and Hispanic women compared to White women. Analyses with the composite variable found no RAs, but there were several LPCs for Hispanic and Black women, for lower-income, and for uninsured women. White, uninsured, lower-income women were among those with the lowest utilization.
Results were consistent with the possibility that access-enhancing programs for lower-income, uninsured and often Non-White women can lead to overestimates of screening, RA's and LPCs in multivariable analyses. Attention should be given to identifying large percent changes to unadjusted odds ratios. Lower-income, uninsured White women are also a group at risk of extremely low mammography and Pap test utilization.
Combining variables to create better-targeted population subgroups may help in the interpretation of analyses that produce RAs, and LPCs for correlates of cancer screening utilization.
mammography; Pap testing; behavioral science; women's health; preventive health services
Prostate cancer (Pca) is the most common type of cancer among men in the United States, and its incidence and mortality rates are disproportionate among ethnic groups. While genome-wide association studies of European descents have identified candidate loci associated with Pca risk, including a variant in IL16, replication studies in African Americans (AAs) have been inconsistent. Here we explore SNP variation in IL16 in AAs and test for association with Pca.
Association tests were performed for 2,257 genotyped and imputed SNPs spanning IL16 in 605 AA Pca cases and controls from Washington, DC. Eleven of them were also genotyped in a replication population of 1,093 AAs from Chicago. We tested for allelic association adjusting for age, global and local West African ancestry.
Analyses of genotyped and imputed SNPs revealed that a cluster of IL16 SNPs were significantly associated with Pca risk. The strongest association was found at rs7175701 (P=9.8 × 10−8). In the Chicago population, another SNP (rs11556218) was associated with Pca risk (P=0.01). In the pooled analysis, we identified three independent loci within IL16 that were associated with Pca risk. SNP eQTL analyses revealed that rs7175701 is predicted to influence the expression of IL16 and other cancer related genes.
Our study provides evidence that IL16 polymorphisms play a role in Pca susceptibility among AAs.
Our findings are significant given that there has been limited focus on the role of IL16 genetic polymorphisms on Pca risk in AAs.
In the Women’s Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio.
In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by EIA at baseline, and for those randomized to active treatment (n=1259), at 1 year.
The 1 year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 vs. 43.5 pg/ml, p<0.001), but both increased 2-OHE1 by ~300 pg/ml. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and. for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant.
Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer.
Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT which may explain smaller than expected increase in breast cancer compared with endogenous estrogens.
Breast cancer; estrogen metabolism; hormone therapy; postmenopausal