Overweight and obesity are health problems of epidemic proportions, increasing the risk not only of cardiovascular disease and type 2 diabetes mellitus but also of various types of cancer. Obesity is strongly associated with changes in the physiological function of adipose tissue, leading to insulin resistance, chronic inflammation, and altered secretion of adipokines. Several of these factors, such as insulin resistance, increased levels of leptin, plasminogen activator inhibitor-1, and endogenous sex steroids, decreased levels of adiponectin, and chronic inflammation, are involved in carcinogenesis and cancer progression. This article reviews these mechanisms, focusing on adipose tissue dysfunction as a unifying causal factor. Although understanding of the link between obesity and cancer might provide therapeutic targets, preventing overweight and obesity still remains number one priority. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2569–78)

Background: Although numerous studies have examined the association of area socioeconomic status (SES) and cancer screening after controlling for individual SES, findings have been inconsistent. A systematic review of existing studies is timely to identify conceptual and methodologic limitations and to provide a basis for future research directions and policy.

Objective: The objectives were to (a) describe the study designs, constructs, methods, and measures; (b) describe the independent association of area SES and cancer screening; and (c) identify neglected areas of research.

Methods: We searched six electronic databases and manually searched cited and citing articles. Eligible studies were published before 2008 in peer-reviewed journals in English, represented primary data on individuals ages ≥18 years from developed countries, and measured the association of area and individual SES with breast, cervical, or colorectal cancer screening.

Results: Of 19 eligible studies, most measured breast cancer screening. Studies varied widely in research design, definitions, and measures of SES, cancer screening behaviors, and covariates. Eight employed multilevel logistic regression, whereas the remainder analyzed data with standard single-level logistic regression. The majority measured one or two indicators of area and individual SES; common indicators at both levels were poverty, income, and education. There was no consistent pattern in the association between area SES and cancer screening.

Discussion: The gaps and conceptual and methodologic heterogeneity in the literature to date limit definitive conclusions about an underlying association between area SES and cancer screening. We identify five areas of research deserving greater attention in the literature. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2579–99)

Background: The Healthy Exercise for Lymphoma Patients trial showed that aerobic exercise training improved important health outcomes in lymphoma patients. Here, we examine potential moderators of the exercise training response.

Methods: Lymphoma patients were stratified by major disease type and current treatment status and randomly assigned to usual care (n = 62) or aerobic exercise training (n = 60) for 12 weeks. Endpoints were quality of life, cardiovascular fitness, and body composition. Moderators were patient preference for group assignment, age, sex, marital status, disease stage, body mass index, and general health.

Results: Patient preference did not statistically moderate the effects of exercise training on quality of life (P for interaction = 0.36), but the interaction effect of 7.8 points favoring patients with no preference was clinically meaningful. Marital status (P for interaction = 0.083), general health (P for interaction = 0.012), and body mass index (P for interaction = 0.010) moderated the effects of aerobic exercise training on quality of life with better outcomes for unmarried versus married patients, patients in poor/fair health versus good-to-excellent health, and normal weight/obese versus overweight patients. Disease stage (P for interaction = 0.056) and general health (P for interaction = 0.012) moderated the effects of aerobic exercise training on body composition with better outcomes for patients with advanced disease versus early disease/no disease and patients in good health versus very good-to-excellent health. No variables moderated intervention effects on cardiovascular fitness. Findings were not explained by differences in adherence.

Conclusions: Clinically available variables predicted quality of life and body composition responses to aerobic exercise training in lymphoma patients. If replicated, these results may inform future randomized trials and clinical practice. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2600–7)

Genes coding for nicotinic acetylcholine receptors may influence response to nicotine replacement therapy for smoking cessation. We examined the association of a 3' untranslated region polymorphism (rs2072661) in the nicotinic acetylcholine receptor β2 subunit (CHRNB2) gene with quitting success in response to nicotine versus placebo patch during a short-term test of patch effects. In a within-subjects cross-over design, smokers of European descent (n = 156) received 21 mg nicotine and placebo patch in counter-balanced order, during two separate 5-day simulated quit attempts, each preceded by a week of ad libitum smoking. Abstinence was assessed daily by CO < 5 ppm. Smokers with the CHRNB2 GG genotype had more days of abstinence during the nicotine versus placebo patch week compared with those with the AG or AA genotypes (P < 0.01). Moreover, nicotine patch increased the probability of quitting on the target quit day, quitting anytime during the patch week, and avoiding relapse among those with the GG genotype but not the AA/AG genotypes, although the nicotine x genotype interaction was significant only for quitting on the target quit day (P < 0.05). Regardless of patch condition, quitting on the target quit day was more likely in those with the GG genotype versus AA/AG genotypes (P < 0.05). Genetic associations were not observed for craving or withdrawal responses to nicotine versus placebo patch. These findings are consistent with previous evidence of association of this variant with smoking cessation and suggest that polymorphisms in the nicotinic acetylcholine receptor β2 subunit gene may influence therapeutic responsiveness to cessation medications. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2608–12)

Background: Behaviors such as sunscreen use and wearing sun-protective clothing are thought to prevent certain types of skin cancer and precancerous lesions, but few studies have examined differences in these prevention behaviors by skin type.

Methods: We carried out a cross-sectional study (n = 6,858) nested within a community-based prospective cohort in Washington County, Maryland. We measured the associations between skin type, complexion, freckling, and eye color, and sunscreen and sun-protective clothing use.

Results: The prevalence of regular sunscreen use was 23% and regular sun-protective clothing use was 21%. There were consistent trends indicating those with the most sun-sensitive skin type were most likely to engage in prevention behaviors. For example, compared with those who tan without burning, those who develop blistering sunburns were more likely to use sunscreen [odds ratio (OR), 6.04; 95% confidence interval (95% CI), 2.82-12.95 men; OR, 4.89; 95% CI, 3.34-7.16 women] and sun-protective clothing (OR, 2.87; 95% CI, 1.71-4.80 men; OR, 4.44; 95% CI, 2.88-6.85 women). Health-related characteristics such as body mass index and cigarette smoking were also significantly inversely associated with prevention behaviors.

Conclusion: The overall prevalence of prevention behaviors was low. Those with phenotypic risk factors for skin cancer were most likely to use sunscreen and sun-protective clothing. Those with high-risk skin cancer phenotypes may also be those who are most receptive to skin cancer prevention educational interventions. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2613–9)

Background: Optimizing participant response rates is important for obtaining representative samples and the timely completion of studies. It is a common practice to use participant incentives to boost response rates, but few studies have systematically examined their effectiveness, particularly among minority groups.

Methods: We experimentally tested three incentive strategies for their effectiveness in improving response rates among colorectal cancer cases (n = 3,816) and their relatives (n = 2,353). A 2 x 2 x 2 factorial design compared (a) registered versus first class mail, (b) $5 cash with the initial mailing (yes/no), and (c) $20 promise (yes/no) upon completion of the information form (for cases) or $10 promise (yes/no) upon completion of the baseline survey (for relatives). Outcome measures were provision of contact information on first-degree relatives for cases and completion of the baseline survey for relatives.

Results: The response rate among cases was low in all ethnic groups (28-37%) and incentive strategies did not have an effect. Among relatives, the overall baseline survey response rate was 71%, ranging from 66% among Asians to 76% among Whites. Modest absolute increases were observed for payment schedules that included a $5 cash enclosure with the initial mailing in the total sample [odds ratio (OR), 1.65 and 1.47] and among Latinos (OR, 1.94 and 1.74) but not among Asians (OR, 1.61 and 1.55) or African Americans (OR, 1.19 and 1.02). Response rates were not influenced by registered versus first-class mailing.

Conclusion: The effects of incentives in this study were modest with some suggestion of differences by ethnic group and type of incentive. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2620–5)

Background/Objective: Adult survivors of childhood cancer can have altered social functioning. We sought to identify factors that predict marriage and divorce outcomes in this growing population.

Methods: This was a retrospective cohort study of 8,928 ≥5-year adult survivors of childhood malignancy and 2,879 random sibling controls participating in the Childhood Cancer Survivor Study. Marital status, current health, psychological status, and neurocognitive functioning were determined from surveys and validated instruments.

Results: Survivors were more likely to be never-married than siblings [relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.15-1.26] and the U.S. population (RR, 1.25; 95% CI, 1.21-1.29), after adjusting for age, gender, and race. Patients with central nervous system tumors were at greatest risk of not marrying (RR, 1.50; 95% CI, 1.41-1.59). Married survivors divorced at frequencies similar to controls. In multivariable regression analysis, nonmarriage was most associated with cranial radiation (RR, 1.15; 95% CI, 1.02-1.31 for >2,400 centigray). In analysis of neurobehavioral functioning, nonmarriage was associated with worse task efficiency (RR, 1.27; 95% CI, 1.20-1.35), but not with emotional distress, or problems with emotional regulation, memory, or organization. Physical conditions predictive of nonmarriage included short stature (RR, 1.27; 95% CI, 1.20-1.34) and poor physical function (RR, 1.08; 95% CI, 1.00-1.18). Structural equation modeling suggested that cranial radiation influenced marriage status through short stature, cognitive problems, and poor physical function.

Conclusions: Childhood cancer survivors married at lower frequencies compared with peers. Patients with central nervous system tumors, cranial radiation, impaired processing efficiency, and short stature were more likely to never marry. Divorce patterns in survivors were similar to peers. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2626–35)

Many of the same inflammatory factors that promote tumor growth are also hypothesized to function as pain modulators. There is substantial interindividual variation in pain severity in cancer patients. Therefore, we evaluated 59 single nucleotide polymorphisms in 37 inflammation genes in newly diagnosed non-Hispanic Caucasian lung cancer patients (n = 667) and assessed their association with pain severity. Patients rated their pain "during the past week" on an 11-point numeric scale (0 = "no pain" and 10 = "pain as bad as you can imagine") at presentation before initiating cancer therapy. Reported analgesic use was abstracted from charts and converted to morphine equivalent daily dose. Results showed that 16% of the patients reported severe pain (score ≥7). Advanced stage of disease [odds ratio (OR), 2.34; 95% confidence interval (95% CI), 1.50-3.65; P = 0.001], age ≤50 years (OR, 2.10; 95% CI, 1.32-3.30; P = 0.002), reports of depressed mood (OR, 3.68; 95% CI, 1.96-6.93; P = 0.001), fatigue (OR, 3.72; 95% CI, 2.36-5.87; P = 0.001), and morphine equivalent daily dose (OR, 1.02; 95% CI, 1.01-1.03) were significantly correlated with severe pain. Controlling for these nongenetic covariates, we found that patients with CC genotypes for PTGS2 exon10+837T>C (rs5275) were at lower risk for severe pain (OR, 0.33; 95% CI, 0.11-0.97) and an additive model for TNF –308GA (rs1800629; OR, 1.67; 95% CI, 1.08-2.58) and NFKBIA Ex6+50C>T (rs8904) was predictive of severe pain (OR, 0.64; 95% CI, 0.43-0.93). In a multigene analysis, we found a gene-dose effect, with each protective genotype reducing the risk for severe pain by as much as 38%. This study suggests the importance of inflammation gene polymorphisms in modulating pain severity. Additional studies are needed to validate our findings. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2636–42)

Background: Several studies have examined serum creatinine as a marker for prostate cancer stage, recurrence, and prognosis. We evaluated whether serum creatinine concentration was associated with risk of developing prostate cancer in a prospective cohort of male smokers.

Methods: A nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men was conducted. Two controls (n = 464) were matched to each case (n = 232) on study center, intervention group, date of baseline blood draw (±45 days), and age (±5 years). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. All P values were two-sided.

Results: Cases had significantly higher prediagnostic serum creatinine concentrations compared with controls (medians of 1.13 versus 1.10 mg/dL, respectively; P = 0.004). Serum creatinine was associated with a significantly greater risk of prostate cancer (multivariate odds ratio, 2.23; 95% confidence interval, 1.33-3.75 for highest versus lowest quartile), with a significant trend (P trend = 0.0008). Exclusion of subjects with a reported history of diabetes, benign prostatic hyperplasia, or hypertension, or whose cancer was diagnosed within the first 5 years of follow-up, did not alter the association. Risk did not differ by disease stage or time from blood draw to diagnosis.

Conclusion: Prospectively measured serum creatinine, within normal ranges, is positively related to prostate cancer risk. Future research should reexamine the association in other populations, including any interrelationship with serum prostate-specific antigen. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2643–9)

Objectives. Exposure to high molecular weight (HMW) allergens that provoke immune reactivity through an IgE-mediated pathway has been associated with a decreased risk of B-cell lymphoma. The present analysis was conducted to assess the associations between occupational exposure to specific HMW allergens and the risk of B-cell, T-cell, and Hodgkin's lymphomas.

Methods. We analyzed data from 2,290 incident lymphoma cases and 1,771 population-based controls enrolled in a multicenter study of hematolymphopoietic malignancies conducted in Italy between 1991 and 1993. All cases were histologically or cytologically confirmed. Controls were frequency-matched to cases based on age, sex, and study center. An industrial hygienist evaluated HMW occupational exposure classifications after an asthma-specific job exposure matrix was applied to participants' job histories. Unconditional logistic regression was used to assess associations between occupational exposures that occurred ≥10 years before the date of lymphoma diagnosis and B-cell, T-cell, and Hodgkin's lymphomas.

Results. Ten percent of cases and 11% of controls were occupationally exposed to HMW allergens. Exposed individuals had a decreased risk for all lymphomas combined (odds ratio, 0.78; 95% confidence interval, 0.63-0.97), particularly for B-cell lymphomas (odds ratio, 0.75; 95% confidence interval, 0.59-0.94). The decreased risks for all lymphomas were also observed when HMW allergen exposure was limited to animal and latex allergens.

Conclusions. These findings support the hypothesis that occupational exposure to immunologically active HMW allergens is inversely associated with the risk for lymphoma. The effect of exposure to specific allergens warrants further assessment. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2650–4)

Vitamin D status may affect risk of cancer. In a cross-sectional study with a nested case-control analysis, we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D (25OHD) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer. We studied women without a prior history of breast cancer referred to a diagnostic mammography examination (n = 2,465). Cases were women diagnosed with an incident breast cancer (n = 142). Controls were women not diagnosed with a breast cancer matched to cases on age, menopausal status, and time of year of blood sampling (n = 420). Characteristics of cases and controls were assessed by a self-administrated questionnaire. Blood samples were collected prior to the diagnostic mammography examination. Cases had lower plasma 25OHD levels than controls. Compared with the lowest tertile of 25OHD levels, risk of breast cancer was significantly reduced among women in the highest tertile (relative risk, 0.52; 95% confidence interval, 0.32-0.85). Risk estimates were similar in women with an estrogen receptor–positive and estrogen receptor–negative breast cancer. Use of vitamin D supplements, sunbathing frequency, and fish intake was associated with 25OHD levels, but did not affect the risk of breast cancer. Accordingly, risk of breast cancer was inversely associated with 25OHD levels. Randomized controlled trials are warranted in order to assess whether a causal relationship exists. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2655–60)

Maternal vitamin supplementation has been linked to a reduced risk of several pediatric malignancies. We examined this relationship in a study of childhood germ cell tumors (GCT). Subjects included 278 GCT cases diagnosed <15 years during 1993 to 2001 at a United States or Canadian Children's Oncology Group Institution and 423 controls that were ascertained through random digit dialing matched to cases on sex, and age within 1 year. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between GCTs and maternal vitamin use at several time points during and around pregnancy. In models controlling for the child's age, sex, household income, and maternal education, any maternal vitamin use during the 6 months before conception through nursing was associated with a nonsignificant reduced risk of GCTs (OR, 0.7; 95% CI, 0.4-1.2). Inverse associations were observed for both extragonadal (OR, 0.8; 95% CI, 0.4-1.6) and gonadal (OR, 0.6; 95% CI, 0.3-1.1) tumors, and for dysgerminoma/seminoma (OR, 0.6; 95% CI, 0.2-1.3) and teratoma (OR, 0.5; 95% CI, 0.2-0.9) but not yolk sac tumors (OR, 1.1; 95% CI, 0.5-2.3). No consistent patterns were found with respect to vitamin use during the periconceptional period (6 months before pregnancy and first trimester) or first trimester specifically. In conclusion, although our study suggests that maternal vitamin supplementation may reduce the risk or pediatric GCTs in the offspring, the small study size and limitations inherent to observational studies must be considered when interpreting these results. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2661–4)

Studies of self-reported sexually transmitted infections (STI) suggesting an association with prostate cancer may reflect underreporting of such infections among nondiseased subjects. To reduce such bias, we studied archived sera in a cohort of U.S. military personnel known to have high rates of both STIs and prostate cancer. Using a nested case-control design, serum samples from 534 men who served on active duty between September 1, 1993 and September 1, 2003 were examined. Controls were individually matched to cases based on date of serum collection, date of birth, branch of service, military rank, marital status, and race. Each of the 267 case-control pairs had two serum samples: a recent serum sample, taken ~1 year before the case's prostate cancer diagnosis, and an earlier serum sample, taken ~8 years before diagnosis. Each serum specimen was studied for antibodies against human papillomavirus, herpes simplex virus-2 (HSV-2), and Chlamydia trachomatis. Logistic regression accounted for matching and potential confounding factors. Study data indicated no association between prostate cancer and serologic evidence of infections just before the reference date. However, a statistically significant association between prostate cancer and serologic evidence of HSV-2 infection was detected in the earlier sample (odds ratio, 1.60; 95% confidence interval, 1.05-2.44). The strength of this association increased when analyses were restricted to sera collected at least 60 months before diagnosis (odds ratio, 2.04; 95% confidence interval, 1.26-3.29; 204 pairs). If this association is causal, then our findings would suggest a long latency period for prostate cancer development after HSV-2 infection. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2665–71)

We compared systemic and cervical total IgA and IgG during the menstrual cycle among 154 women who attended clinic visits at follicular/early, periovulatory/mid, and luteal/late phases of menstrual cycle. Paired serum and cervical secretions were tested at each visit for total IgA and IgG using ELISA. Geometric mean titers for systemic IgA and IgG were 1.92 and 8.25 mg/mL, respectively. There were no differences in titers by menstrual cycle phase, neither were they correlated to cervical titers ( = 0.17 and 0.16, respectively). The lack of correlation between systemic and cervical total IgA and IgG suggests that systemic concentrations are not reflective of cervical levels. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2672–6)

Background: Duodenal cancer is the leading cause of cancer death in familial adenomatous polyposis after colorectal cancer. The lifetime risk for developing duodenal cancer is 4% to 10%. Current treatment guidelines recommend endoscopic surveillance with a prophylactic pancreaticoduodenectomy in advanced duodenal polyposis, defined using the Spigelman staging system. Because no clinical trials have assessed this recommendation, a modeling approach was used to evaluate the cost-effectiveness of various treatment strategies.

Methods: A Markov model was constructed to estimate the life expectancy and cost of three different strategies: pancreaticoduodenectomy at Spigelman stage III, pancreaticoduodenectomy at Spigelman stage IV, and pancreaticoduodenectomy at cancer diagnosis. A cohort of 30-year-old familial adenomatous polyposis patients with total colectomies was simulated until age 80. The analysis was from a societal perspective. Extensive sensitivity analysis was performed to assess the impact of model uncertainty on results.

Results: At all stages of polyposis and all ages <80 years, prophylactic surgery at Spigelman stage IV resulted in the greatest life expectancy. Surgery at stage IV was more effective and more expensive than surgery at cancer diagnosis, with an incremental cost of $3,200 per quality-adjusted life year gained. Surgery at stage III was not a viable option. The results were robust to wide variation in model parameters but were sensitive to the post-pancreaticoduodenectomy quality of life score.

Conclusions: Prophylactic pancreaticoduodenectomy at stage IV duodenal polyposis in familial adenomatous polyposis is a cost-effective approach that results in greater life expectancy than surgery at either stage III or cancer diagnosis. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2677–84)

Purpose: This retrospective study aimed to examine the expression and localization of SAM68 (Src-associated in mitosis, 68 kDa) in a larger cohort of surgical specimens of renal cell carcinoma and their correlation with the progression of human renal cell carcinoma.

Experimental Design: The protein and mRNA expression levels of SAM68 in normal renal tubular epithelial cells, renal cell carcinoma cell lines, as well as nine pairs of renal cell carcinoma and matched tumor-adjacent renal tissues were examined using reverse transcription-PCR and Western blot. Moreover, SAM68 protein expression and localization in 241 clinicopathologically characterized renal cell carcinoma samples were examined by immunohistochemistry. Prognostic and diagnostic associations were examined by statistical analyses.

Results: SAM68 was markedly overexpressed in renal cell carcinoma cell lines and renal cell carcinoma tissues at both the transcriptional and translational levels. Immunohistochemical analysis revealed high SAM68 protein expression in 129 of the 241 (53.5%) paraffin-embedded archival renal cell carcinoma specimens. Moreover, there was a significant correlation between SAM68 expression and pathologic stage (P < 0.001), T classification (P = 0.003), N classification (P = 0.001), M classification (P = 0.006), and Fuhrman grade (P < 0.001). Patients with higher SAM68 expression had shorter overall survival time than patients with lower SAM68 expression, and the cytoplasmic localization of SAM68 significantly correlated with clinicopathologic grade and outcome. Multivariate analysis indicated that SAM68 protein overexpression and cytoplasmic localization were independent predictors for poor survival of renal cell carcinoma patients.

Conclusions: Our results suggest that SAM68 could represent a novel and useful prognostic marker for renal cell carcinoma. High SAM68 expression and cytoplasmic localization are associated with poor overall survival in renal cell carcinoma patients. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2685–93)

Aberrant promoter methylation of several known or putative tumor suppressor genes occurs frequently during carcinogenesis, and this epigenetic change has been considered as a potential molecular marker for cancer. We examined the methylation status of nine genes (APC, CDH1, CTNNB1, TIMP3, ESR1, GSTP1, MGMT, THBS1, and TMS1), by quantitative methylation specific PCR. Synchronous preinvasive lesions (atypical ductal hyperplasia and/or ductal carcinoma in situ) and invasive ductal breast carcinoma from 52 patients, together with pure lesions from 24 patients and 12 normal tissues paired to tumor and 20 normal breast distant from tumor were analyzed. Aberrant promoter methylation was detected in both preinvasive and invasive lesions for genes APC, CDH1, CTNNB1, TIMP3, ESR1, and GSTP1. However, hierarchical mixed model and Generalized Estimating Equations model analyses showed that only APC, CDH1, and CTNNB1 promoter regions showed a higher frequency and methylation levels in pathologic samples when compared with normal breast. Whereas APC and CTNNB1 did not show differences in methylation levels or frequencies, CDH1 showed higher methylation levels in invasive tumors as compared with preinvasive lesions (P < 0.04, Mann-Whitney test with permutation correction). The analysis of APC, CDH1, and CTNNB1 methylation status was able to distinguish between normal and pathologic samples with a sensitivity of 67% (95% confidence interval, 60-71%) and a specificity of 75% (95% confidence interval, 69-81%). Our data point to the direct involvement of APC, CDH1, and CTNNB1 promoter methylation in the early stages of breast cancer progression and suggest that they may represent a useful tool for the detection of tumor cells in clinical specimens. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2694–700)

Background: Although advances in early detection and treatment of cancer improve overall population survival, these advances may not benefit all population groups equally and may heighten racial/ethnic differences in survival.

Methods: We identified cancer cases in the Surveillance, Epidemiology and End Results program, who were ages ≥20 years and diagnosed with one invasive cancer in 1995 to 1999 (n = 580,225). We used 5-year relative survival rates to measure the degree to which mortality from each cancer is amenable to medical interventions (amenability index). We used Kaplan-Meier methods and Cox proportional hazards regression to estimate survival differences between each racial/ethnic minority group relative to Whites, by the overall amenability index, and three levels of amenability (nonamenable, partly amenable, and mostly amenable cancers, corresponding to cancers with 5-year relative survival rate <40%, 40-69%, and ≥70%, respectively), adjusting for gender, age, disease stage, and county-level poverty concentration.

Results: As amenability increased, racial/ethnic differences in cancer survival increased for African Americans, American Indians/Native Alaskans, and Hispanics relative to Whites. For example, the hazard ratios (95% confidence intervals) for African Americans versus Whites from nonamenable, partly amenable, and mostly amenable cancers were 1.05 (1.03-1.07), 1.38 (1.34-1.41), and 1.41 (1.37-1.46), respectively. Asians/Pacific Islanders had similar or longer survival relative to Whites across amenability levels; however, several subgroups experienced increasingly poorer survival with increasing amenability.

Conclusions: Cancer survival disparities for most racial/ethnic minority populations widen as cancers become more amenable to medical interventions. Efforts in developing cancer control measures must be coupled with specific strategies for reducing the expected disparities. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2701–8)

Purpose: Nasopharyngeal carcinoma is an epithelial malignancy with a remarkable racial and geographic distribution. Previous cytogenetic studies have shown nasopharyngeal carcinoma to be characterized by gross genomic aberrations. However, identification of susceptible gene loci in advanced nasopharyngeal carcinoma has been poorly discussed.

Experimental Design: A genome-wide survey of gene copy number changes was initiated with two nasopharyngeal carcinoma cell lines by array-based comparative genomic hybridization analysis. These alterations were confirmed by a parallel analysis with the data from the gene expression microarray and were validated by quantitative PCR. Clinical association of the defined target genes was analyzed by fluorescence in situ hybridization on 48 metastatic tumors.

Results: A high percentage of genes were consistently altered in dosage and expression levels with gain on 3q26.2-q26.32 and losses on 3p12.3-p14.2 and 9p21.3-p23. Six candidate genes, GPR160 (3q26.2-q27), SKIL (3q26), ADAMTS9 (3p14.2-p14.3), LRIG1 (3p14), MPDZ (9p22-p24), and ADFP (9p22.1) were validated by quantitative PCR. Fluorescence in situ hybridization studies revealed amplification of GPR160 (in 25% of cases) and SKIL (33%); and deletion of ADAMTS9 (30%), LRIG1 (35%), MPDZ (15%), and ADFP (15%). Clinical association analyses indicated a poor survival rate with genetic alterations at the defined 3p deletion (P = 0.0012) and the 3q amplification regions (P = 0.0114).

Conclusion: The combined microarray technologies suggested novel candidate oncogenes, amplification of GPR160 and SKIL at 3q26.2-q26.32, and deletion of tumor suppressor genes ADAMTS9 and LRIG1 at 3p12.3-p14.2. Altered expression of these genes may be responsible for malignant progression and could be used as potential markers for nasopharyngeal carcinoma. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2709–16)

The goal of this retrospective, multicenter study was to evaluate the ability of a newly developed refinement of a quantitative methylation-specific PCR assay to detect prostate cancer in histopathologically negative biopsy samples collected from men who were later positively diagnosed during a follow-up biopsy procedure. Biomarkers tested in the assay included the much-studied glutathione-S-transferase P1 gene and others reported to be frequently methylated in prostate cancer. Core biopsy tissue from subjects with serial negative biopsies served as a negative control to assess assay specificity. As a positive control, biopsy core tissue from patients histopathologically diagnosed with prostate cancer was used to gauge true marker sensitivity in known cancer-containing specimens. Testing was completed in 971 archived paraffin-embedded tissue blocks from 264 men screened for prostate cancer. More samples were initially tested, but due to the advanced age of the paraffinized tissue, DNA quality for quantitative methylation-specific PCR analysis was insufficient in 34% of the available blocks. The glutathione-S-transferase P1 gene has been confirmed as a powerful indicator of the presence of prostate cancer cells. A sensitivity of 52% was observed in the "potentially false-negative first biopsies," with a corresponding specificity of 85% and the sensitivity in biopsy tissue cores containing histopathologically confirmed prostate cancer was 95%. An even higher sensitivity can be reached with RAR-2β (84%) and APC (72%), with respective specificities of 48% and 50%. Gene methylation was detected in initial, negative biopsy tissue in men who were later diagnosed with prostate cancer. Testing for methylation in histopathologically negative biopsies could improve the early detection of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2717–22)

In addition to classic genetic mechanisms such as deletions and mutations, growth regulatory genes can be inactivated via methylation of cytosine-residues in their promoter regions. Hypermethylation of promoter CpG islands is now recognized as an important and early event in carcinogenesis. Detection of methylated DNA in serum or plasma has been suggested to be a marker for early cancer development. We examined methylation changes in RASSF1A, a growth regulatory gene in plasma DNA from blood collected before diagnosis from women with breast cancer and from controls. Samples were from two sets of subjects, 28 women with breast cancer and 10 of their unaffected siblings, and 33 women with breast cancer and 29 age- and ethnicity-matched population-based controls. Using methylation specific PCR, we found 11 of 61 (18%) cases were positive for methylation of RASSF1A in their plasma DNA collected before diagnosis. Two of 10 healthy high-risk sibling controls (20%) had plasma DNA positive for RASSF1A methylation in their plasma DNA compared with 0 of 29 (0%) population-based controls. Tumor tissue was available for 12 cases and all were positive for RASSF1A methylation. These results, if replicated, suggest that aberrant promoter hypermethylation in serum/plasma DNA may be common among high-risk women and may be present years before cancer diagnosis. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2723–5)

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the production of prostaglandins, potent mediators of inflammation. Chronic inflammation plays an important role in the development and progression of colorectal cancer. Aspirin inhibits COX-2 activity and lowers the risk for colorectal adenomas and cancer. We investigated whether common genetic variation in COX-2 influenced risk for colorectal adenoma recurrence among 979 participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or aspirin and followed for 3 years for the occurrence of new adenomas. Of these participants, 44.2% developed at least one new adenoma during follow-up. Adjusted relative risks and 95% confidence intervals (95% CI) were calculated to test the association between genetic variation at six COX-2 single-nucleotide polymorphisms and adenoma occurrence and interaction with aspirin treatment. Two single-nucleotide polymorphisms were significantly associated with increased adenoma recurrence: for rs5277, homozygous carriers of the minor C allele had a 51% increased risk compared with GG homozygotes (relative risk, 1.51; 95% CI, 1.01-2.25), and for rs4648310, heterozygous carriers of the minor G allele had a 37% increased risk compared with AA homozygotes (relative risk, 1.37; 95% CI, 1.05-1.79). (There were no minor allele homozygotes.) In stratified analyses, there was suggestive evidence that rs4648319 modified the effect of aspirin. These results support the hypothesis that COX-2 plays a role in the etiology of colon cancer and may be a target for aspirin chemoprevention and warrant further investigation in other colorectal adenoma and cancer populations.(Cancer Epidemiol Biomarkers Prev 2009;18(10):2726–33)

Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10^-5], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734–44)

Introduction: Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer (CRC). Reports have suggested that these associations may differ by tumor molecular subtype, with stronger associations for microsatellite unstable (MSI-H) tumors.

Methods: We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings) recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption, and CRC. Associations were assessed using conditional logistic regression, treating sibship as the matching factor.

Results: Although there were no statistically significant associations between any smoking variable and CRC overall, smoking did confer an increased risk of certain types of CRC. We observed an association between pack-years of smoking and rectal cancer [odds ratio (OR), 1.85; 95% confidence interval (CI), 1.23-2.79 for >40 pack-years versus nonsmokers; P_trend = 0.03], and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR, 1.94; 95% CI, 1.09-3.46 for >30 years of smoking versus nonsmokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR, 1.21; 95% CI, 1.03-1.44 for 12+ drinks per week versus nondrinkers), with more marked increases in risk for MSI-L CRC (OR, 1.85; 95% CI, 1.06-3.24) and rectal cancer (OR, 1.48; 95% CI, 1.08-2.02).

Conclusions: We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering tumor phenotype in studies of risk factors for CRC. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2745–50)

Introduction: In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography-tandem mass spectrometry.

Methods: Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii). They were postmenopausal (n = 167) or premenopausal in luteal phase (n = 263) when 12-hour urine samples were collected. Robust linear regression was used to assess soy tertiles as predictors of log-transformed EM measures. Individual and grouped EM were considered as concentrations (pmol/mg creatinine) and as percentages of total EM (%EM).

Results: Factor analysis confirmed that EM groups defined by metabolic pathways appropriately captured covariation in EM profiles. Total EM concentrations were not significantly associated with soy in premenopausal or postmenopausal women. Among all women, %2-hydroxylated EM and %4-hydroxylation pathway EM were 16% higher (P_trend = 0.02) and 19% higher (P_trend = 0.03) in the highest versus lowest soy tertiles, respectively. In contrast, 16% hydroxylated EM were 11% lower (P_trend < 0.01). Results were consistent across ethnic and menopausal groups and after adjustment for westernization measured by birthplace (Asia or United States).

Discussion: Findings suggest that regular soy intake is associated with increased ratios of 2:16-pathway EM and with higher relative levels of 4-hydroxylated EM. The observed variations in estrogen metabolism might modify breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2751–60)

Recent genome-wide association studies (GWAS) have identified multiple common genetic risk variants for breast cancer among women of Asian and European ancestry. Investigating these genetic susceptibility loci in other populations would be helpful to evaluate the generalizability of the findings and identify the causal variants for breast cancer. We evaluated 11 GWAS-identified genetic susceptibility loci for breast cancer in a study including 2,594 African-American women (810 cases and 1,784 controls). Two single-nucleotide polymorphisms, rs13387042 (2q35) and rs1219648 (FGFR2 gene), were found to be associated with breast cancer risk. Risk increased nearly linearly with the number of affected risk alleles, with a 2-fold elevated risk for women homozygous for the risk alleles in both single-nucleotide polymorphisms. No additional significant associations, however, were identified for the other nine loci evaluated in the study. The results from this study extend some of the recent GWAS findings to African-Americans and may guide future efforts to identify the causal variants for breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2761–4)

Vitamin D is associated with decreased risks of various cancers, including colon cancer. The vitamin D receptor (VDR) is a transcription factor, which plays an important role in cellular differentiation and inhibition of proliferation. A link between VDR and the RAS–mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K)–AKT pathway has been suggested. However, the prognostic role of VDR expression or its relationship with PIK3CA or KRAS mutation remains uncertain. Among 619 colorectal cancers in two prospective cohort studies, 233 (38%) tumors showed VDR overexpression by immunohistochemistry. We analyzed for PIK3CA and KRAS mutations and LINE-1 methylation by Pyrosequencing, microsatellite instability (MSI), and DNA methylation (epigenetic changes) in eight CpG island methylator phenotype (CIMP)–specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by MethyLight (real-time PCR). VDR overexpression was significantly associated with KRAS mutation (odds ratio, 1.55; 95% confidence interval, 1.11-2.16) and PIK3CA mutation (odds ratio, 2.17; 95% confidence interval, 1.36-3.47), both of which persisted in multivariate logistic regression analysis. VDR was not independently associated with body mass index, family history of colorectal cancer, tumor location (colon versus rectum), stage, tumor grade, signet ring cells, CIMP, MSI, LINE-1 hypomethylation, BRAF, p53, p21, β-catenin, or cyclooxygenase-2. VDR expression was not significantly related with patient survival, prognosis, or clinical outcome. In conclusion, VDR overexpression in colorectal cancer is independently associated with PIK3CA and KRAS mutations. Our data support potential interactions between the VDR, RAS–MAPK and PI3K–AKT pathways, and possible influence by KRAS or PIK3CA mutation on therapy or chemoprevention targeting VDR. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2765–72)

This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P_trend < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2773–81)

Aberrant DNA methylation is a recognized feature of human cancers, and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also suggest that folate status is associated with the natural history of human papillomavirus (HPV) infection. A cross-sectional study was conducted to test the hypothesis that folate status and aberrant DNA methylation show a progressive change across stages of cervical pathology from normal cells to cervical cancer. Additionally, we postulated that a gene-specific hypermethylation profile might be used as a predictive biomarker of cervical cancer risk. DNA hypermethylation of seven tumor suppressor genes, global DNA hypomethylation, systemic folate status, and HPV status were measured in 308 women with a diagnosis of normal cervix (n = 58), low-grade cervical intraepithelial neoplasia (CIN1; n = 68), high-grade cervical intraepithelial neoplasia (CIN2, n = 56; and CIN3, n = 76), or invasive cervical cancer (ICC; n = 50). Lower folate status was associated with high-risk HPV infection (P = 0.031) and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (P < 0.05). Global DNA hypomethylation was greater in women with invasive cervical cancer than all other groups (P < 0.05). A cluster of three tumor suppressor genes, CDH1, DAPK, and HIC1, displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (P < 0.05). These findings are compatible with a role for folate in modulating the risk of cervical cancer, possibly through an influence over high-risk HPV infection. DAPK, CDH1, and HIC1 genes are potential biomarkers of cervical cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2782–9)

We performed a large nested case-control study within the Finnish and Icelandic maternity cohorts to verify/falsify the association of maternal EBV infection with an increased risk of acute lymphoblastic leukemia (ALL) in the offspring found in previous studies. All hematologic malignancies diagnosed among children born during 1983 to 2006 in Finland and 1997 to 2005 in Iceland were identified through national cancer registries. For each index mother of a leukemia case, three matched control mothers with cancer-free offspring were identified. First trimester sera from 561 ALL and 144 non-ALL index mothers and from 2,105 control mothers were analyzed for antibodies to EBV viral capsid antigen (IgG and IgM), early antigen (IgG) and ZEBRA protein (IgG). Conditional logistic regression-based estimates of odds ratios and 95% confidence intervals adjusted for birth order and sib-ship size were calculated. Overall, there was no evidence of increased risk of ALL associated to EBV viral capsid antigen IgM (odds ratio, 0.9; 95% confidence interval, 0.5-1.8). The early antigen and ZEBRA antibodies (EBV reactivation markers) were also not associated with risk. The data argue against a role of EBV in ALL. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2790–2)