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Cancer Epidemiology Biomarkers & Prevention

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Cancer Epidemiology Biomarkers & Prevention

Large-scale surveys that assess cancer prevention and control behaviors are a readily available, rich resource for public health researchers. Although these data are used by a subset of researchers who are familiar with them, their potential is not fully realized by the research community for reasons including lack of awareness of the data and limited understanding of their content, methodology, and utility. Until now, no comprehensive resource existed to describe and facilitate use of these data. To address this gap and maximize use of these data, we catalogued the characteristics and content of four surveys that assessed cancer screening behaviors in 2005, the most recent year with concurrent periods of data collection: the National Health Interview Survey, Health Information National Trends Survey, Behavioral Risk Factor Surveillance System, and California Health Interview Survey. We documented each survey's characteristics, measures of cancer screening, and relevant correlates; examined how published studies (n = 78) have used the surveys' cancer screening data; and reviewed new cancer screening constructs measured in recent years. This information can guide researchers in deciding how to capitalize on the opportunities presented by these data resources. Cancer Epidemiol Biomarkers Prev; 24(1); 3–14. ©2014 AACR.

Marijuana use is legal in two states and additional states are considering legalization. Approximately 18 million Americans are current marijuana users. There is currently no consensus on whether marijuana use is associated with cancer risk. Our objective is to review the epidemiologic studies on this possible association. We identified 34 epidemiologic studies on upper aerodigestive tract cancers (n = 11), lung cancer (n = 6), testicular cancer (n = 3), childhood cancers (n = 6), all cancers (n = 1), anal cancer (n = 1), penile cancer (n = 1), non-Hodgkin lymphoma (n = 2), malignant primary gliomas (n = 1), bladder cancer (n = 1), and Kaposi sarcoma (n = 1). Studies on head and neck cancer reported increased and decreased risks, possibly because there is no association, or because risks differ by human papillomavirus status or geographic differences. The lung cancer studies largely appear not to support an association with marijuana use, possibly because of the smaller amounts of marijuana regularly smoked compared with tobacco. Three testicular cancer case–control studies reported increased risks with marijuana use [summary ORs, 1.56; 95% confidence interval (CI), 1.09–2.23 for higher frequency and 1.50 (95% CI, 1.08–2.09) for ≥10 years]. For other cancer sites, there is still insufficient data to make any conclusions. Considering that marijuana use may change due to legalization, well-designed studies on marijuana use and cancer are warranted. Cancer Epidemiol Biomarkers Prev; 24(1); 15–31. ©2015 AACR.

Gastroesophageal cancer has a rapidly increasing incidence worldwide and reliable biomarkers are urgently required to facilitate earlier diagnosis and improve survival. The aromatic amino acids tyrosine, phenylalanine, and tryptophan represent potential biomarkers and their relation to gastroesophageal cancer will be evaluated in this review. An electronic literature search was performed to identify all published research relating to the measurement of tyrosine, phenylalanine, or tryptophan in the biofluids or tissues of patients with gastroesophageal cancer. Sixteen studies were included in this systematic review. Six studies investigated serum concentrations, which all found decreased concentrations of these aromatic amino acids, except one study that found increased phenylalanine. Five studies reported increased concentrations within gastric content of these patients and two reported increased urinary concentrations. Tissue concentrations of these aromatic amino acids were increased in three studies. Tyrosine, phenylalanine, and tryptophan represent potential biomarkers of gastroesophageal cancer, and further research is necessary to definitively establish the mechanism responsible for altered concentrations of these compounds in patients with gastroesophageal cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 32–38. ©2014 AACR.

Background: Colorectal cancer is the third most common cancer in males and the second in females worldwide. Incidence and mortality are higher in men than women. Colorectal cancer screening is effective in reducing mortality. Internationally, fecal immunochemical testing (FIT) is increasingly being recommended as the primary screening test. This systematic review and meta-analysis aimed to determine whether uptake of FIT screening differs between men than women.

Methods: We searched PubMed and Embase for peer-reviewed articles published in English during 2000–2013 for randomized controlled trials (RCT) or observational studies of screening using FIT that quantified numbers invited and participating by gender. Meta-analysis was performed using a random effects model.

Results: Six hundred and eighty-five citations were identified, 19 meeting the inclusion criteria. Random effects meta-analysis found male uptake was significantly lower than female uptake [odds ratio (OR), 0.84; 95% confidence interval (CI), 0.75–0.95; P < 0.01]. This generally persisted throughout subgroup analysis of study design (RCTs vs. observational studies and study quality), screening organization (methods of invitation, number of samples, age range of screening, recommendations, and reminders), and setting.

Conclusions: Meta analysis of FIT screening studies indicates significantly lower uptake among men.

Impact: Further investigation is required into factors influencing acceptability and participation of FIT screening in both sexes. Cancer Epidemiol Biomarkers Prev; 24(1); 39–47. ©2014 AACR.

Background: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case–control study (2003–2007).

Methods: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case–parent trios were also analyzed.

Results: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39–0.91] and 0.64 (95% CI, 0.40–1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02–1.93) and 1.81 (95% CI, 1.06–3.07). ORs varied little by maternal folic acid supplementation.

Conclusions: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation.

Impact: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results. Cancer Epidemiol Biomarkers Prev; 24(1); 48–56. ©2014 AACR.

Background: Few studies have investigated the association between post-diagnosis physical activity and mortality among men diagnosed with prostate cancer. The aim of this study was to investigate the effect of physical activity after a prostate cancer diagnosis on both overall and prostate cancer–specific mortality in a large cohort.

Methods: Data from 4,623 men diagnosed with localized prostate cancer 1997–2002 and followed-up until 2012 were analyzed. HRs with 95% confidence intervals (CI) were estimated using Cox proportional hazards models to examine the association between post-diagnosis recreational MET-h/d, time spent walking/bicycling, performing household work or exercising, and time to overall and prostate cancer–specific death. All models were adjusted for potential confounders.

Results: During the follow-up, 561 deaths of any cause and 194 deaths from prostate cancer occurred. Statistically significantly lower overall mortality rates were found among men engaged in ≥5 recreational MET-h/d (HR, 0.63; 95% CI, 0.52–0.77), walking/bicycling ≥20 min/d (HR, 0.70; 95% CI, 0.57–0.86), performing household work ≥1 h/d (HR, 0.71; 95% CI, 0.59–0.86), or exercising ≥1 h/wk (HR, 0.74; 95% CI, 0.61–0.90), compared with less active men within each activity type. For prostate cancer–specific mortality, statistically significantly lower mortality rates were seen among men walking/bicycling ≥20 min/d (HR, 0.61; 95% CI, 0.43–0.87) or exercising ≥1 h/wk (HR, 0.68; 95% CI, 0.48–0.94).

Conclusions: Higher levels of physical activity were associated with reduced rates of overall and prostate cancer–specific mortality.

Impact: Our study further strengthens previous results indicating beneficial effects of physical activity on survival among men with prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 57–64. ©2014 AACR.

Background: miRNAs act as post-transcriptional regulators of gene expression. Genetic variation in miRNA-encoding sequences or their corresponding binding sites may affect the fidelity of the miRNA–mRNA interaction and subsequently alter the risk of cancer development.

Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer across the genome using a novel platform, the Axiom miRNA Target Site Genotyping Array (237,858 markers). After quality control, the study included 596 cases and 429 controls from the Molecular Epidemiology of Colorectal Cancer study, a population-based case–control study of colorectal cancer in northern Israel. The association between each marker and colorectal cancer status was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and two principal components.

Results: Twenty-three markers had P values less than 5.0E–04, and the most statistically significant association involved rs2985 (chr6:34845648; intronic of UHRF1BP1; OR = 0.66; P = 3.7E–05). Furthermore, this study replicated a previously published risk locus, rs1051690, in the 3'-untranslated region of the insulin receptor gene INSR (OR = 1.38; P = 0.03), with strong evidence of differences in INSR gene expression by genotype.

Conclusions: This study is the first to examine associations between genetic variation in miRNA target sites and colorectal cancer using a genome-wide approach. Functional studies to identify allele-specific effects on miRNA binding are needed to confirm the regulatory capacity of genetic variation to influence risk of colorectal cancer.

Impact: This study demonstrates the potential for an miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization. Cancer Epidemiol Biomarkers Prev; 24(1); 65–72. ©2014 AACR.

Background: Prolactin is a lactogenic hormone associated with breast cancer risk in prospective studies, which used immunoassays. The immunoassay captures multiple isoforms and may not fully reflect the biologic activity of prolactin relevant to breast carcinogenesis.

Methods: We considered plasma bioactive prolactin levels measured by the Nb2 lymphoma cell bioassay, which is sensitive to the somatolactogenic activity of prolactin and growth hormone, within a nested case–control study of invasive breast cancer in the Nurses' Health Studies (NHS/NHSII). We also considered associations with breast cancer risk factors.

Results: We had bioassay measures on 1,329 cases and 1,329 controls. Bioassay levels were inversely associated with parity (4+ vs. 0 children = –18%, P = 0.01), body mass index (30+ vs. <22 kg/m2 = –16%, P < 0.01), and age at menopause (53+ vs. 48 years = –18%, P = 0.03) and positively with family history of breast cancer (yes vs. no = 14%, P < 0.01). The relative risk (RR) comparing the top versus bottom quartile of bioassay levels was 1.19 [95% confidence intervals (CI), 0.94–1.51; Ptrend = 0.18]. The association was suggestively stronger for postmenopausal (RR = 1.36; 95% CI, 0.93–1.98; Ptrend = 0.12) versus premenopausal women (RR = 0.99; 95% CI, 0.71–1.37; Ptrend = 0.71). There was an association for cases diagnosed <4 years after blood draw (RR = 2.66; 95% CI, 1.45–4.89; Ptrend < 0.01), but not for cases diagnosed later. We did not observe differential associations by estrogen receptor status or other tumor characteristics.

Conclusions: Our results show similar associations for prolactin levels measured by bioassay and by immunoassay with both breast cancer risk factors and risk.

Impact: Future work examining risk prediction model of breast cancer can use the immunoassay to accurately characterize risk. Cancer Epidemiol Biomarkers Prev; 24(1); 73–80. ©2014 AACR.

Background: An inactive lifestyle is a risk factor for several types of cancer. A proposed pathway through which exercise influences cancer risk is via insulin. We aim to investigate the effect of a one-year exercise intervention on insulin sensitivity, and the role of body fat in this association, in healthy, normal to overweight/obese, postmenopausal women.

Methods: In the Sex Hormones And Physical Exercise (SHAPE) study, 189 healthy, inactive and postmenopausal women [ages, 50–69 years; body mass index (BMI), 22–40 kg/m2] were randomly assigned to a one-year aerobic and strength exercise intervention (150 min/wk), or a control group. Between-group differences in fasting insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA2) over time were estimated using linear mixed models.

Results: Follow-up measurements of insulin sensitivity were available for 181 (95.8%) and 182 (96.3%) women at 4 and 12 months, respectively. The intention-to-treat analysis showed no significant differences between the two study groups [treatment effect ratio of the exercise group vs. control (β; 95% confidence interval): insulin, β, 1.07 (0.96–1.19); glucose, β, 1.01 (0.99–1.02); and HOMA2, β, 1.07 (0.96–1.20)]. Similar results were found in a per protocol analysis in compliant women, and in a subgroup of women who lost >2% body fat [measured by dual-energy X-ray absorptiometry (DEXA)].

Conclusions: Participation in a one-year aerobic and strength exercise intervention program did not result in changes in insulin sensitivity in healthy postmenopausal and inactive women.

Impact: Our findings suggest that 150 min/wk of exercise, as recommended by current guidelines, is not enough to achieve improvements in insulin sensitivity and subsequent cancer risk, in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev; 24(1); 81–87. ©2014 AACR.

Background: Genome-wide association studies (GWAS) have produced weak (OR = 1.1–1.5) but significant associations between single nucleotide polymorphisms (SNPs) and prostate cancer. However, these associations may be explained by detection bias caused by SNPs influencing PSA concentration. Thus, in a simulation study, we quantified the extent of bias in the association between a SNP and prostate cancer when the SNP influences PSA concentration.

Methods: We generated 2,000 replicate cohorts of 20,000 men using real-world estimates of prostate cancer risk, prevalence of carrying ≥1 minor allele, PSA concentration, and the influence of a SNP on PSA concentration. We modeled risk ratios (RR) of 1.00, 1.25, and 1.50 for the association between carrying ≥1 minor allele and prostate cancer. We calculated mean betas from the replicate cohorts and quantified bias under each scenario.

Results: Assuming no association between a SNP and prostate cancer, the estimated mean bias in betas ranged from 0.02 to 0.10 for ln PSA being 0.05 to 0.20 ng/mL higher in minor allele carriers; the mean biased RRs ranged from 1.03 to 1.11. Assuming true RRs = 1.25 and 1.50, the biased RRs were as large as 1.39 and 1.67, respectively.

Conclusion: Estimates of the association between SNPs and prostate cancer can be biased to the magnitude observed in published GWAS, possibly resulting in type I error. However, large associations (RR > 1.10) may not fully be explained by this bias.

Impact: The influence of SNPs on PSA concentration should be considered when interpreting results from GWAS on prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 88–93. ©2014 AACR.

Background: Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo.

Methods: Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.

Results: Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008–0.04) and cotinine (P = <0.001–0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02–0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007–0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02–0.03) variants in African Americans were nominally associated with NNAL glucuronidation.

Conclusions: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation.

Impact: Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94–104. ©2014 AACR.

Background: The Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center (KTB) was established in 2007 with funding from Susan G. Komen for the Cure to provide scientists with a resource for normal breast tissue. To date, nearly 3,500 women have donated their healthy breast tissue to the bank, but little is known about their perspectives. This study was designed to examine their motivations, concerns, and experiences.

Methods: We conducted brief interviews with donors (n = 221) to investigate their donation-related motivations, concerns, and experiences. Donor responses were coded and quantitatively analyzed (descriptive statistics and 2).

Results: The most frequent motivation to donate (48% of donors) was personal connection to a breast cancer patient/survivor. A majority of donors (60%) were unconcerned about donation before the event; reported concerns included pain, fear, and dislike of surgical procedures. The most frequent positive experiences were minimal pain and positive behavior by KTB staff and volunteers. A majority of donors (61%) reported no negative experience, but reported negative experiences included the biopsy machine and anesthetic. Younger donors (ages 18–24) reported more concerns and negative experiences than older donors (25+).

Conclusions: Donors of healthy breast tissue are motivated by survivor connections and the ability to help by donating. Their concerns and experiences are relatively positive and consistent with undergoing a minor surgical procedure. Younger donors have more concerns and negative experiences.

Impact: Findings from this study can inform recruitment campaigns and donation procedures for banking of healthy tissue. Cancer Epidemiol Biomarkers Prev; 24(1); 105–10. ©2014 AACR.

Background: Age- and type-specific high-risk human papillomavirus (hrHPV) incidence estimates in screen-eligible women are relevant from a public health perspective because they provide an indication of the effect of vaccination on the occurrence of screen-positives in HPV-based screening. However, limited data from women over 25 years of age are available.

Methods: In 24,105 hrHPV-negative women participating in Dutch (Population-Based Screening Study Amsterdam: POBASCAM) and Italian (New Technologies for Cervical Cancer: NTCC) population-based randomized controlled screening trials the age- and type-specific distribution of incident hrHPV infections detected at the next screening round was assessed. HPV types were grouped into vaccine (bivalent: HPV16/18; polyvalent HPV16/18/31/33/45/52/58) and nonvaccine types.

Results: The incidence of screen-detected hrHPV among women ages 29 to 56 years was 2.54% (95% confidence interval, 2.30–2.78) in POBASCAM and 2.77% (2.36–3.19) in NTCC. In both studies, the incidence of bivalent, polyvalent, and nonpolyvalent infections decreased with age (P < 0.0001). Among women with incident infection(s), vaccine-type positivity changed quadratically with age, in particular for the polyvalent vaccine (P values: POBASCAM: bivalent 0.264, polyvalent 0.038; NTCC bivalent 0.039, polyvalent 0.005). However, more than 20% and 50% of women with incident hrHPV were positive for bivalent and polyvalent vaccine types, respectively, in all ages in both studies.

Conclusions: We observed decreasing age trends of hrHPV vaccine and nonvaccine type incidences and age-related differences in the vaccine-type positivity among women with incident infections. Most importantly, hrHPV infections continued to be detected in all ages and the contribution of vaccine types remained substantial.

Impact: Our results indicate a considerable reduction of new hrHPV infections in vaccinated cohorts, ensuing revision of screening guidelines. Cancer Epidemiol Biomarkers Prev; 24(1); 111–8. ©2014 AACR.

Background: The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism.

Methods: We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined.

Results: Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5x10–8). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 x 10–155). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 x 10–43) was in high LD (r2 = 0.99) with rs115765562.

Conclusions: Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose.

Impact: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk. Cancer Epidemiol Biomarkers Prev; 24(1); 119–27. ©2014 AACR.

Background: Few studies have assessed the association of body size with postmenopausal breast cancer risk in Hispanic women. Findings are inconsistent and appear to contradict those reported for non-Hispanic white (NHW) women.

Methods: We pooled interview and anthropometric data for 2,023 Hispanic and 2,384 NHW women from two U.S. population-based case–control studies. Using logistic regression analysis, we examined associations of overall and abdominal adiposity with risk of postmenopausal breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status.

Results: Weight gain was associated with increased risk of ER+PR+ breast cancer in Hispanics not currently using menopausal hormone therapy (HT), but only among those with a low young-adult body mass index (BMI). In the subset of Hispanics with data on genetic ancestry, the association with weight gain was limited to women with lower Indigenous American ancestry. Young-adult BMI was inversely associated with both ER+PR+ and ERPR breast cancers for both ethnicities combined, with similar, although nonsignificant, inverse trends in Hispanics and NHWs. Among all Hispanics, regardless of HT use, height was associated with risk of ERPR breast cancer and hip circumference with risk of breast cancer overall.

Conclusions: Body size throughout adult life is associated with breast cancer risk among postmenopausal Hispanic women, as has been reported for NHW women. Associations were specific for breast cancer subtypes defined by hormone receptor status.

Impact: Avoiding weight gain and maintaining a healthy weight are important strategies to reduce the risk of postmenopausal ER+PR+ breast cancer, the most common breast cancer subtype. Cancer Epidemiol Biomarkers Prev; 24(1); 128–37. ©2014 AACR.

See related article by John et al., p. 138

Background: Few studies in Hispanic women have examined the relation between adult body size and risk of premenopausal breast cancer defined by hormone receptor status.

Methods: The Breast Cancer Health Disparities Study pooled interview and anthropometric data from two large U.S. population-based case–control studies. We examined associations of overall and abdominal adiposity with risk of estrogen receptor– and progesterone receptor–positive (ER+PR+) and –negative (ERPR) breast cancer in Hispanic and non-Hispanic White (NHW) women, calculating ORs and 95% confidence intervals.

Results: Among Hispanics, risk of ER+PR+ breast cancer was inversely associated with measures of overall adiposity, including young-adult and current body mass index (BMI). Risk was substantially reduced among those with high (above the median) young-adult BMI and current overweight or obesity. The findings for overall adiposity were similar for Hispanics and NHWs. In the subset of Hispanics with data on genetic ancestry, inverse associations of current BMI, and weight gain with ER+PR+ breast cancer were limited to those with lower Indigenous American ancestry. For ERPR breast cancer, height was associated with increased risk, and young-adult BMI was associated with reduced risk. For all breast cancers combined, positive associations were seen for waist circumference, waist-to-hip ratio, and waist-to-height ratio in Hispanic women only.

Conclusions: Our findings of body size associations with specific breast cancer subtypes among premenopausal Hispanic women were similar to those reported for NHW women.

Impact: Adiposity throughout the premenopausal years has a major influence on breast cancer risk in Hispanic women. Cancer Epidemiol Biomarkers Prev; 24(1); 138–47. ©2014 AACR.

See related article by John et al., p. 128

Background: Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data.

Methods: In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from prediagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI).

Results: Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR, 2.21; 95% CI, 1.03–4.72; Ptrend: 0.049) and pooled (T3 vs. T1: OR, 3.12; 95% CI, 1.72–5.68; Ptrend: 0.0002). Association was stronger among male smokers (Ptrend: <0.0001) and essentially identical for cases diagnosed <6, >6–8, and >8 years from blood draw (pooled: Pinteraction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association.

Conclusions and Impact: Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as 8 years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development. Cancer Epidemiol Biomarkers Prev; 24(1); 148–53. ©2014 AACR.

Background: Implementing optimal lung cancer screening programs requires knowledge of the natural history and detectability of lung cancer. This information can be derived from the results of clinical trials with the aid of microsimulation models.

Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) program and individual-level data from the National Lung Screening Trial (NLST) and the Prostate, Lung, Colon, and Ovarian Cancer Screening trial (PLCO) were used to investigate the sensitivity (by histology and stage) of CT and chest radiography (CXR) and the mean preclinical sojourn time (MPST) of lung cancer (by gender, histology, and stage). The MISCAN-Lung model was used to reproduce the lung cancer incidence by method of detection (clinically or screen-detected), gender, histology, and stage in both trials and SEER, by calibrating CT and CXR sensitivity and natural history parameters.

Results: CT sensitivity ranges from 8.83% to 99.35% and CXR sensitivity from 2.51% to 97.31%, depending on histology and stage. CT sensitivity for stage IA is more than 3-fold higher compared with CXR, for all histologies. The total MPST estimates for lung cancer progressing through preclinical stages IA to IV range from 3.09 to 5.32 years for men and 3.35 to 6.01 years for women. The largest difference in total MPST between genders was estimated for adenocarcinoma.

Conclusions: We estimate longer MPSTs for lung cancer compared with previous research, suggesting a greater window of opportunity for lung cancer screening.

Impact: This study provides detailed insights into the natural history of lung cancer and CT screening effectiveness. Cancer Epidemiol Biomarkers Prev; 24(1); 154–61. ©2014 AACR.

Background: Research shows that multilevel factors influence healthcare delivery and patient outcomes. The study goal was to examine how clinic type [academic medical center (AMC) or federally qualified health center (FQHC)] and patient characteristics influence time to resolution (TTR) among individuals with an abnormal cancer-screening test enrolled in a patient navigation (PN) intervention.

Methods: Data were obtained from the Ohio Patient Navigation Research Project, a group-randomized trial of 862 patients from 18 clinics in Columbus, Ohio. TTR of patient after an abnormal breast, cervical, or colorectal screening test and the clinics' patient and provider characteristics were obtained. Descriptive statistics and Cox shared frailty proportional hazards regression models of TTR were used.

Results: The mean patient age was 44.8 years and 71% of patients were white. In models adjusted for study arm, FQHC patients had a 39% lower rate of resolution than AMC patients (P = 0.004). Patient factors of having a college education, private insurance, higher income, and being older were significantly associated with lower TTR. After adjustment for factors that substantially affected the effect of clinic type (patient insurance status, education level, and age), clinic type was not significantly associated with TTR.

Conclusions: These results suggest that TTR among individuals participating in PN programs are influenced by multiple socioeconomic patient-level factors rather than clinic type. Consequently, PN interventions should be tailored to address socioeconomic status factors that influence TTR.

Impact: These results provide clues regarding where to target PN interventions and the importance of recognizing predictors of TTR according to clinic type. Cancer Epidemiol Biomarkers Prev; 24(1); 162–8. ©2014 AACR.

Background: First-degree relatives of melanoma survivors have a substantially higher lifetime risk for melanoma than individuals with no family history. Exposure to ultraviolet radiation (UVR) is the primary modifiable risk factor for the disease. Reducing UV exposure through sun protection may be particularly important for children with a parental history of melanoma. Nonetheless, limited prior research has investigated sun protection practices and sun exposure among these children.

Methods: The California Cancer Registry was used to identify melanoma survivors eligible to participate in a survey to assess their children's sun protection practices and sun exposure. The survey was administered by mail, telephone, or web to Latino and non-Latino white melanoma survivors with at least one child (0–17 years; N = 324).

Results: Sun exposure was high and the rate of sunburn was equivalent to or higher than estimates from average-risk populations. Use of sun protection was suboptimal. Latino children were less likely to wear sunscreen and hats and more likely to wear sunglasses, although these differences disappeared in adjusted analyses. Increasing age of the child was associated with lower sun protection and higher risk for sunburn, whereas higher objective risk for melanoma predicted improved sun protection and a higher risk for sunburns. Perception of high barriers to sun protection was the strongest modifiable correlate of sun protection.

Conclusions: Interventions to improve sun protection and reduce sun exposure and sunburns in high-risk children are needed.

Impact: Intervening in high-risk populations may help reduce the burden of melanoma in the United States. Cancer Epidemiol Biomarkers Prev; 24(1); 169–77. ©2015 AACR.

Background: Increased oxidative stress has been linked to prostate cancer. We investigated oxidative stress–related genetic variants in relation to advanced prostate cancer risk and examined potential interactions with pro- and antioxidant exposures.

Methods: A case-cohort analysis was conducted in the prospective Netherlands Cohort Study, which included 58,279 men ages 55 to 69 years. Cohort members completed a baseline questionnaire and provided toenail clippings, which were used to isolate DNA. Advanced prostate cancer cases were identified during 17.3 years of follow-up. The analysis included 14 genetic variants and 11 exposures. Cox regression models were used for analysis and FDR Q-values were calculated.

Results: Complete genotyping data were available for 952 cases and 1,798 subcohort members. CAT rs1001179 was associated with stage III/IV and stage IV prostate cancer risk, with HRs per minor allele of 1.16 [95% confidence intervals (CI), 1.01–1.33; P = 0.032] and 1.25 (95% CI, 1.07–1.46; P = 0.006), respectively. We tested 151 gene–environment interactions in relation to both stage III/IV and IV prostate cancer risk. Seven interactions were statistically significant after adjusting for multiple testing (FDR Q-value <0.20); for stage III/IV prostate cancer, these involved intake of β-carotene (GPX1 rs17650792, hOGG1 rs1052133) and heme iron (GPX1 rs1800668 and rs3448), and for stage IV prostate cancer, these involved intake of catechin (SOD2 rs4880) and heme iron (hOGG1 rs1052133, SOD1 rs10432782).

Conclusion: This study of advanced prostate cancer risk showed a marginal association with a CAT polymorphism and seven novel gene–environment interactions in the oxidative stress pathway.

Impact: Oxidative stress–related genes and exposures may have a joint effect on advanced prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 178–86. ©2014 AACR.

Background: Colon cancer prognosis and treatment are currently based on a classification system still showing large heterogeneity in clinical outcome, especially in TNM stages II and III. Prognostic biomarkers for metastasis risk are warranted as development of distant recurrent disease mainly accounts for the high lethality rates of colon cancer. miRNAs have been proposed as potential biomarkers for cancer. Furthermore, a verified standard for normalization of the amount of input material in PCR-based relative quantification of miRNA expression is lacking.

Methods: A selection of frozen tumor specimens from two independent patient cohorts with TNM stage II–III microsatellite stable primary adenocarcinomas was used for laser capture microdissection. Next-generation sequencing was performed on small RNAs isolated from colorectal tumors from the Dutch cohort (N = 50). Differential expression analysis, comparing in metastasized and nonmetastasized tumors, identified prognostic miRNAs. Validation was performed on colon tumors from the German cohort (N = 43) using quantitative PCR (qPCR).

Results: miR25-3p and miR339-5p were identified and validated as independent prognostic markers and used to construct a multivariate nomogram for metastasis risk prediction. The nomogram showed good probability prediction in validation. In addition, we recommend combination of miR16-5p and miR26a-5p as standard for normalization in qPCR of colon cancer tissue–derived miRNA expression.

Conclusions: In this international study, we identified and validated a miRNA classifier in primary cancers, and propose a nomogram capable of predicting metastasis risk in microsatellite stable TNM stage II–III colon cancer.

Impact: In conjunction with TNM staging, by means of a nomogram, this miRNA classifier may allow for personalized treatment decisions based on individual tumor characteristics. Cancer Epidemiol Biomarkers Prev; 24(1); 187–97. ©2014 AACR.

Background: Red meat intake has been associated with risk of colorectal cancer, potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and colorectal cancer has been inconsistently reported.

Methods: We used pooled individual-level data from the Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models.

Results: From 11 studies, 8,290 colorectal cancer cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of colorectal cancer compared with the lowest quartile [OR, 1.41; 95% confidence interval (CI), 1.29–1.55]. However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with colorectal cancer in those with a rapid/intermediate NAT2 genotype (OR, 1.38; 95% CI, 1.20–1.59) as with a slow genotype (OR, 1.43; 95% CI, 1.28–1.61; P interaction = 0.9).

Conclusion: We found that high red meat intake was associated with increased risk of colorectal cancer only from retrospective case–control studies and not modified by NAT2 enzyme activity.

Impact: Our results suggest no interaction between NAT2 genotype and red meat intake in mediating risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 198–205. ©2014 AACR.

Background: Circulating tumor DNA (ctDNA) has offered a minimally invasive and feasible approach for detection of EGFR mutation for non–small cell lung cancer (NSCLC). This meta-analysis was designed to investigate the diagnostic value of ctDNA, compared with current "gold standard," tumor tissues.

Methods: We searched PubMed, EMBASE, Cochrane Library, and Web of Science to identify eligible studies that reported the sensitivity and specificity of ctDNA for detection of EGFR mutation status in NSCLC. Eligible studies were pooled to calculate the pooled sensitivity, specificity, and diagnostic odds ratio (DOR). The summary ROC curve (SROC) and area under SROC (AUSROC) were used to evaluate the overall diagnostic performance.

Results: Twenty-seven eligible studies involving 3,110 participants were included and analyzed in our meta-analysis, and most studies were conducted among Asian population. The pooled sensitivity, specificity, and DOR were 0.620 [95% confidence intervals (CI), 0.513–0.716), 0.959 (95% CI, 0.929–0.977), and 38.270 (95% CI, 21.090–69.444), respectively. The AUSROC was 0.91 (95% CI, 0.89–0.94), indicating the high diagnostic performance of ctDNA.

Conclusion: ctDNA is a highly specific and effective biomarker for the detection of EGFR mutation status.

Impact: ctDNA analysis will be a key part of personalized cancer therapy of NSCLC. Cancer Epidemiol Biomarkers Prev; 24(1); 206–12. ©2014 AACR.

Background: Many SNPs influence prostate cancer risk. To what extent genetic risk can be reduced by environmental factors is unknown.

Methods: We evaluated effect modification by environmental factors of the association between susceptibility SNPs and prostate cancer in 1,230 incident prostate cancer cases and 1,361 controls, all white and similar ages, nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Trial. Genetic risk scores were calculated as number of risk alleles for 20 validated SNPs. We estimated the association between higher genetic risk (≥12 SNPs) and prostate cancer within environmental factor strata and tested for interaction.

Results: Men with ≥12 risk alleles had 1.98, 2.04, and 1.91 times the odds of total, advanced, and nonadvanced prostate cancer, respectively. These associations were attenuated with the use of selenium supplements, aspirin, ibuprofen, and higher vegetable intake. For selenium, the attenuation was most striking for advanced prostate cancer: compared with <12 alleles and no selenium, the OR for ≥12 alleles was 2.06 [95% confidence interval (CI), 1.67–2.55] in nonusers and 0.99 (0.38–2.58) in users (Pinteraction = 0.031). Aspirin had the most marked attenuation for nonadvanced prostate cancer: compared with <12 alleles and nonusers, the OR for ≥12 alleles was 2.25 (1.69–3.00) in nonusers and 1.70 (1.25–2.32) in users (Pinteraction = 0.009). This pattern was similar for ibuprofen (Pinteraction = 0.023) and vegetables (Pinteraction = 0.010).

Conclusions: This study suggests that selenium supplements may reduce genetic risk of advanced prostate cancer, whereas aspirin, ibuprofen, and vegetables may reduce genetic risk of nonadvanced prostate cancer.

Impact: The effect of genetic factors on prostate cancer risk may vary by lifestyle interventions. Cancer Epidemiol Biomarkers Prev; 24(1); 213–20. ©2014 AACR.

Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.e., markers that are variable in the population, yet stable over time.

Methods: We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately 6 years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake, and smoking.

Results: Approximately 17% of probes had an ICC > 0.50 and were considered stable VMPs (stable-VMPs). Stable-VMPs were enriched for probes located in "shores" bordering CpG islands, and at approximately 1.3 kb downstream from the transcription start site in the transition between the unmethylated promoter and methylated gene body. Both cross-sectional and longitudinal data analyses provided strong evidence for associations between changes in methylation levels and aging. Smoking-related probes at 2q37.1 and AHRR were stable-VMPs and related to time since quitting. We also observed associations between methylation and weight changes.

Conclusion: Our results provide support for the use of white blood cell DNA methylation as a biomarker of exposure in EWAS.

Impact: Larger studies, preferably with repeated measures over time, will be required to establish associations between specific probes and exposures. Cancer Epidemiol Biomarkers Prev; 24(1); 221–9. ©2014 AACR.

Background: The New Mexico HPV Pap Registry was established to measure the impact of cervical cancer prevention strategies in the United States. Before widespread human papillomavirus (HPV) vaccine implementation, we established the baseline prevalence for a broad spectrum of HPV genotypes across the continuum of cervical intraepithelial neoplasia (CIN) and cancer.

Methods: A population-based sample of 6,272 tissue specimens was tested for 37 HPV genotypes. The number of specimens tested within each diagnostic category was: 541 negative, 1,411 CIN grade 1 (CIN1), 2,226 CIN grade 2 (CIN2), and 2,094 CIN grade 3 (CIN3) or greater. Age-specific HPV prevalence was estimated within categories for HPV genotypes targeted by HPV vaccines.

Results: The combined prevalence of HPV genotypes included in the quadrivalent and nonavalent vaccines increased from 15.3% and 29.3% in CIN1 to 58.4% and 83.7% in CIN3, respectively. Prevalence of HPV types included in both vaccines tended to decrease with increasing age for CIN1, CIN2, CIN3, and squamous cell carcinoma (SCC), most notably for CIN3 and SCC. The six most common HPV types in descending order of prevalence were HPV-16, -31, -52, -58, -33, and -39 for CIN3 and HPV-16, -18, -31, -45, -52, and -33 for invasive cancers.

Conclusions: Health economic modeling of HPV vaccine impact should consider age-specific differences in HPV prevalence.

Impact: Population-based HPV prevalence in CIN is not well described, but is requisite for longitudinal assessment of vaccine impact and to understand the effectiveness and performance of various cervical screening strategies in vaccinated and unvaccinated women. Cancer Epidemiol Biomarkers Prev; 24(1); 230–40. ©2014 AACR.

Background: Because the burden of colorectal cancer (CRC) seems to be increasing in First Nations, it is important to better understand CRC screening utilization. The objective of this study was to describe CRC screening among First Nations living in Manitoba.

Methods: The Federal Indian Register was linked to two provincial databases. A negative binomial model was used to compare the probability of First Nations having a fecal occult blood test (FOBT), colonoscopy, or flexible sigmoidoscopy (FS) with all other Manitobans.

Results: First Nations who lived in Winnipeg were significantly less likely to have had a FOBT in the previous 2 years than all other Manitobans who lived in Winnipeg [rate ratio (RR) = 0.40; 95% confidence intervals (CI), 0.37–0.44]. There was no difference in the likelihood of having a colonoscopy or FS for First Nations individuals who resided in northern Manitoba compared with all other Manitobans (RR, 1.04; 95% CI, 0.91–1.19). However, First Nations who lived in the rural south or urban areas were less likely than all other Manitobans to have had a colonoscopy or FS (RR, 0.81, 95% CI, 0.75–0.87, rural south; RR, 0.86, 95% CI, 0.81–0.92, urban).

Conclusions: First Nations living in Winnipeg were significantly less likely to be screened for CRC using the FOBT. Colonoscopy and FS use depended on area of residence.

Impact: First Nations experience barriers that impede the use of CRC screening. Further research is needed to understand these barriers to extend the benefit of CRC screening to this population. Cancer Epidemiol Biomarkers Prev; 24(1); 241–8. ©2014 AACR.

Background: It has been hypothesized that alteration of hormone systems is involved in the carcinogenesis of acrylamide. The aim of the present study was to examine the cross-sectional associations between dietary acrylamide intake and sex hormone levels in premenopausal Japanese women.

Methods: Study subjects were 393 women who had regular menstrual cycles less than 40 days long. Acrylamide intake was assessed with a food-frequency questionnaire and was based on acrylamide concentration reported from analyses of Japanese foods. We measured the plasma concentrations of estradiol, testosterone, dehydroepiandrosterone sulfate, sex hormone–binding globulin, follicle-stimulating hormone, luteinizing hormone, and prolactin.

Results: After controlling for age, the phase of the menstrual cycle, and other covariates, acrylamide intake was statistically significantly inversely associated with total and free estradiol levels and statistically significantly positively associated with follicle-stimulating hormone level. Total and free estradiol levels were 18.2% and 19.3% lower, respectively, in women in the highest quartile of acrylamide intake than in those in the lowest quartile of intake. Follicle-stimulating hormone levels were 23.5% higher in women in the highest quartile of acrylamide intake than in those in the lowest quartile of intake.

Conclusion: The data suggest that acrylamide intake may alter estradiol and follicle-stimulating hormone levels.

Impact: High estradiol levels have been associated with an increased risk of breast cancer. Although the results need confirmation, they highlight the need to investigate the relationships among dietary acrylamide, sex hormones, and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(1); 249–54. ©2014 AACR.

Background: Numerous germline genetic variants are associated with prostate cancer risk, but their biologic role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide.

Methods: We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N = 160) and prostate tumor (N = 264) tissue from participants of the Physicians' Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test.

Results: In addition to confirming previously reported associations, we detected several new significant (P < 0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, five genes (MSMB, NUDT11, RBPMS2, NEFM, and KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (P < 2.5 x 10–6). Many more genes had an FDR <10%, including SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue.

Conclusions: The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biologic and epidemiologic studies.

Impact: Determining the biologic role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention. Cancer Epidemiol Biomarkers Prev; 24(1); 255–60. ©2014 AACR.

Background: Metabolic syndrome and its component feature, central obesity, are associated with endometrial cancer risk. It remains unclear whether associations with the other metabolic factors that comprise metabolic syndrome are independent of the obesity–endometrial cancer association. Furthermore, the link with specific endometrial cancer subtypes remains ill-defined, despite evidence of etiologic heterogeneity among these tumors.

Methods: In a case–control study within the SEER–Medicare linked database, we examined whether metabolic factors, individually or combined, were associated with endometrial cancer. Cases (n = 16,323) were women diagnosed with endometrial cancer from 1993 through 2007. Controls (n = 100,751) were a 5% sample of female Medicare enrollees residing in the same SEER registry area as cases. Metabolic syndrome was defined using ICD-9-CM codes from inpatient/outpatient diagnoses 1 to 3 years before case diagnosis and a comparable time period in controls. ORs and 95% confidence intervals (CI) were estimated using logistic regression.

Results: Endometrial cancer risk was associated with metabolic syndrome [OR (95% CI): 1.39 (1.32–1.47)] and its component factors: overweight/obesity [1.95 (1.80–2.11)], impaired fasting glucose [1.36 (1.30–1.43)], high blood pressure [1.31 (1.25–1.36)], and high triglycerides [1.13 (1.08–1.18)]. After adjusting for overweight/obesity, the increased risks associated with the metabolic syndrome factors remained. Heterogeneity of associations by subtype were not identified (Pheterogeneity = 0.82).

Conclusions: Among women age 65 and older in the United States, metabolic syndrome, and its component factors, increased endometrial cancer risk similarly across endometrial cancer subtypes.

Impact: Strategies to reduce the prevalence of metabolic syndrome factors might have a favorable effect on endometrial cancer incidence. Cancer Epidemiol Biomarkers Prev; 24(1); 261–7. ©2015 AACR.

Background: PCA3 is a long noncoding RNA (lncRNA) with unknown function, upregulated in prostate cancer. LncRNAs may be processed into smaller active species. We hypothesized this for PCA3.

Methods: We computed feasible RNA hairpins within the BMCC1 gene (encompassing PCA3) and searched a prostate transcriptome for these. We measured expression using qRT-PCR in three cohorts of prostate cancer tissues (n = 60), exfoliated urinary cells (n = 484 with cancer and n = 166 controls), and in cell lines (n = 22). We used in silico predictions and RNA knockup to identify potential mRNA targets of short transcribed RNAs.

Results: We predicted 13 hairpins, of which PCA3-shRNA2 was most abundant within the prostate transcriptome. PCA3-shRNA2 is located within intron 1 of PCA3 and appears regulated by androgens. Expression of PCA3-shRNA2 was upregulated in malignant prostatic tissues, exfoliated urinary cells from men with prostate cancer (13–273 fold change; t test P < 0.003), and closely correlated to PCA3 expression (r = 0.84–0.93; P < 0.001). Urinary PCA3-shRNA2 (C-index, 0.75–0.81) and PCA3 (C-index, 0.78) could predict the presence of cancer in most men. PCA3-shRNA2 knockup altered the expression of predicted target mRNAs, including COPS2, SOX11, WDR48, TEAD1, and Noggin. PCA3-shRNA2 expression was negatively correlated with COPS2 in patient samples (r = –0.32; P < 0.001).

Conclusion: We identified a short RNA within PCA3, whose expression is correlated to PCA3, which may target mRNAs implicated in prostate biology.

Impact: This short RNA is stable ex vivo, suggesting a role as a robust biomarker. We identify cytoplasmic enrichment of this RNA and potential targeting of mRNAs implicated in prostate carcinogenesis. Cancer Epidemiol Biomarkers Prev; 24(1); 268–75. ©2014 AACR.

Background: Inequalities in cervical cancer may be increased following mass vaccination against the human papillomavirus (HPV) if girls with low vaccine uptake also have low future participation in cervical cancer screening. We evaluated how vaccine uptake distribution affects inequalities in squamous cell carcinoma (SCC) incidence between groups with different screening participation.

Methods: We used an individual-based transmission dynamic model of HPV infection and disease (HPV-ADVISE). Females were stratified by routine screening frequency. We modeled the impact of vaccination on SCC incidence rate differences (absolute inequality) and incidence rate ratios (relative inequality) between women who have routine screening intervals of <5 years (frequently screened), ≥5 years (underscreened), and who are never screened. We compared simulations with uniform vaccine uptake with scenarios with unequal vaccine uptake, in which never and underscreened women have lower vaccine uptake than frequently screened women.

Results: Absolute SCC inequalities between groups with different screening rates were predicted to decrease after vaccination, even when women with the lowest screening participation had the lowest vaccine uptake. Herd effects helped reduce absolute inequalities when vaccine uptake was unequal. Conversely, relative SCC inequalities remained unchanged or increased after vaccination. Results were robust to different overall vaccination coverages and sexual mixing scenarios.

Conclusion: Though mass HPV vaccination is predicted to substantially decrease SCC incidence rates, never screened women will still have the highest disease burden after vaccination.

Impact: To reduce both absolute and relative SCC inequalities, public health initiatives will need to address inequalities in both vaccine uptake and in cervical cancer screening participation. Cancer Epidemiol Biomarkers Prev; 24(1); 276–85. ©2014 AACR.

It has been hypothesized that, following a reduction in human papillomavirus (HPV) vaccine–targeted genotypes, an increase in prevalence of other HPV types may occur due to reduced competition during natural infection. Any apparent postvaccination increase must be distinguished from diagnostic artifacts consequent to consensus PCR assays failing to detect HPV types present in low copy numbers in coinfected specimens (under the assumption that with a drop in vaccine-preventable types there may be increased detection of previously "masked" types). We reanalyzed anogenital specimens to evaluate unmasking of HPV52 that may be caused by elimination of HPV16. Using highly sensitive type-specific real-time HPV52 PCR, we retested 1,200 anogenital specimens (all HPV52 negative according to consensus PCR assays) from six epidemiologic studies (200 specimens/study; 100 HPV16+/study). Multivariate logistic regression, with adjustment for age and number of sexual partners, was used to evaluate the association between HPV16 positivity and detection of HPV52. In our pooled analysis (n = 1,196), the presence of HPV16 was positively associated with HPV52 detection [adjusted OR, 1.47; 95% confidence interval (CI), 0.76–2.82]. In our separate (study specific) analyses, a statistically significant association was observed in one study that included HIV-infected males (HIPVIRG study; adjusted OR, 3.82; 95% CI, 1.19–12.26). We observed a positive association between HPV16 viral load (tertiles) and detection of HPV52 (P for trend = 0.003). These results indicate that diagnostic artifacts, resulting from unmasking of HPV52, may occur in some settings in the evaluation of HPV type replacement. Additional studies exploring the extent and severity of unmasking are needed. Cancer Epidemiol Biomarkers Prev; 24(1); 286–90. ©2014 AACR.

Acrylamide, classified in 1994 by the International Agency for Research on Cancer (IARC) as "probably carcinogenic" to humans, was discovered in 2002 in some heat-treated, carbohydrate-rich foods. The association between dietary acrylamide intake and epithelial ovarian cancer risk (EOC) has been previously studied in one case–control and three prospective cohort studies which obtained inconsistent results and could not further examine histologic subtypes other than serous EOC. The present study was carried out in the European Prospective Investigation into Cancer and Nutrition (EPIC) subcohort of women (n = 325,006). Multivariate Cox proportional hazards models were used to assess the association between questionnaire-based acrylamide intake and EOC risk. Acrylamide was energy-adjusted using the residual method and was evaluated both as a continuous variable (per 10 μg/d) and in quintiles; when subgroups by histologic EOC subtypes were analyzed, acrylamide intake was evaluated in quartiles. During a mean follow-up of 11 years, 1,191 incident EOC cases were diagnosed. At baseline, the median acrylamide intake in EPIC was 21.3 μg/d. No associations and no evidence for a dose–response were observed between energy-adjusted acrylamide intake and EOC risk (HR10μg/d,1.02; 95% CI, 0.96–1.09; HRQ5vsQ1, 0.97; 95% CI, 0.76–1.23). No differences were seen when invasive EOC subtypes (582 serous, 118 endometrioid, and 79 mucinous tumors) were analyzed separately. This study did not provide evidence that acrylamide intake, based on food intake questionnaires, was associated with risk for EOC in EPIC. Additional studies with more reliable estimates of exposure based on biomarkers may be needed. Cancer Epidemiol Biomarkers Prev; 24(1); 291–7. ©2014 AACR.

To date, all population-based epidemiologic data on gastrointestinal stromal tumor (GIST) in the United States predate the 2001 implementation of GIST-specific histology coding. As such, results from previous studies were limited because of inclusion of non-GIST abdominal or gastrointestinal sarcomas. We used a national cancer registry with modern day histologic codes to gain greater insight into the true epidemiology of GIST in the United States. We identified 6,142 patients diagnosed with GIST between 2001 and 2011 in the Surveillance, Epidemiology, and End Results database. Incidence, survival, demographic risk factors, and prognostic factors were analyzed. Annual age-adjusted incidence rose from 0.55/100,000 in 2001 to 0.78/100,000 in 2011 and increased with age, peaking among 70- to 79-year-olds (3.06/100,000). GIST was also more common in males than females [rate ratio (RR), 1.35], non-Hispanics than Hispanics (RR, 1.23), and blacks (RR, 2.07) or Asians/Pacific Islanders (RR, 1.50) than whites. The study period had 5-year overall and GIST-specific survival rates of 65% and 79%, respectively. The 5-year overall survival rates for those with localized, regional, and metastatic disease at diagnosis were 77%, 64%, and 41%, respectively. Multivariate analyses demonstrated that older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors for worse overall survival. Multivariate analysis also showed the four aforementioned characteristics, along with earlier year of diagnosis, to be independent risk factors for worse GIST-specific survival. As the first population-based, epidemiologic study of histologically confirmed disease, our findings provide a robust representation of GIST in the era of immunohistochemical diagnoses. Cancer Epidemiol Biomarkers Prev; 24(1); 298–302. ©2014 AACR.

Studies on outcomes in bladder cancer rely on accurate methods to identify patients with bladder cancer and differentiate bladder cancer stage. Medical record and administrative databases are increasingly used to study cancer incidence, but few have distinguished cancer stage, and none have focused on bladder cancer. In this study, we used data from The UK Health Improvement Network (THIN) to identify patients with bladder cancer using at least one diagnostic code for bladder cancer, and distinguish muscle-invasive from non-invasive disease using a subsequent code for cystectomy. Algorithms were validated against a gold standard of physician-completed questionnaires, pathology reports, and consultant letters. Algorithm performance was evaluated by measuring positive predictive value (PPV) and corresponding 95% confidence interval (CI). Among all patients coded with bladder cancer (n = 194), PPV for any bladder cancer was 99.5% (95% CI, 97.2–99.9). PPV for incident bladder cancer was 93.8% (95% CI, 89.4–96.7). PPV for muscle-invasive bladder cancer was 70.1% (95% CI, 59.4–79.5) in patients with cystectomy (n = 95) and 83.9% (95% CI, 66.3–94.5) in those with cystectomy plus additional codes for metastases and death (n = 31). Using our codes for bladder cancer, the age- and sex-standardized incidence rate (SIR) of bladder cancer in THIN approximated that measured by cancer registries (SIR within 20%), suggesting that sensitivity was high as well. THIN is a valid and novel database for the study of bladder cancer. Our algorithm can be used to examine the epidemiology of muscle-invasive bladder cancer or outcomes following cystectomy for patients with muscle invasion. Cancer Epidemiol Biomarkers Prev; 24(1); 303–7. ©2014 AACR.

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.

Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.

Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.

Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.