bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus
Authors: Yu Ming , O'Leary Rachele M. , Kaz Andrew M. , Morris Shelli M. , Carter Kelly T. , Chak Amitabh , Chandar Apoorva , Willis Joseph E. , Moinova Helen R. , Markowitz Sanford D. , Brenner Dean E. , Anandabapasathy Sharmila , Westerhoff Maria , Wong Chao-Jen , Shaheen Nicholas J. , Chen Yanwen , Barnholtz-Sloan Jill S. , Grady William M.
Published: April 2023

Abstract
Background: Barrett's esophagus (BE) is a preneoplastic condition in which normal esophageal squamous epithelium (SQ) is replaced by specialized intestinal metaplasia. It is the presumed precursor for esophageal adenocarcinoma (EAC) as well as the strongest risk factor for this cancer. Unfortunately, many patients with BE go undiagnosed under the current BE screening guidelines. The development of noninvasive and accurate BE detection assays could potentially identify many of these undiagnosed BE patients.

Methods: DNA methylation is a common epigenetic alteration in BE. Therefore, we conducted a genome-wide methylation screen to identify potential BE biomarkers. Samples from SQ (N = 12), stomach (N = 28), and BE (N = 29) were analyzed and methylation levels at over 485,000 CpG sites were compared. Pyrosequencing assays were used to validate the results and MethyLight assays were developed to detect the methylated alleles in endoscopic brushings.

Results: We discovered two genes, B3GAT2 and ZNF793, that are aberrantly methylated in BE. Clinical validation studies confirmed B3GAT2 and ZNF793 methylation levels were significantly higher in BE samples (median = 32.5% and 33.1%, respectively) than in control tissues (median = 2.29% and 2.52%, respectively; P < 0.0001 for both genes). Furthermore, gene-specific MethyLight assays could accurately detect BE (P < 0.0001 for both) in endoscopic brushing samples.

Conclusion: B3GAT2 and ZNF793 are hypermethylated in BE, and the methylation status of these genes can be used to detect BE in tissue samples.

Impact: These findings support the development of methylated B3GAT2 and ZNF793 as biomarkers for noninvasive assays for the detection of BE. Cancer Epidemiol Biomarkers Prev; 24(12); 1890–7. ©2015 AACR.
Data from Interaction between Common Breast Cancer Susceptibility Variants, Genetic Ancestry, and Nongenetic Risk Factors in Hispanic Women
Authors: Fejerman Laura , Stern Mariana C. , John Esther M. , Torres-Mejía Gabriela , Hines Lisa M. , Wolff Roger K. , Baumgartner Kathy B. , Giuliano Anna R. , Ziv Elad , Pérez-Stable Eliseo J. , Slattery Martha L.
Published: April 2023

Abstract
Background: Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene–environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified SNPs among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population.

Methods: We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions.

Results: We found that the rs13387042–2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele OR: 0.94 (95% confidence intervals, 0.74–1.20), 1.20 (0.94–1.53), and 1.49 (1.28–1.75) for current, former, and never hormone therapy users, respectively, Pinteraction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72–1.42), 1.19 (0.98–1.45), and 1.69 (1.26–2.26) for never, <12 months, and >12 months breastfeeding, respectively, Pinteraction 0.014].

Conclusions: The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women.

Impact: These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and nongenetic risk factors and their contribution to breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1731–8. ©2015 AACR.
Data from A Composite Cytology–Histology Endpoint Allows a More Accurate Estimate of Anal High-Grade Squamous Intraepithelial Lesion Prevalence
Authors: Machalek Dorothy A. , Poynten I. Mary , Jin Fengyi , Hillman Richard J. , Templeton David J. , Law Carmella , Roberts Jennifer M. , Tabrizi Sepehr N. , Garland Suzanne M. , Farnsworth Annabelle , Fairley Christopher K. , Grulich Andrew E.
Published: April 2023

Abstract
Background: There is debate about the accuracy of anal cytology and high-resolution anoscopy (HRA), in the diagnosis of anal human papillomavirus (HPV)-related squamous intraepithelial lesions (SIL). Few studies have performed both simultaneously in a large sample of high-risk individuals.

Methods: At baseline in a community-based cohort of HIV-infected and uninfected homosexual men ages ≥35 years in Sydney, Australia, all men underwent anal swabbing for cytology and HPV genotyping, and HRA-guided biopsy. We evaluated the separate and combined diagnostic accuracy of cytology and histology, based on a comparison with the prevalence of HPV16 and other high-risk (HR) HPV. We examined trends in HPV prevalence across cytology–histology combinations.

Results: Anal swab, HRA, and HPV genotyping results were available for 605 of 617 participants. The prevalence of cytologically predicted high-grade SIL (HSIL, 17.9%) was lower than histologically diagnosed HSIL (31.7%, P < 0.001). The prevalence of composite-HSIL (detected by either method) was 37.7%. HPV16 prevalence was similar in men with HSIL by cytology (59.3%), HSIL by histology (51.0%), and composite-HSIL (50.0%). HPV16 prevalence was 31.1% in men with composite-atypical squamous cells suggestive of HSIL, to 18.5% in men with composite-low-grade SIL, to 12.1% in men with composite-negative results (Ptrend < 0.001).

Conclusions: Significantly more HSIL was detected when a composite cytology–histology endpoint was used. Increasing grade of composite endpoint was associated with increasing HPV16 prevalence.

Impact: These data suggest that a composite cytology–histology endpoint reflects meaningful disease categories and is likely to be an important biomarker in anal cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(7); 1134–43. ©2016 AACR.
Data from European Breast Cancer Service Screening Outcomes: A First Balance Sheet of the Benefits and Harms
Authors: Paci Eugenio , Broeders Mireille , Hofvind Solveig , Puliti Donella , Duffy Stephen William
Published: April 2023

Abstract
A recent comprehensive review has been carried out to quantify the benefits and harms of the European population-based mammographic screening programs. Five literature reviews were conducted on the basis of the observational published studies evaluating breast cancer mortality reduction, breast cancer overdiagnosis, and false-positive results. On the basis of the studies reviewed, the authors present a first estimate of the benefit and harm balance sheet. For every 1,000 women screened biennially from ages 50 to 51 years until ages 68 to 69 years and followed up until age 79 years, an estimated seven to nine breast cancer deaths are avoided, four cases are overdiagnosed, 170 women have at least one recall followed by noninvasive assessment with a negative result, and 30 women have at least one recall followed by invasive procedures yielding a negative result. The chance of a breast cancer death being avoided by population-based mammography screening of appropriate quality is more than that of overdiagnosis by screening. These outcomes should be communicated to women offered service screening in Europe. Cancer Epidemiol Biomarkers Prev; 23(7); 1159–63. ©2014 AACR.
Data from Age at Menarche and Late Adolescent Adiposity Associated with Mammographic Density on Processed Digital Mammograms in 24,840 Women
Authors: Alexeeff Stacey E. , Odo Nnaemeka U. , Lipson Jafi A. , Achacoso Ninah , Rothstein Joseph H. , Yaffe Martin J. , Liang Rhea Y. , Acton Luana , McGuire Valerie , Whittemore Alice S. , Rubin Daniel L. , Sieh Weiva , Habel Laurel A.
Published: April 2023

Abstract
Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density.

Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders.

Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend <0.0001) and DA (P value for trend <0.0001) in fully adjusted models. Compared with the reference category of ages 12 to 13 years at menarche, menarche at age >16 years was associated with an increase in PD of 1.47% (95% CI, 0.69–2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48–2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models.

Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images.

Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. Cancer Epidemiol Biomarkers Prev; 26(9); 1450–8. ©2017 AACR.
Data from Long-Term Effects of Weight Loss and Exercise on Biomarkers Associated with Angiogenesis
Authors: Duggan Catherine , Tapsoba Jean de Dieu , Wang Ching-Yun , Schubert Karen E. Foster , McTiernan Anne
Published: April 2023

Abstract
Background: We tested the effect of weight loss on circulating levels of the angiogenic factors VEGF and pigment epithelium-derived factor (PEDF) in postmenopausal overweight/obese women, 18 months after completing a year-long 4-arm randomized controlled trial of behavioral weight loss and/or exercise versus control (i.e., 30 months postrandomization).

Methods: The 439 overweight/obese, postmenopausal women, ages 50 to 75 years, were randomized to: diet (goal: 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), diet + exercise (N = 117), or control (N = 87). At 12 months, 399 women gave a blood sample; 156 returned at 30 months. Biomarkers were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity.

Results: Participants randomized to diet, exercise, and diet + exercise arms had greater reductions in VEGF at 30 months (−14.1% P = 0.02; −19.7% P = 0.003; −14.5% P = 0.002, respectively) versus controls (−4.5%). There were no statistically significant changes in PEDF in any intervention arm. Participants maintaining ≥10% of baseline weight loss at 30 months had greater reductions in VEGF versus those who gained weight/had no weight change (−22.3% vs. −10.2% respectively, P = 0.002). Participants maintaining any weight loss had significantly lower levels of PEDF at 30 months versus those who gained weight/no weight change.

Conclusions: Sustained weight loss via diet and/or exercise results in reductions in angiogenic factors, and can be maintained up to 30-month follow-up. Limitations include relatively small numbers, and possible bias toward more successful weight loss among women who returned at 30 months.

Impact: Maintaining weight loss can achieve long-term reductions in biomarkers of angiogenesis that can persist up to 18 months after completion of a weight loss intervention. Cancer Epidemiol Biomarkers Prev; 26(12); 1788–94. ©2017 AACR.
Data from One versus Two Breast Density Measures to Predict 5- and 10-Year Breast Cancer Risk
Authors: Kerlikowske Karla , Gard Charlotte C. , Sprague Brian L. , Tice Jeffrey A. , Miglioretti Diana L.
Published: April 2023

Abstract
Background: One measure of Breast Imaging Reporting and Data System (BI-RADS) breast density improves 5-year breast cancer risk prediction, but the value of sequential measures is unknown. We determined whether two BI-RADS density measures improve the predictive accuracy of the Breast Cancer Surveillance Consortium 5-year risk model compared with one measure.

Methods: We included 722,654 women of ages 35 to 74 years with two mammograms with BI-RADS density measures on average 1.8 years apart; 13,715 developed invasive breast cancer. We used Cox regression to estimate the relative hazards of breast cancer for age, race/ethnicity, family history of breast cancer, history of breast biopsy, and one or two density measures. We developed a risk prediction model by combining these estimates with 2000–2010 Surveillance, Epidemiology, and End Results incidence and 2010 vital statistics for competing risk of death.

Results: The two-measure density model had marginally greater discriminatory accuracy than the one-measure model (AUC, 0.640 vs. 0.635). Of 18.6% of women (134,404 of 722,654) who decreased density categories, 15.4% (20,741 of 134,404) of women whose density decreased from heterogeneously or extremely dense to a lower density category with one other risk factor had a clinically meaningful increase in 5-year risk from <1.67% with the one-density model to ≥1.67% with the two-density model.

Conclusion: The two-density model has similar overall discrimination to the one-density model for predicting 5-year breast cancer risk and improves risk classification for women with risk factors and a decrease in density.

Impact: A two-density model should be considered for women whose density decreases when calculating breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(6); 889–97. ©2015 AACR.
Data from Screening Mammography Use among Current, Former, and Never Hormone Therapy Users May Not Explain Recent Declines in Breast Cancer Incidence
Authors: Buist Diana S.M. , Walker Rod , Bowles Erin J. Aiello , Carney Patricia A. , Taplin Stephen H. , Onega Tracy , Kerlikowske Karla , Clinton Walter , Miglioretti Diana L.
Published: April 2023

Abstract
Background: Screening mammography and invasive breast cancer and ductal carcinoma in situ (DCIS) rates recently declined in the United States; screening mammography declines among former hormone therapy (HT) users may be an important contributor. We longitudinally examined women and compared mammography use and cancer rates by HT use [current, former, and never users of estrogen + progestin (EPT) and estrogen only (ET)].

Methods: We studied 163,490 unique women aged 50–79 years enrolled in Group Health (Washington State) between 1994–2009. Electronic data identified HT dispensing, mammography use and incident breast cancer diagnosis. We calculated age-adjusted screening compliance as a time-varying variable (screened-within-the-past-26 months, yes/no).

Results: Before 2002, screening compliance differed significantly by HT with current EPT users having the highest rates (83%) followed by former EPT (77%), current ET (77%), former ET (72%), and never users (56%). After 2002, screening was high (∼81%) among current and former EPT and ET users and significantly increased among never users (∼62%). Invasive breast cancer rates significantly decreased over the whole study period (Ptrend ≤ 0.05) for all HT users, except EPT current users (Ptrend = 0.68); DCIS rates did not change in any group.

Conclusions: Differential screening mammography rates by HT use do not explain invasive breast cancer incidence declines. Our data suggest discontinuing HT has an immediate effect on breast cancer rates, lending support to the mechanism that cessation leads to tumor regression.

Impact: Studies examining the influence of a changing exposure in relation to outcomes should account for varying exposures, individuals' characteristics, as well as screening methods and frequency. Cancer Epidemiol Biomarkers Prev; 21(5); 720–7. ©2012 AACR.
Data from Cannabis Use and Incidence of Testicular Cancer: A 42-Year Follow-up of Swedish Men between 1970 and 2011
Authors: Callaghan Russell C. , Allebeck Peter , Akre Olof , McGlynn Katherine A. , Sidorchuk Anna
Published: April 2023

Abstract
Background: Given current drug policy reforms to decriminalize or legalize cannabis in numerous countries worldwide, the current study assesses the relation between cannabis use and the development of testicular cancer.

Methods: The study included a population-based sample (n = 49,343) of young men ages 18–21 years who underwent conscription assessment for Swedish military service in 1969–1970. The conscription process included a nonanonymous questionnaire eliciting information about drug use. Conscription information was linked to Swedish health and administrative registry data. Testicular cancers diagnosed between 1970 and 2011 were identified by International Classification of Diseases-7/8/9/10 testicular cancer codes in the Swedish National Patient Register, the Cancer Register, or the Cause of Death Register. Cox regression modeling was used to estimate the hazards associated with cannabis use and time to diagnosis of testicular cancer.

Results: No evidence was found of a significant relation between lifetime “ever” cannabis use and the subsequent development of testicular cancer [n = 45,250; 119 testicular cancer cases; adjusted HR (aHR), 1.42; 95% confidence interval (CI), 0.83–2.45]. “Heavy” cannabis use (defined as usage of more than 50 times in lifetime, as measured at conscription) was associated with the incidence of testicular cancer (n = 45,250; 119 testicular cancer cases; aHR 2.57; 95% CI, 1.02–6.50).

Conclusions: The current study provides additional evidence to the limited prior literature suggesting cannabis use may contribute to the development of testicular cancer.

Impact: Emerging changes to cannabis drug policy should consider the potential role of cannabis use in the development of testicular cancer. Cancer Epidemiol Biomarkers Prev; 26(11); 1644–52. ©2017 AACR.
Data from Metformin Use and Risk of Colorectal Adenoma after Polypectomy in Patients with Type 2 Diabetes Mellitus
Authors: Marks Amy R. , Pietrofesa Ralph A. , Jensen Christopher D. , Zebrowski Alexis , Corley Douglas A. , Doubeni Chyke A.
Published: April 2023

Abstract
Background: Existing literature suggests that metformin, the most commonly used biguanide, may lower colorectal cancer risk. Because most colorectal cancers originate in precancerous adenomas, we examined whether metformin use lowered colorectal adenoma risk after polypectomy in patients with type-2 diabetes.

Methods: Retrospective cohort study of 40- to 89-year-old Kaiser Permanente Northern California patients who had type 2 diabetes, and ≥1 adenoma detected at baseline colonoscopy during 2000 to 2009 and a repeat colonoscopy 1 to 10 years from baseline adenoma diagnosis through 2012. Cox models evaluated the association between metformin use during follow-up and subsequent adenoma diagnoses, controlling for age, race/ethnicity, sex, body mass index, and repeat examination indication.

Results: Study included 2,412 patients followed for a median of 4.5 years; cumulatively, 1,117 (46%) patients had ≥1 adenoma at repeat colonoscopy. Compared with patients not receiving diabetes medications (n = 1,578), metformin-only use (n = 457) was associated with lower adenoma recurrence risk [adjusted HR, 0.76; 95% confidence interval (CI), 0.65–0.89], and the association was stronger with increasing total metformin dose [quartile (Q) 1: HR, 0.90; 95% CI, 0.72–1.12; Q2: HR, 0.89; 95% CI, 0.70–1.12; Q3: HR, 0.80; 95% CI, 0.63–1.01; Q4: HR, 0.50; 95% CI, 0.42–0.60, Ptrend < 0.001]. Findings were unchanged in sensitivity analyses, including evaluating only outcomes during the 3- to 10-year period from baseline.

Conclusion: Our study suggests a potential benefit of metformin use in lowering the risk of subsequent adenomas after polypectomy in patients with type 2 diabetes.

Impact: Metformin may lower colorectal cancer risk by reducing the formation of precancerous lesions, reinforcing the potential additional benefits of its use. Cancer Epidemiol Biomarkers Prev; 24(11); 1692–8. ©2015 AACR.
Data from History of Diabetes and Risk of Head and Neck Cancer: A Pooled Analysis from the International Head and Neck Cancer Epidemiology Consortium
Authors: Stott-Miller Marni , Chen Chu , Chuang Shu-Chun , Lee Yuan-Chin Amy , Boccia Stefania , Brenner Hermann , Cadoni Gabriela , Dal Maso Luigino , La Vecchia Carlo , Lazarus Philip , Levi Fabio , Matsuo Keitaro , Morgenstern Hal , Müller Heiko , Muscat Joshua , Olshan Andrew F. , Purdue Mark P. , Serraino Diego , Vaughan Thomas L. , Zhang Zuo-Feng , Boffetta Paolo , Hashibe Mia , Schwartz Stephen M.
Published: April 2023

Abstract
Background: A history of diabetes is associated with an increased risk of several types of cancers. Whether diabetes is a risk factor for head and neck cancer (HNC) has received little attention.

Methods: We pooled data from 12 case–control studies including 6,448 cases and 13,747 controls, and estimated OR and 95% CI for the associations between diabetes and HNC, adjusted for age, education level, sex, race/ethnicity, study center, cigarette smoking, alcohol use, and body mass index.

Results: We observed a weak association between diabetes and the incidence of HNC overall (OR, 1.09; 95% CI: 0.95–1.24). However, we observed a modest association among never smokers (OR, 1.59; 95% CI: 1.22–2.07), and no association among ever smokers (OR, 0.96; 95% CI: 0.83–1.11); likelihood ratio test for interaction P = 0.001.

Conclusion: A history of diabetes was weakly associated with HNC overall, but we observed evidence of effect modification by smoking status, with a positive association among those who never smoked cigarettes.

Impact: This study suggests that glucose metabolism abnormalities may be a HNC risk factor in subgroups of the population. Prospective studies incorporating biomarkers are needed to improve our understanding of the relationship between diabetes and HNC risk, possibly providing new strategies in the prevention of HNC. Cancer Epidemiol Biomarkers Prev; 21(2); 294–304. ©2011 AACR.
Data from Biology and Etiology of Young-Onset Breast Cancers among Premenopausal African American Women: Results from the AMBER Consortium
Authors: Chollet-Hinton Lynn , Olshan Andrew F. , Nichols Hazel B. , Anders Carey K. , Lund Jennifer L. , Allott Emma H. , Bethea Traci N. , Hong Chi-Chen , Cohen Stephanie M. , Khoury Thaer , Zirpoli Gary R. , Borges Virginia F. , Rosenberg Lynn A. , Bandera Elisa V. , Ambrosone Christine B. , Palmer Julie R. , Troester Melissa A.
Published: April 2023

Abstract
Background: African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered.

Methods: We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (≥40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls). Unconditional logistic regression models assessed heterogeneity of tumor biology and risk factor associations by age, overall, and by estrogen receptor status.

Results: Premenopausal AA women <40 years had higher frequency of poorer-prognosis tumor characteristics compared with older women, including negative estrogen and progesterone receptor status, triple-negative subtype, higher grade, higher stage, and larger tumors. Adiposity (i.e., waist-to-hip ratio) and family history of breast cancer were more strongly associated with young-onset disease [case–control OR = 1.46, 95% confidence interval (CI) = 1.04–2.05; OR = 3.10, 95% CI = 2.08–4.63, respectively] compared with older-onset disease (OR = 1.11, 95% CI = 0.91–1.35; OR = 1.57, 95% CI = 1.26–1.94). Breastfeeding showed a slight inverse risk association among young women (OR = 0.70, 95% CI = 0.43–1.16). Oral contraceptive use was associated with increased risk regardless of age. Considering various cutoff points for young age (<40, <45, <50), age-related heterogeneity was greatest when <40 was used.

Conclusions: Among premenopausal AA women, diagnosis before age 40 is associated with more aggressive breast tumor biology and some etiologic differences.

Impact: Modifiable risk factors including breastfeeding, adiposity, and oral contraceptive use may be important targets for mitigating harms of young-onset breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1722–9. ©2017 AACR.
Data from How Are Spousal Depressed Mood, Distress, and Quality of Life Associated with Risk of Depressed Mood in Cancer Survivors? Longitudinal Findings from a National Sample
Authors: Litzelman Kristin , Yabroff K. Robin
Published: April 2023

Abstract
Background: Spouses of cancer survivors experience both positive and negative effects from caregiving. However, it is less clear what role spousal well-being may have on cancer survivors. This study aimed to determine the impact of spousal psychosocial factors on survivor depressed mood and whether this association differed by gender.

Methods: We examined longitudinal data on cancer survivors and their spouses (n = 910 dyads) from the 2004–2012 Medical Expenditures Panel Survey and a matched sample of cancer-free dyads. Subjects reported depressed mood, psychologic distress, and mental and physical health-related quality of life (HRQoL) at two time points (T1/T2). Dyadic multilevel models evaluated the impact of psychosocial factors at T1 on depressed mood at T2, controlling for sociodemographics, cancer type, survivor treatment status, and depressed mood at T1.

Results: Cancer survivors whose spouses reported depressed mood at T1 were 4.27 times more likely to report depressed mood at T2 [95% confidence interval (CI), 2.01–9.07]; this was stronger for female survivors (OR, 9.49; 95% CI, 2.42–37.20). Better spousal mental and physical HRQoL at T1 were associated with a 30% decrease in survivor depressed mood risk at T2. Most spillover effects were not observed in comparison dyads.

Conclusion: Depressed mood and poor HRQoL in spouses may increase the risk of depressed mood in cancer survivors. The risk may be especially strong for female survivors.

Impact: Identifying and improving spousal mental health and HRQoL problems may reduce the risk of depressed mood in cancer survivors. Future research should examine whether incorporating spousal care into psychooncology and survivorship programs improves survivor outcomes. Cancer Epidemiol Biomarkers Prev; 24(6); 969–77. ©2015 AACR.
Data from Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci
Authors: Reid Brett M. , Permuth Jennifer B. , Chen Y. Ann , Teer Jamie K. , Monteiro Alvaro N.A. , Chen Zhihua , Tyrer Jonathan , Berchuck Andrew , Chenevix-Trench Georgia , Doherty Jennifer A. , Goode Ellen L. , Iverson Edwin S. , Lawrenson Kate , Pearce Celeste L. , Pharoah Paul D. , Phelan Catherine M. , Ramus Susan J. , Rossing Mary Anne , Schildkraut Joellen M. , Cheng Jin Q. , Gayther Simon A. , Sellers Thomas A.
Published: April 2023

Abstract
Background: Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P < 5 × 10−8). Most risk SNPs lie within non–protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets.

Methods: Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10−5 > P > 5 × 10−8) overlapping lncRNAs.

Results: Of 5,294 EOC-associated SNPs (P < 1.0 × 10−5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0 × 10−4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression.

Conclusions: lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC.

Impact: lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116–25. ©2016 AACR.
Data from A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure–Cancer Associations
Authors: Ertaylan Gökhan , Le Cornet Charlotte , van Roekel Eline H. , Jung Audrey Y. , Bours Martijn J.L. , Damms-Machado Antje , van den Brandt Piet A. , Schock Helena , de Kok Theo M. , Theys Jan , Arts Ilja C.W. , Kaaks Rudolf , Weijenberg Matty P. , Fortner Renée Turzanski
Published: April 2023

Abstract
The World Cancer Research Fund (WCRF) International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure–cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-commissioned validation study. In stage I, a “hypothesis-free” approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In stage II, a systematic review was conducted on the insulin-like growth factor 1 receptor (IGF1R) chosen as an intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness–IGF1R association and modest evidence linking IGF1R to breast cancer, and therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic reviews by integrating evidence from mechanistic studies on exposure–cancer associations. On the basis of our experience, we provide recommendations for future users. Cancer Epidemiol Biomarkers Prev; 26(11); 1583–94. ©2017 AACR.
Data from Influence of Quercetin-Rich Food Intake on microRNA Expression in Lung Cancer Tissues
Authors: Lam Tram K. , Shao Stephanie , Zhao Yingdong , Marincola Francesco , Pesatori Angela , Bertazzi Pier Alberto , Caporaso Neil E. , Wang Ena , Landi Maria Teresa
Published: April 2023

Abstract
Background: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.

Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).

Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047).

Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases.

Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.
Data from Rare Variation in TET2 Is Associated with Clinically Relevant Prostate Carcinoma in African Americans
Authors: Koboldt Daniel C. , Kanchi Krishna L. , Gui Bin , Larson David E. , Fulton Robert S. , Isaacs William B. , Kraja Aldi , Borecki Ingrid B. , Jia Li , Wilson Richard K. , Mardis Elaine R. , Kibel Adam S.
Published: April 2023

Abstract
Background: Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease.

Method: To identify such variants, we performed a two-stage approach using whole-exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 × 10−5 to correct for multiple testing.

Results: TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 × 10−5, OR = 3.0; SKAT-O P = 2.74 × 10−5). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6. Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2. This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer.

Conclusions: Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment.

Impact: This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456–63. ©2016 AACR.
Data from Effects of Tailored Risk Communications for Skin Cancer Prevention and Detection: The PennSCAPE Randomized Trial
Authors: Glanz Karen , Volpicelli Kathryn , Jepson Christopher , Ming Michael E. , Schuchter Lynn M. , Armstrong Katrina
Published: April 2023

Abstract
Background: Prevention and early detection measures for melanoma, such as sun avoidance and skin examinations, are important, but are practiced inconsistently. In this replication of the Project SCAPE trial, we sought to determine whether tailored print materials were more effective at improving adherence than generic print materials for patients at increased risk of skin cancer.

Methods: Participants were randomized to receive personalized mailed communications about their skin cancer risk and recommended sun protection, or generic mailings. Participants were Caucasian adults, at moderate or high risk for skin cancer, recruited in outpatient primary care. The main outcomes were overall sun protection behaviors and specific protective behaviors including use of sunscreen, shirt, hat, sunglasses, shade, and sun avoidance; recent sunburns; and skin self-examination and provider skin examination.

Results: One hundred ninety-two (93.2%) subjects completed the study. Six outcome variables showed significant intervention condition effects in mixed effects models: overall sun protection behavior (P = 0.025); sunscreen use (P = 0.026); use of sunglasses (P = 0.011); sunburns in the past three months (P = 0.033); recency of last skin self-exam (P = 0.017); and frequency of skin exams by health care provider (P = 0.016).

Conclusions: Relative to generic communications, tailored risk communications resulted in improved adherence to six skin cancer protective behaviors, including a composite sun protection behavior measure, sunburns, and health care provider skin examinations.

Impact: Tailored interventions can be more effective in improving patient prevention behaviors than nontailored, generic information for patients at moderate to high risk of skin cancer. Cancer Epidemiol Biomarkers Prev; 24(2); 415–21. ©2014 AACR.
Data from Human Papillomavirus Genotype-Specific Prevalence across the Continuum of Cervical Neoplasia and Cancer
Authors: Joste Nancy E. , Ronnett Brigitte M. , Hunt William C. , Pearse Amanda , Langsfeld Erika , Leete Thomas , Jaramillo MaryAnn , Stoler Mark H. , Castle Philip E. , Wheeler Cosette M.
Published: April 2023

Abstract
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.
Data from Diabetes, Abnormal Glucose, Dyslipidemia, Hypertension, and Risk of Inflammatory and Other Breast Cancer
Authors: Schairer Catherine , Gadalla Shahinaz M. , Pfeiffer Ruth M. , Moore Steven C. , Engels Eric A.
Published: April 2023

Abstract
Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged).

Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992–2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression.

Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21–1.71), distant (OR 1.24; 99.9% CI, 1.09–1.40) and regional (OR 1.29 (99.9% CI, 1.14–1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10–1.39) and unstaged (OR 1.32; 99.9% CI, 1.18–1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67–0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type.

Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors.

Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862–8. ©2017 AACR.
Data from Hormone Therapy, Estrogen Metabolism, and Risk of Breast Cancer in the Women's Health Initiative Hormone Therapy Trial
Authors: Mackey Rachel H. , Fanelli Theresa J. , Modugno Francesmary , Cauley Jane A. , McTigue Kathleen M. , Brooks Maria Mori , Chlebowski Rowan T. , Manson JoAnn E. , Klug Thomas L. , Kip Kevin E. , Curb J. David , Kuller Lewis H.
Published: April 2023

Abstract
Background: In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio.

Methods: In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (n = 1,259), at 1 year.

Results: The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, P < 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant.

Conclusions: Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer.

Impact: Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens. Cancer Epidemiol Biomarkers Prev; 21(11); 2022–32. ©2012 AACR.
Data from Effect of Occupational Exposures on Lung Cancer Susceptibility: A Study of Gene–Environment Interaction Analysis
Authors: Malhotra Jyoti , Sartori Samantha , Brennan Paul , Zaridze David , Szeszenia-Dabrowska Neonila , Świątkowska Beata , Rudnai Peter , Lissowska Jolanta , Fabianova Eleonora , Mates Dana , Bencko Vladimir , Gaborieau Valerie , Stücker Isabelle , Foretova Lenka , Janout Vladimir , Boffetta Paolo
Published: April 2023

Abstract
Background: Occupational exposures are known risk factors for lung cancer. Role of genetically determined host factors in occupational exposure–related lung cancer is unclear.

Methods: We used genome-wide association (GWA) data from a case–control study conducted in 6 European countries from 1998 to 2002 to identify gene–occupation interactions and related pathways for lung cancer risk. GWA analysis was performed for each exposure using logistic regression and interaction term for genotypes, and exposure was included in this model. Both SNP-based and gene-based interaction P values were calculated. Pathway analysis was performed using three complementary methods, and analyses were adjusted for multiple comparisons. We analyzed 312,605 SNPs and occupational exposure to 70 agents from 1,802 lung cancer cases and 1,725 cancer-free controls.

Results: Mean age of study participants was 60.1 ± 9.1 years and 75% were male. Largest number of significant associations (P ≤ 1 × 10−5) at SNP level was demonstrated for nickel, brick dust, concrete dust, and cement dust, and for brick dust and cement dust at the gene-level (P ≤ 1 × 10−4). Approximately 14 occupational exposures showed significant gene–occupation interactions with pathways related to response to environmental information processing via signal transduction (P < 0.001 and FDR < 0.05). Other pathways that showed significant enrichment were related to immune processes and xenobiotic metabolism.

Conclusion: Our findings suggest that pathways related to signal transduction, immune process, and xenobiotic metabolism may be involved in occupational exposure–related lung carcinogenesis.

Impact: Our study exemplifies an integrative approach using pathway-based analysis to demonstrate the role of genetic variants in occupational exposure–related lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 24(3); 570–9. ©2015 AACR.