bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppementary Figure 1 from Shifts in the Fecal Microbiota Associated with Adenomatous Polyps
Authors: Hale Vanessa L. , Chen Jun , Johnson Stephen , Harrington Sean C. , Yab Tracy C. , Smyrk Thomas C. , Nelson Heidi , Boardman Lisa A. , Druliner Brooke R. , Levin Theodore R. , Rex Douglas K. , Ahnen Dennis J. , Lance Peter , Ahlquist David A. , Chia Nicholas
Published: April 2023

Supplementary Figure 1. Gut microbial composition and diversity in patients with and without adenomas. A) Microbial composition was similar between groups across all taxonomic levels. The groups did not differ in terms of α-diversity: B) observed number of operational taxonomic units (OTUs) or C) the Shannon diversity index. The groups did not cluster by β-diversity: D) unweighted and E) weighted UniFrac distance metrics.
Supplementary Table 1 from Epstein–Barr Virus Serology as a Potential Screening Marker for Nasopharyngeal Carcinoma among High-Risk Individuals from Multiplex Families in Taiwan
Authors: Coghill Anna E. , Hsu Wan-Lun , Pfeiffer Ruth M. , Juwana Hedy , Yu Kelly J. , Lou Pei-Jen , Wang Cheng-Ping , Chen Jen-Yang , Chen Chien-Jen , Middeldorp Jaap M. , Hildesheim Allan
Published: April 2023

PDF file - 70K, Application of EBNA1 IgA as a Screening Tool for Incident NPC in varying Target Populations.
Supplementary Figure S2 from Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm
Authors: Sun Xiangqing , Elston Robert C. , Barnholtz-Sloan Jill S. , Falk Gary W. , Grady William M. , Faulx Ashley , Mittal Sumeet K. , Canto Marcia , Shaheen Nicholas J. , Wang Jean S. , Iyer Prasad G. , Abrams Julian A. , Tian Ye D. , Willis Joseph E. , Guda Kishore , Markowitz Sanford D. , Chandar Apoorva , Warfe James M. , Brock Wendy , Chak Amitabh
Published: April 2023

The consistency of true age and the corresponding imputed age that was imputed according to the family structure and the known ages of family members
Supplementary Figure 1 from Serum Proteoglycans as Prognostic Biomarkers of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis
Authors: Nault Jean-Charles , Guyot Erwan , Laguillier Christelle , Chevret Sylvie , Ganne-Carrie Nathalie , N'Kontchou Gisèle , Beaugrand Michel , Seror Olivier , Trinchet Jean-Claude , Coelho Jessica , Lasalle Philippe , Charnaux Nathalie , Delehedde Maryse , Sutton Angela , Nahon Pierre
Published: April 2023

PDF file - 194K, Subgroup analysis according to the Levels of serum proteoglycans and VEGF.
Supplementary Tables from Prediagnostic Levels of Serum One-Carbon Metabolites and Risk of Hepatocellular Carcinoma
Authors: Butler Lesley M. , Arning Erland , Wang Renwei , Bottiglieri Teodoro , Govindarajan Sugantha , Gao Yu-Tang , Yuan Jian-Min
Published: April 2023

PDF file, 96K, Table S1. Mass transitions and method statistics for the determination of serum one-carbon metabolites Table S2. Linear regression ratio of prediagnostic serum levels of one-carbon metabolites in relation to baseline characteristics and other lifestyle factors among control subjects Table S3. Conditional odds ratios (ORs) and 95% confidence intervals (CIs) of hepatocellular carcinoma in relation to prediagnostic serum levels of one-carbon metabolites Table S4. Spearman correlation coefficients between prediagnostic serum levels of one-carbon metabolites among control subjects (n = 631) Table S5. Odds ratios (ORs) and 95% confidence intervals (CIs) of hepatocellular carcinoma relation to prediagnostic serum levels of choline, methionine and pyridoxal phosphate by smoking status and alcohol consumption.
Supplementary Table 1 from Limited PSA Testing in Indigent Men in South Texas: An Appropriate Care or Missing a Prevention Opportunity?
Authors: Liang Yuanyuan , Du Fei , Thompson Ian M. , Turner Barbara J.
Published: April 2023

PDF file, 58K, PSA testing and abnormal PSA result by primary care clinic.
Supplementary Table 1 from Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility
Authors: FitzGerald Liesel M. , Kumar Akash , Boyle Evan A. , Zhang Yuzheng , McIntosh Laura M. , Kolb Suzanne , Stott-Miller Marni , Smith Tiffany , Karyadi Danielle M. , Ostrander Elaine A. , Hsu Li , Shendure Jay , Stanford Janet L.
Published: April 2023

PDF - 109K, Information on the 174 single nucleotide variants identified by whole-exome sequencing.
Supplemental Table S1-S5 from Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma
Authors: Zhang Weikang , Liu Hongliang , Liu Zhensheng , Zhu Dakai , Amos Christopher I. , Fang Shenying , Lee Jeffrey E. , Wei Qingyi
Published: April 2023

Supplemental Table S1-S5. Table S1. List of 4,949 common genotyped and imputed SNPs in the Notch signaling pathway. Table S2. List of 78 common SNPs in the Notch signaling pathway found to be associated with CM DSS with FPRP<0.2 Table S3. Predictors of DSS in CM patients obtained from stepwise cox regression analysis of selected variables. Table S4. Association between selected SNPs in the Notch pathway genes and OS of CM patients. Table S5. Stratified association analyses on OS and HRs for CM patients with different numbers of unfavorable genotypes across genes in the Notch pathway.
Supplemental Figures S1-S4 from Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma
Authors: Zhang Weikang , Liu Hongliang , Liu Zhensheng , Zhu Dakai , Amos Christopher I. , Fang Shenying , Lee Jeffrey E. , Wei Qingyi
Published: April 2023

Supplemental Figures S1-S4. Figure S1. Flow-chart of SNPs selection among Notch pathway genes. Figure S2. Manhattan plot of associations between 4,949 SNPs in Notch pathway and CM DSS. There are 181 SNPs with P-value < 0.05. Figure S3. Linkage disequilibrium (indicated by pairwise r-sqaure) map for SNPs in NCOR2 (A) and MAML2 (B) with stepwise-P < 0.05. Figure S4. The regional association plots in the 2 kb neighborhood of NCOR2 (A), NCSTN (B) and MAML2 (C). The left-hand y-axis shows the association P value of individual SNPs in the discovery dataset, which is plotted as -log10 (P) against chromosomal base-pair position. The right-hand y-axis shows the recombination rate estimated from the HapMap CEU population.
Supplementary Table 1 from Risk of Precancer Determined by HPV Genotype Combinations in Women with Minor Cytologic Abnormalities
Authors: Gage Julia C. , Schiffman Mark , Solomon Diane , Wheeler Cosette M. , Gravitt Patti E. , Castle Philip E. , Wentzensen Nicolas
Published: April 2023

PDF file - 50K, HPV DNA genotyping result at enrollment visit, stratified by cytology and age at enrollment.
Supplementary Tables S1-S3 from A Comprehensive Meta-analysis of Case–Control Association Studies to Evaluate Polymorphisms Associated with the Risk of Differentiated Thyroid Carcinoma
Authors: Figlioli Gisella , Elisei Rossella , Romei Cristina , Melaiu Ombretta , Cipollini Monica , Bambi Franco , Chen Bowang , Köhler Aleksandra , Cristaudo Alfonso , Hemminki Kari , Gemignani Federica , Försti Asta , Landi Stefano
Published: April 2023

Table S1. Comparison between results from literature and results from the present GWAS for all the SNPs extracted from literature. Table S2. Data published in literature where only one genetic model (either dominant or recessive) was reported in the manuscript. No allelic OR or additive model could be evaluated according to the data reported in the manuscript. Table S3. Meta-analyses of the literature data for the SNPs evaluated in two or more than one study.
Supplementary Figure 4 from Circulating Biomarkers of Tryptophan and the Kynurenine Pathway and Lung Cancer Risk
Authors: Chuang Shu-Chun , Fanidi Anouar , Ueland Per Magne , Relton Caroline , Midttun Øivind , Vollset Stein Emil , Gunter Marc J. , Seckl Michael J. , Travis Ruth C. , Wareham Nicholas , Trichopoulou Antonia , Lagiou Pagona , Trichopoulos Dimitrios , Peeters Petra H.M. , Bueno-de-Mesquita H. Bas , Boeing Heiner , Wientzek Angelika , Kuehn Tilman , Kaaks Rudolf , Tumino Rosario , Agnoli Claudia , Palli Domenico , Naccarati Alessio , Aicua Eva Ardanaz , Sánchez María-José , Quirós José Ramón , Chirlaque María-Dolores , Agudo Antonio , Johansson Mikael , Grankvist Kjell , Boutron-Ruault Marie-Christine , Clavel-Chapelon Françoise , Fagherazzi Guy , Weiderpass Elisabete , Riboli Elio , Brennan Paul J. , Vineis Paolo , Johansson Mattias
Published: April 2023

PDF file - 100K, Odds Ratios with 95% Confidence Intervals (CI) of Lung Cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by histological type. P for trend were assessed by the base 2 logarithm of the circulating levels.
Supplementary Table 1 from Genetic Polymorphisms in Inflammation Pathway Genes and Prostate Cancer Risk
Authors: Kwon Erika M. , Salinas Claudia A. , Kolb Suzanne , Fu Rong , Feng Ziding , Stanford Janet L. , Ostrander Elaine A.
Published: April 2023

Supplementary Table 1 from Genetic Polymorphisms in Inflammation Pathway Genes and Prostate Cancer Risk
Supplementary Figures 1 - 6, Tables 1 - 2, Methods from The Ability of Plasma Cotinine to Predict Nicotine and Carcinogen Exposure is Altered by Differences in CYP2A6: the Influence of Genetics, Race, and Sex
Authors: Zhu Andy Z.X. , Renner Caroline C. , Hatsukami Dorothy K. , Swan Gary E. , Lerman Caryn , Benowitz Neal L. , Tyndale Rachel F.
Published: April 2023

PDF file - 215K, Supplementary Table 1: Descriptive participant characteristics. Supplementary Table 2: Regression analyses of the predictive ability of cotinine and CYP2A6 genotype (or sex) on tobacco and tobacco-derived carcinogen exposure (Study 2). Supplementary Figure 1. Within the male participants (Study 1): A. CYP2A6 RM (n=10) metabolized a significantly lower amount nicotine to cotinine compared to CYP2A6 NM (n=44). B. CYP2A6 RM (n=10) had lower cotinine clearance (CLCOT) compared to CYP2A6 NM (n=44). C. The fNICCOT/CLCOT ratio was higher in CYP2A6 RM compared to CYP2A6 NM. Within the female participants (Study 1): D. CYP2A6 RM metabolized a significantly lower amount of nicotine to cotinine compared to CYP2A6 NM. E. CYP2A6 RM had lower cotinine clearance (CLCOT) compared to CYP2A6 NM. F. The fNICCOT/CLCOT ratio was higher in CYP2A6 RM compared to CYP2A6 NM. With all participants (Study 1): G. Individuals with slower NMR metabolized a significant lower amount of nicotine to cotinine compared to the individuals with faster NMR. H. Individuals with slower NMR had lower cotinine clearance (CLCOT) compared to the individuals with faster NMR. I. fNICCOT/CLCOT was higher among individuals in the slower NMR stratum compared to the individuals in the faster NMR stratum. Data presented as mean � 95% confidence interval. Supplementary Figure 2: Cotinine�s ability to predict tobacco exposure was different between NMR strata (Study 2). Supplementary Figure 3. TNE�s ability to predict tobacco specific nitrosamines exposure is independent of CYP2A6 genotype (Study 2).Supplementary Figure 4. Cotinine�s ability to predict polycyclic aromatic hydrocarbon exposure (as indicated by 1-hydroxyfluorene) was different between CYP2A6 genotypes (Study 2). Supplementary Figure 5. Among the CYP2A6 normal metabolizers (Study 1, n=148), males, who have reduced CYP2A6 activity compared to females, had a greater ratio of cotinine formation over removal.Supplementary Figure 6. A nicotine patch study: abstinent individuals with slower NMR have higher steady state plasma cotinine compared to individuals with faster NMR after receiving the same 21 mg nicotine patch.
Supplementary Table 1 from Low-Dose CT Lung Cancer Screening Practices and Attitudes among Primary Care Providers at an Academic Medical Center
Authors: Lewis Jennifer A. , Petty W. Jeffrey , Tooze Janet A. , Miller David P. , Chiles Caroline , Miller Antonius A. , Bellinger Christina , Weaver Kathryn E.
Published: April 2023

Supplementary Table 1. Items Assessing Lung Cancer Screening Guideline Knowledge
Supplementary Tables 1 and 2 from Outcomes of Breast Cancer in Brazil Related to Health Care Coverage: A Retrospective Cohort Study
Authors: Liedke Pedro E.R. , Finkelstein Dianne M. , Szymonifka Jackie , Barrios Carlos H. , Chavarri-Guerra Yanin , Bines José , Vasconcelos Cláudia , Simon Sérgio D. , Goss Paul E.
Published: April 2023

PDF - 69KB, Supplementary Table 1 - Primary treatment received by all patients and according to insurance type presented by stage at diagnosis. Supplamentary Table 2 - Minimally adjusted Cox Multivariate analysis.
Supplementary Table 1 from Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake
Authors: Han Summer S. , Sue Laura Y. , Berndt Sonja I. , Selhub Jacob , Burdette Laurie A. , Rosenberg Philip S. , Ziegler Regina G.
Published: April 2023

PDF file - 125K
Data from Parental Occupational Exposure to Heavy Metals and Welding Fumes and Risk of Testicular Germ Cell Tumors in Offspring: A Registry-Based Case–Control Study
Authors: Togawa Kayo , Le Cornet Charlotte , Feychting Maria , Tynes Tore , Pukkala Eero , Hansen Johnni , Olsson Ann , Oksbjerg Dalton Susanne , Nordby Karl-Christian , Uuksulainen Sanni , Wiebert Pernilla , Woldbæk Torill , Skakkebæk Niels E. , Fervers Béatrice , Schüz Joachim
Published: April 2023

Abstract
Background: Data are scarce on the association between prenatal/preconception environmental exposure and testicular germ cell tumor (TGCT) in offspring. We examined parental occupational exposures to heavy metals and welding fumes in relation to TGCT in offspring in a registry-based case–control study (NORD-TEST Study).

Methods: We identified TGCT cases diagnosed at ages 14–49 years in Finland (1988–2012), Norway (1978–2010), and Sweden (1979–2011) through nationwide cancer registries. These cases were individually matched by country and year of birth to controls selected from population registries. Information on parental occupations was retrieved from censuses. From this, we estimated prenatal/preconception exposures of chromium, iron, nickel, lead, and welding fumes (all three countries), and cadmium (Finland only) for each parent using job-exposure matrices specifying prevalence (P) and mean exposure level (L). Exposure indices were calculated as a product of P and L (P × L), and exposure categories were based on P × L or different combinations of P and L.

Results: The study comprised 8,112 cases and 26,264 controls. We observed no statistically significant TGCT risk associated with presence of heavy metals/welding fumes (P × L > 0) and no dose-response relationship (Ptrend ≥ 0.32). A statistically significant elevated TGCT risk was found in paternal exposure category where both P and L of chromium were high (vs. no chromium; OR = 1.37, 95% confidence interval; 1.05–1.79).

Conclusions: Our study provides little evidence of associations between parental exposures to heavy metals/welding fumes and TGCT in offspring with the potential exception of high paternal chromium exposure.

Impact: Further research on paternal chromium exposure is warranted. Cancer Epidemiol Biomarkers Prev; 25(10); 1426–34. ©2016 AACR.
Data from A Comparison of Human Papillomavirus Genotype-Specific DNA and E6/E7 mRNA Detection to Identify Anal Precancer among HIV-Infected Men Who Have Sex with Men
Authors: Castle Philip E. , Follansbee Stephen , Borgonovo Sylvia , Tokugawa Diane , Schwartz Lauren M. , Lorey Thomas S. , LaMere Brandon , Gage Julia C. , Fetterman Barbara , Darragh Teresa M. , Rodriguez Ana Cecilia , Wentzensen Nicolas
Published: April 2023

Abstract
Background: Human papillomavirus (HPV) RNA detection is reportedly more specific for the detection of anogenital precancer than HPV DNA but it is unknown whether this is due to detection of RNA or due to HPV genotype restriction.

Methods: A total of 363 human immunodeficiency virus (HIV)–positive men who have sex with men had two anal cytology samples taken and were evaluated using high-resolution anoscopy and biopsies of visible lesions. Anal specimens were tested for E6/E7 RNA for five carcinogenic HPV genotypes (HPV16, 18, 31, 33, and 45) and tested for the DNA of 13 carcinogenic HPV genotypes.

Results: DNA testing was more likely to be positive than RNA testing (53% vs. 48%; P = 0.02) for the same five HPV genotypes in aggregate. When restricted to five HPV genotypes targeted by the RNA test, the sensitivity to detect anal precancer was the same for DNA and RNA (81%), whereas RNA was more specific than DNA (65% vs. 58%; P = 0.007). In comparison, DNA detection of all 13 carcinogenic HPV genotypes was more sensitive (96% vs. 81%; P = 0.001) but much less specific (65% vs. 33%; P < 0.001) as compared with RNA detection of the five HPV genotypes.

Conclusion: After controlling for HPV genotypes, RNA was only slightly more specific than DNA detection for anal precancer.

Impact: DNA or RNA testing for a subset of the most carcinogenic HPV genotypes may be useful for distinguishing between those HPV-positive men at higher and lower risk of anal precancer and cancer. Cancer Epidemiol Biomarkers Prev; 22(1); 42–9. ©2012 AACR.
Data from Sex-Specific Associations of Arsenic Exposure with Global DNA Methylation and Hydroxymethylation in Leukocytes: Results from Two Studies in Bangladesh
Authors: Niedzwiecki Megan M. , Liu Xinhua , Hall Megan N. , Thomas Tiffany , Slavkovich Vesna , Ilievski Vesna , Levy Diane , Alam Shafiul , Siddique Abu B. , Parvez Faruque , Graziano Joseph H. , Gamble Mary V.
Published: April 2023

Abstract
Background: Depletion of global 5-hydroxymethylcytosine (5-hmC) is observed in human cancers and is strongly implicated in skin cancer development. Although arsenic (As)—a class I human carcinogen linked to skin lesion and cancer risk—is known to be associated with changes in global %5-methylcytosine (%5-mC), its influence on 5-hmC has not been widely studied.

Methods: We evaluated associations of As in drinking water, urine, and blood with global %5-mC and %5-hmC in two studies of Bangladeshi adults: (i) leukocyte DNA in the Nutritional Influences on Arsenic Toxicity study (n = 196; 49% male, 19–66 years); and (ii) peripheral blood mononuclear cell DNA in the Folate and Oxidative Stress study (n = 375; 49% male, 30–63 years).

Results: Overall, As was not associated with global %5-mC or %5-hmC. Sex-specific analyses showed that associations of As exposure with global %5-hmC were positive in males and negative in females (P for interaction < 0.01). Analyses examining interactions by elevated plasma total homocysteine (tHcys), an indicator of B-vitamin deficiency, found that tHcys also modified the association between As and global %5-hmC (P for interaction < 0.10).

Conclusion: In two samples, we observed associations between As exposure and global %5-hmC in blood DNA that were modified by sex and tHcys.

Impact: Our findings suggest that As induces sex-specific changes in 5-hmC, an epigenetic mark that has been associated with cancer. Future research should explore whether altered %5-hmC is a mechanism underlying the sex-specific influences of As on skin lesion and cancer outcomes. Cancer Epidemiol Biomarkers Prev; 24(11); 1748–57. ©2015 AACR.
Data from Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case–Control Study
Authors: Wibom Carl , Späth Florentin , Dahlin Anna M. , Langseth Hilde , Hovig Eivind , Rajaraman Preetha , Johannesen Tom Børge , Andersson Ulrika , Melin Beatrice
Published: April 2023

Abstract
Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case–control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.

Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.

Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.

Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.

Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. Cancer Epidemiol Biomarkers Prev; 24(5); 810–6. ©2015 AACR.
Data from Evaluation of Glycomic Profiling as a Diagnostic Biomarker for Epithelial Ovarian Cancer
Authors: Kim Kyoungmi , Ruhaak L. Renee , Nguyen Uyen Thao , Taylor Sandra L. , Dimapasoc Lauren , Williams Cynthia , Stroble Carol , Ozcan Sureyya , Miyamoto Suzanne , Lebrilla Carlito B. , Leiserowitz Gary S.
Published: April 2023

Abstract
Background: Prior studies suggested that glycans were differentially expressed in patients with ovarian cancer and controls. We hypothesized that glycan-based biomarkers might serve as a diagnostic test for ovarian cancer and evaluated the ability of glycans to distinguish ovarian cancer cases from matched controls.

Methods: Serum samples were obtained from the tissue-banking repository of the Gynecologic Oncology Group, and included healthy female controls (n = 100), women diagnosed with low malignant potential (LMP) tumors (n = 52), and epithelial ovarian cancers (EOC) cases (n = 147). Cases and controls were matched on age at enrollment within ±5 years. Serum samples were analyzed by glycomics analysis to detect abundance differences in glycan expression levels. A two-stage procedure was carried out for biomarker discovery and validation. Candidate classifiers of glycans that separated cases from controls were developed using a training set in the discovery phase and the classification performance of the candidate classifiers was assessed using independent test samples that were not used in discovery.

Results: The patterns of glycans showed discriminatory power for distinguishing EOC and LMP cases from controls. Candidate glycan-based biomarkers developed on a training set (sensitivity, 86% and specificity, 95.8% for distinguishing EOC from controls through leave-one-out cross-validation) confirmed their potential use as a detection test using an independent test set (sensitivity, 70% and specificity, 86.5%).

Conclusion: Formal investigations of glycan biomarkers that distinguish cases and controls show great promise for an ovarian cancer diagnostic test. Further validation of a glycan-based test for detection of ovarian cancer is warranted.

Impact: An emerging diagnostic test based on the knowledge gained from understanding the glycobiology should lead to an assay that improves sensitivity and specificity and allows for early detection of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 611–21. ©2014 AACR.
Data from Peripheral Blood Immune Cell Methylation Profiles Are Associated with Nonhematopoietic Cancers
Authors: Koestler Devin C. , Marsit Carmen J. , Christensen Brock C. , Accomando William , Langevin Scott M. , Houseman E. Andres , Nelson Heather H. , Karagas Margaret R. , Wiencke John K. , Kelsey Karl T.
Published: April 2023

Abstract
Background: Blood leukocytes from patients with solid tumors exhibit complex and distinct cancer-associated patterns of DNA methylation. However, the biologic mechanisms underlying these patterns remain poorly understood. Because epigenetic biomarkers offer significant clinical potential for cancer detection, we sought to address a mechanistic gap in recently published works, hypothesizing that blood-based epigenetic variation may be due to shifts in leukocyte populations.

Methods: We identified differentially methylated regions (DMR) among leukocyte subtypes using epigenome-wide DNA methylation profiling of purified peripheral blood leukocyte subtypes from healthy donors. These leukocyte-tagging DMRs were then evaluated using epigenome-wide blood methylation data from three independent case-control studies of different cancers.

Results: A substantial proportion of the top 50 leukocyte DMRs were significantly differentially methylated among head and neck squamous cell carcinoma (HNSCC) cases and ovarian cancer cases compared with cancer-free controls (48 and 47 of 50, respectively). Methylation classes derived from leukocyte DMRs were significantly associated cancer case status (P < 0.001, P < 0.03, and P < 0.001) for all three cancer types: HNSCC, bladder cancer, and ovarian cancer, respectively and predicted cancer status with a high degree of accuracy (area under the curve [AUC] = 0.82, 0.83, and 0.67).

Conclusions: These results suggest that shifts in leukocyte subpopulations may account for a considerable proportion of variability in peripheral blood DNA methylation patterns of solid tumors.

Impact: This illustrates the potential use of DNA methylation profiles for identifying shifts in leukocyte populations representative of disease, and that such profiles may represent powerful new diagnostic tools, applicable to a range of solid tumors. Cancer Epidemiol Biomarkers Prev; 21(8); 1293–302. ©2012 AACR.
Data from Time Trends in Rates of Hodgkin Lymphoma Histologic Subtypes: True Incidence Changes or Evolving Diagnostic Practice?
Authors: Glaser Sally L. , Clarke Christina A. , Keegan Theresa H.M. , Chang Ellen T. , Weisenburger Dennis D.
Published: April 2023

Abstract
Background: Histologic subtypes of classical Hodgkin lymphoma [cHL; e.g., nodular sclerosis, mixed cellularity, not otherwise specified (NOS)] are epidemiologically and prognostically distinctive. Therefore, unexplained, ongoing incidence rate declines for mixed cellularity and increases for NOS require examination.

Methods: We analyzed detailed histology-specific Hodgkin lymphoma incidence rates in 1992 through 2011 U.S. SEER data (n = 21,372) and reviewed a regional subset of 2007 through 2011 NOS pathology reports for insight into diagnostic practices.

Results: cHL rates were stable until 2007, then decreased for whites [annual percent change (APC) and 95% confidence interval (CI), −3.6% (−5.6% to −1.5%)]. Nodular sclerosis rates declined after 2007 by 5.9% annually, with variation by gender, age, and race/ethnicity. In 1992 through 2011, mixed cellularity rates declined [APC −4.0% (−4.7% to −3.3%)], whereas NOS rates rose [5.3% (4.5%–6.2%)] overall and in most patient groups. The 2007–2011 NOS age-specific rates were more similar to mixed cellularity rates for 1992–1996 than 2007–2011. Trends in combined rates were minimal, supporting increasing misclassification of mixed cellularity, lymphocyte depletion, and specific nodular sclerosis subtypes as NOS. Eighty-eight of 165 reviewed NOS pathology reports addressed classification choice. Twenty (12.1%) justified the classification, 21 (12.7%) described insufficient biopsy material, and coders missed specific subtype information for 27 (16.4%).

Conclusion: Recent nodular sclerosis rate declines largely represent true incidence changes. Long-term rate decreases for mixed cellularity and other less common subtypes, and increases for NOS (comprising ∼30% of cHL cases in 2011), likely reflect changes in diagnostic and/or classification practice.

Impact: Diminishing histologic subtyping undermines future surveillance and epidemiologic study of Hodgkin lymphoma. Guideline-based use of excisional biopsies and more coding quality control are warranted. Cancer Epidemiol Biomarkers Prev; 24(10); 1474–88. ©2015 AACR.
Data from Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis
Authors: Schwartz Ann G. , Lusk Christine M. , Wenzlaff Angela S. , Watza Donovan , Pandolfi Stephanie , Mantha Laura , Cote Michele L. , Soubani Ayman O. , Walworth Garrett , Wozniak Antoinette , Neslund-Dudas Christine , Ardisana Amy A. , Flynn Michael J. , Song Thomas , Spizarny David L. , Kvale Paul A. , Chapman Robert A. , Gadgeel Shirish M.
Published: April 2023

Abstract
Background: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk.

Methods: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than −950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than −856 HU on expiratory scan (HUE).

Results: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels <−856 HUE as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03–1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21–2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD.

Conclusion: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer.

Impact: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341–7. ©2016 AACR.
Data from Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC
Authors: Wang Mengjun , Sanda Miloslav , Comunale Mary Ann , Herrera Harmin , Swindell Charles , Kono Yuko , Singal Amit G. , Marrero Jorge , Block Timothy , Goldman Radoslav , Mehta Anand
Published: April 2023

Abstract
Background: Hepatocellular carcinoma (HCC) has the greatest increase in mortality among all solids tumors in the United States related to low rates of early tumor detection. Development of noninvasive biomarkers for the early detection of HCC may reduce HCC-related mortality.

Methods: We have developed an algorithm that combines routinely observed clinical values into a single equation that in a study of >3,000 patients from 5 independent sites improved detection of HCC as compared with the currently used biomarker, alpha-fetoprotein (AFP), by 4% to 20%. However, this algorithm had limited benefit in those with AFP <20 ng/mL. To that end, we have developed a secondary algorithm that incorporates a marker, fucosylated kininogen, to improve the detection of HCC, especially in those with AFP <20 ng/mL and early-stage disease.

Results: The ability to detect early-stage AFP-negative (AFP <20 ng/mL) HCC increased from 0% (AFP alone) to 89% (for the new algorithm). Glycan analysis revealed that kininogen has several glycan modifications that have been associated with HCC, but often not with specific proteins, including increased levels of core and outer-arm fucosylation and increased branching.

Conclusions: An algorithm combining fucosylated kininogen, AFP, and clinical characteristics is highly accurate for early HCC detection.

Impact: Our biomarker algorithm could significantly improve early HCC detection and curative treatment eligibility in patients with cirrhosis. Cancer Epidemiol Biomarkers Prev; 26(5); 795–803. ©2017 AACR.
Data from Factorial Validity and Invariance of Four Psychosocial Constructs of Colorectal Cancer Screening: Does Screening Experience Matter?
Authors: Murphy Caitlin C. , McQueen Amy , Bartholomew L. Kay , del Junco Deborah J. , Coan Sharon P. , Vernon Sally W.
Published: April 2023

Abstract
Background: Few studies have examined the psychometric properties and invariance of scales measuring constructs relevant to colorectal cancer screening (CRCS). We sought to: (i) evaluate the factorial validity of four core constructs associated with CRCS (benefits, barriers, self-efficacy, and optimism); and (ii) examine measurement invariance by screening status (currently screened, overdue, never screened).

Methods: We used baseline survey data from a longitudinal behavioral intervention trial to increase CRCS among U.S. veterans. Respondents were classified as currently screened (n = 3,498), overdue (n = 418), and never screened (n = 1,277). The measurement model was developed using a random half of the sample and then validated with the second half of the sample and the full baseline sample (n = 5,193). Single- and multi-group confirmatory factor analysis was used to examine measurement invariance by screening status.

Results: The four-factor measurement model demonstrated good fit. Factor loadings, item intercepts, and residual item variance and covariance were invariant when comparing participants never screened and overdue for CRCS, indicating strict measurement invariance. All factor loadings were invariant among the currently screened and overdue groups. Only the benefits scale was invariant across current screeners and never screeners. Non-invariant items were primarily from the barriers scale.

Conclusion: Our findings provide additional support for the construct validity of scales of CRCS benefits, barriers, self-efficacy, and optimism. A greater understanding of the differences between current and never screeners may improve measurement invariance.

Impact: Measures of benefits, barriers, self-efficacy, and optimism may be used to specify intervention targets and effectively assess change pre- and post-intervention across screening groups. Cancer Epidemiol Biomarkers Prev; 22(12); 2295–302. ©2013 AACR.
Data from The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review
Authors: Busch Evan L. , McGraw Kathleen A. , Sandler Robert S.
Published: April 2023

Abstract
Epithelial–mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164–75. ©2014 AACR.
Data from The Association between Fatalistic Beliefs and Late Stage at Diagnosis of Lung and Colorectal Cancer
Authors: Lyratzopoulos Georgios , Liu Michael Pang-Hsiang , Abel Gary A. , Wardle Jane , Keating Nancy L.
Published: April 2023

Abstract
Background: Fatalistic beliefs may be implicated in longer help-seeking intervals, and consequently, greater risk of advanced stage at cancer diagnosis.

Methods: We examined associations between fatalism and stage at diagnosis in a population-based cohort of 4,319 U.S. patients with newly diagnosed lung or colorectal cancer participating in the Cancer Care Outcomes and Research Surveillance (CanCORS) study. Fatalistic beliefs were assessed with an established measure. A fatalism score (range, 4–16) was created by summing Likert scale responses to four items. Cancer stage at diagnosis was abstracted from medical records by trained staff. Logistic regression was used to assess the association between fatalism score and advanced stage at diagnosis (IV vs. I–III), adjusting for sociodemographic and clinical characteristics.

Results: Overall, 917 (21%) patients had stage IV cancers (lung: 28%, colorectal: 16%). The mean fatalism score was 10.7 (median = 11; interquartile range, 9–12). In adjusted analyses, a higher fatalism score was associated with greater odds of stage IV diagnosis (OR per unit increase in fatalism = 1.05; 95% confidence interval 1.02–1.08; P = 0.003). Patients with the highest fatalism score had an adjusted 8.9% higher frequency of stage IV diagnosis compared with patients with the lowest score (25.4% vs. 16.5%).

Discussion: In this large and socioeconomically, geographically, and ethnically diverse population of patients with lung and colorectal cancer, fatalistic beliefs were associated with higher risk of advanced stage at diagnosis. Longitudinal studies are needed to confirm causation.

Impact: These findings support the value of incorporating information about the curability of early-stage cancers in public education campaigns. Cancer Epidemiol Biomarkers Prev; 24(4); 720–6. ©2015 AACR.
Data from Differential Patterns of Risk Factors for Early-Onset Breast Cancer by ER Status in African American Women
Authors: Bertrand Kimberly A. , Bethea Traci N. , Adams-Campbell Lucile L. , Rosenberg Lynn , Palmer Julie R.
Published: April 2023

Abstract
Background: Given the disproportionately high incidence of early-onset breast cancer and aggressive subtypes, such as estrogen receptor (ER)-negative tumors, in African American (AA) women, elucidation of risk factors for early onset of specific subtypes of breast cancer is needed.

Methods: We evaluated associations of reproductive, anthropometric, and other factors with incidence of invasive breast cancer by age at onset (<45, ≥45) in 57,708 AA women in the prospective Black Women's Health Study. From 1995 to 2013, we identified 529 invasive breast cancers among women <45 years of age (151 ER−, 219 ER+) and 1,534 among women ≥45 years (385 ER−, 804 ER+). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) for associations by age and ER status.

Results: Higher parity, older age at first birth, never having breastfed, and abdominal adiposity were associated with increased risk of early-onset ER− breast cancer: HRs were 1.71 for ≥3 births versus one birth; 2.29 for first birth after age 25 versus <20 years; 0.61 for ever having breastfed versus never; and 1.64 for highest versus lowest tertile of waist-to-hip ratio. These factors were not associated with ER− cancer in older women or with ER+ cancer regardless of age.

Conclusions: Differences in risk factors by ER subtype were observed for breast cancer diagnosed before the age of 45 years.

Impact: Etiological heterogeneity by tumor subtype in early-onset breast cancer, in combination with a higher prevalence of the risk factors in AA women, may explain, in part, racial disparities in breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 26(2); 270–7. ©2016 AACR.
Data from Patient Navigation Significantly Reduces Delays in Breast Cancer Diagnosis in the District of Columbia
Authors: Hoffman Heather J. , LaVerda Nancy L. , Young Heather A. , Levine Paul H. , Alexander Lisa M. , Brem Rachel , Caicedo Larisa , Eng-Wong Jennifer , Frederick Wayne , Funderburk William , Huerta Elmer , Swain Sandra , Patierno Steven R.
Published: April 2023

Abstract
Background: Patient Navigation (PN) originated in Harlem as an intervention to help poor women overcome access barriers to timely breast cancer treatment. Despite rapid, nationally widespread adoption of PN, empirical evidence on its effectiveness is lacking. In 2005, National Cancer Institute initiated a multicenter PN Research Program (PNRP) to measure PN effectiveness for several cancers. The George Washington Cancer Institute, a project participant, established District of Columbia (DC)-PNRP to determine PN's ability to reduce breast cancer diagnostic time (number of days from abnormal screening to definitive diagnosis).

Methods: A total of 2,601 women (1,047 navigated; 1,554 concurrent records-based nonnavigated) were examined for breast cancer from 2006 to 2010 at 9 hospitals/clinics in DC. Analyses included only women who reached complete diagnostic resolution. Differences in diagnostic time between navigation groups were tested with ANOVA models including categorical demographic and treatment variables. Log transformations normalized diagnostic time. Geometric means were estimated and compared using Tukey–Kramer P value adjustments.

Results: Average—geometric mean [95% confidence interval (CI)]—diagnostic time (days) was significantly shorter for navigated, 25.1 (21.7, 29.0), than nonnavigated women, 42.1 (35.8, 49.6). Subanalyses revealed significantly shorter average diagnostic time for biopsied navigated women, 26.6 (21.8, 32.5) than biopsied nonnavigated women, 57.5 (46.3, 71.5). Among nonbiopsied women, diagnostic time was shorter for navigated, 27.2 (22.8, 32.4), than nonnavigated women, 34.9 (29.2, 41.7), but not statistically significant.

Conclusions: Navigated women, especially those requiring biopsy, reached their diagnostic resolution significantly faster than nonnavigated women.

Impact: Results support previous findings of PN's positive influence on health care. PN should be a reimbursable expense to assure continuation of PN programs. Cancer Epidemiol Biomarkers Prev; 21(10); 1655–63. ©2012 AACR.
Data from Prospective Study of Human Polyomaviruses and Risk of Cutaneous Squamous Cell Carcinoma in the United States
Authors: Gossai Anala , Waterboer Tim , Nelson Heather H. , Doherty Jennifer A. , Michel Angelika , Willhauck-Fleckenstein Martina , Farzan Shohreh F. , Christensen Brock C. , Hoen Anne G. , Perry Ann E. , Pawlita Michael , Karagas Margaret R.
Published: April 2023

Abstract
Background: Merkel cell polyomavirus (PyV) is causally related to Merkel cell carcinoma, a rare skin malignancy. Little is known about the serostability of other PyVs over time or associations with cutaneous squamous cell carcinoma (SCC).

Methods: As part of a U.S. nested case–control study, antibody response against the PyV VP1 capsid proteins of BK and John Cunningham virus (JC) was measured using multiplex serology on 113 SCC cases and 229 gender, age, and study center–matched controls who had a prior keratinocyte cancer. Repeated serum samples from controls and both pre and postdiagnosis samples from a subset of SCC cases were also tested. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using conditional logistic regression.

Results: Among controls, BK and JC seroreactivity was stable over time, with intraclass correlation coefficients of 0.86 for BK and 0.94 for JC. Among cases, there was little evidence of seroconversion following SCC diagnosis. JC seropositivity prior to diagnosis was associated with an elevated risk of SCC (OR = 2.54; 95% CI, 1.23–5.25), and SCC risk increased with increasing quartiles of JC (Ptrend = 0.004) and BK (Ptrend = 0.02) seroreactivity.

Conclusions: PyV antibody levels were stable over time and following an SCC diagnosis. A history of PyV infection may be involved in the occurrence of SCC in a population at high risk for this malignancy.

Impact: A single measure of PyV seroreactivity appears a reliable indicator of long-term antibody status, and PyV exposure may be a risk factor for subsequent SCC. Cancer Epidemiol Biomarkers Prev; 25(5); 736–44. ©2016 AACR.
Data from Subsequent Primary Malignancies in Patients with Nonmelanoma Skin Cancer in England: A National Record-Linkage Study
Authors: Ong Eugene Liat Hui , Goldacre Raph , Hoang Uy , Sinclair Rodney , Goldacre Michael
Published: April 2023

Abstract
Background: Conflicting evidence exists about whether people with a history of nonmelanoma skin cancer (NMSC) are at higher risk of subsequent primary malignant cancers than those without.

Methods: An all England record-linked hospital and mortality dataset spanning from 1999 to 2011 was used. We constructed two cohorts: one that comprised people with a history of NMSC (502,490 people), and a control cohort that comprised people without. We “followed up” these two cohorts electronically to determine observed and expected numbers of people with subsequent primary cancers in each, based on person-years at risk, and calculated standardized risk ratios (RR).

Results: Comparing the NMSC cohort with the non-NMSC cohort, the RR for all subsequent malignant cancers combined was 1.36 [95% confidence interval (CI), 1.35–1.37]. Significantly increased RRs (P < 0.05) were found for 26 of the 29 cancer types studied, in particular for salivary gland, melanoma, bone, and upper gastrointestinal tract cancers. The RRs were also particularly high when comparing younger people with and without NMSC.

Conclusions: NMSC is strongly associated with a broad spectrum of other primary cancers, particularly in younger age groups. The pattern suggests a genetic or early-acquired etiologic association.

Impact: These results represent what can be done using very large, linked, routinely collected administrative datasets; but such datasets lack detail. Further work to establish the mechanisms behind these associations is warranted. Cancer Epidemiol Biomarkers Prev; 23(3); 490–8. ©2014 AACR.
Data from Endogenous Sex Hormones and Breast Density in Young Women
Authors: Jung Seungyoun , Stanczyk Frank Z. , Egleston Brian L. , Snetselaar Linda G. , Stevens Victor J. , Shepherd John A. , Van Horn Linda , LeBlanc Erin S. , Paris Kenneth , Klifa Catherine , Dorgan Joanne F.
Published: April 2023

Abstract
Background: Breast density is a strong risk factor for breast cancer and reflects epithelial and stromal content. Breast tissue is particularly sensitive to hormonal stimuli before it fully differentiates following the first full-term pregnancy. Few studies have examined associations between sex hormones and breast density among young women.

Methods: We conducted a cross-sectional study among 180 women ages 25 to 29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-up Study. Eighty-five percent of participants attended a clinic visit during their luteal phase of menstrual cycle. Magnetic resonance imaging measured the percentage of dense breast volume (�V), absolute dense breast volume (ADBV), and absolute nondense breast volume (ANDBV). Multiple-linear mixed-effect regression models were used to evaluate the association of sex hormones and sex hormone–binding globulin (SHBG) with �V, ADBV, and ANDBV.

Results: Testosterone was significantly positively associated with �V and ADBV. The multivariable geometric mean of �V and ADBV across testosterone quartiles increased from 16.5% to 20.3% and from 68.6 to 82.3 cm3, respectively (Ptrend ≤ 0.03). There was no association of �V or ADBV with estrogens, progesterone, non–SHBG-bound testosterone, or SHBG (Ptrend ≥ 0.27). Neither sex hormones nor SHBG was associated with ANDBV except progesterone; however, the progesterone result was nonsignificant in analysis restricted to women in the luteal phase.

Conclusions: These findings suggest a modest positive association between testosterone and breast density in young women.

Impact: Hormonal influences at critical periods may contribute to morphologic differences in the breast associated with breast cancer risk later in life. Cancer Epidemiol Biomarkers Prev; 24(2); 369–78. ©2014 AACR.