bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Establishment of the Cancer Prevention Study II Nutrition Cohort Colorectal Tissue Repository
Authors: Campbell Peter T. , Deka Anusila , Briggs Peter , Cicek Mine , Farris Alton B. , Gaudet Mia M. , Jacobs Eric J. , Newton Christina C. , Patel Alpa V. , Teras Lauren R. , Thibodeau Stephen N. , Tillmans Lori , Gapstur Susan M.
Published: April 2023

Abstract
Background: To better understand colorectal cancer etiology and prognosis, archived surgical tissues were collected from Cancer Prevention Study II (CPS-II) Nutrition Cohort participants who were diagnosed with colorectal cancer. Herein, the methodology for this collection is described to help inform other efforts to collect tissues.

Methods: The main components to accruing tissue were: (i) obtaining consent from participants or next-of-kin; (ii) contacting hospitals to request materials; and (iii) pathology review and laboratory processing.

Results: In CPS-II, we identified 3,643 participants diagnosed with colorectal cancer between 1992/1993 and 2009. Of these, tissue could not be sought from cases verified through state cancer registry linkage (N = 1,622), because of insufficient information on tissue location. We sought tissue from the 2,021 cases verified using medical records, and received tissue from 882. When hospitals were contacted within 10 years of diagnosis, we received 87% of tissue materials; beyond that 10-year mark, we received 32%. Compared with the 2,761 colorectal cancer cases without tissue, the 882 cases with tissue were more likely to be alive, diagnosed more recently during follow-up, and had less-advanced staged disease. Cases with and without tissues were similar with respect to age at diagnosis, smoking, body mass index, physical activity, and other epidemiologic factors.

Conclusions: Some of the most important elements in forming a tissue repository included having the cases' hospital contact and surgical accession information as well as contacting patients/next-of-kin and hospitals within 10 years of surgery.

Impact: This tissue repository will serve as an important resource for colorectal cancer studies.

See all the articles in this CEBP Focus section, “Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology.”

Cancer Epidemiol Biomarkers Prev; 23(12); 2694–702. ©2014 AACR.
Data from Estimating TP53 Mutation Carrier Probability in Families with Li–Fraumeni Syndrome Using LFSPRO
Authors: Peng Gang , Bojadzieva Jasmina , Ballinger Mandy L. , Li Jialu , Blackford Amanda L. , Mai Phuong L. , Savage Sharon A. , Thomas David M. , Strong Louise C. , Wang Wenyi
Published: April 2023

Abstract
Background: Li–Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for TP53 mutation testing and LFS management.

Methods: Based on a Mendelian model, LFSPRO estimates TP53 mutation probability through the Elston–Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.

Results: LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99–1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75–0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03–2.55); AUC = 0.67 (0.54–0.79); and the NCI LFS study cohort, OE = 1.28 (1.17–1.39); AUC = 0.82 (0.78–0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.

Conclusions: LFSPRO shows good performance in predicting TP53 mutations in individuals and families in varied situations.

Impact: LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS. Cancer Epidemiol Biomarkers Prev; 26(6); 837–44. ©2017 AACR.
Data from Plasma Isoflavones and Risk of Primary Liver Cancer in Japanese Women and Men with Hepatitis Virus Infection: A Nested Case–Control Study
Authors: Michikawa Takehiro , Inoue Manami , Sawada Norie , Tanaka Yasuhito , Yamaji Taiki , Iwasaki Motoki , Shimazu Taichi , Sasazuki Shizuka , Mizokami Masashi , Tsugane Shoichiro
Published: April 2023

Abstract
Background: Evidence suggests that estrogen plays a preventive role in primary liver cancer development, and it might be thought that isoflavones, which are structurally similar to estrogens and bind to estrogen receptors, are associated with the risk of liver cancer. We investigated this suspected association by measuring plasma concentrations of isoflavones in a nested case–control study of a population-based prospective cohort in Japan.

Methods: From 18,628 target participants ages 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B or hepatitis C virus infection at baseline (n = 1,544). Among these, 90 (28 women and 62 men) were newly diagnosed with primary liver cancer from 1993 through 2006; they were matched with 175 controls (54 women and 121 men). Plasma concentrations of isoflavones (genistein, daidzein, glycitein, and equol) were measured using triple quadrupole tandem liquid chromatography-mass spectrometry. The ORs of liver cancer development based on plasma concentrations were estimated with a conditional logistic regression model.

Results: Basically, distributions of plasma isoflavone concentrations did not differ between the cases and controls. No statistically significant associations of genistein, daidzein, glycitein, and equol with primary liver cancer risk were found in either women or men.

Conclusions: In middle-aged Japanese women and men with hepatitis virus infection, plasma isoflavones were unassociated with the occurrence of primary liver cancer.

Impact: The role of isoflavones in liver carcinogenesis merits further study using both biomarkers and data on dietary intake of isoflavones. Cancer Epidemiol Biomarkers Prev; 24(3); 532–7. ©2014 AACR.
Data from Circulating Biomarkers of Gut Barrier Function: Correlates and Nonresponse to Calcium Supplementation among Colon Adenoma Patients
Authors: Yang Baiyu , Bostick Roberd M. , Tran Hao Quang , Gewirtz Andrew T. , Campbell Peter T. , Fedirko Veronika
Published: April 2023

Abstract
Background: Gut barrier dysfunction contributes to several gastrointestinal disorders, including colorectal cancer, but factors associated with intestinal hyperpermeability have been minimally studied in humans.

Methods: We tested the effects of two doses of calcium (1.0 or 2.0 g/d) on circulating biomarkers of gut permeability [anti-flagellin and anti-lipopolysaccharide (LPS) Ig, measured via ELISA] over a 4-month treatment period among colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193), and evaluated the factors associated with baseline levels of these biomarkers.

Results: Baseline concentrations of anti-flagellin IgA and anti-LPS IgA were, respectively, statistically significantly proportionately higher by 11.8% and 14.1% among men, 31.3% and 39.8% among those with a body mass index ≥ 35 kg/m2, and 19.9% and 22.0% among those in the upper relative to the lowest sex-specific tertile of waist circumference. A combined permeability score (the summed optical densities of all four biomarkers) was 24.3% higher among women in the upper tertile of plasma C–reactive protein (Ptrend < 0.01). We found no appreciable effects of supplemental calcium on anti-flagellin or anti-LPS Igs.

Conclusions: Our results suggest that (i) men and those with higher adiposity may have greater gut permeability, (ii) gut permeability and systemic inflammation may be directly associated with one another, and (iii) supplemental calcium may not modify circulating levels of gut permeability biomarkers within 4 months.

Impact: Our findings may improve the understanding of the factors that influence gut permeability to inform development of treatable biomarkers of risk for colorectal cancer and other health outcomes. Cancer Epidemiol Biomarkers Prev; 25(2); 318–26. ©2015 AACR.
Data from Updated Review of Prevalence of Major Risk Factors and Use of Screening Tests for Cancer in the United States
Authors: Sauer Ann Goding , Siegel Rebecca L. , Jemal Ahmedin , Fedewa Stacey A.
Published: April 2023

Abstract
Much of the suffering and death from cancer could be prevented by more systematic efforts to reduce tobacco use and obesity, improve diet, and increase physical activity and use of established vaccines and screening tests. Monitoring the prevalence of cancer risk factors and preventive tests helps guide cancer prevention and early detection efforts. We provide an updated review, using data through 2015, of the prevalence of major risk factors, cancer screening, and vaccination for U.S. adults and youth. Cigarette smoking among adults decreased to 15.3% in 2015 but remains higher among lower socioeconomic persons (GED: 34.1%, graduate degree: 3.7%), with considerable state variation (Utah: 9.1%, Kentucky: 26.0%). The prevalence of obesity among both adults (37.7%) and adolescents (20.6%) remains high, particularly among black women (57.2%), and ranges from 20.2% (Colorado) to 36.2% (Louisiana) among adults. Pap testing remains the most commonly utilized cancer screening test (81.4%). While colorectal cancer screening has increased, only 62.6% are up-to-date with recommendations. Cancer screening is lowest among the uninsured and varies across states. Despite some improvements, systematic efforts to further reduce the suffering and death from cancer should be enhanced. Continued investment in surveillance of cancer prevention and early detection metrics is also needed. Cancer Epidemiol Biomarkers Prev; 26(8); 1192–208. ©2017 AACR.
Data from A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium
Authors: Costas Laura , Lambert Brice H. , Birmann Brenda M. , Moysich Kirsten B. , De Roos Anneclaire J. , Hofmann Jonathan N. , Baris Dalsu , Wang Sophia S. , Camp Nicola J. , Tricot Guido , Atanackovic Djordje , Brennan Paul , Cocco Pierluigi , Nieters Alexandra , Becker Nikolaus , Maynadié Marc , Foretová Lenka , Boffetta Paolo , Staines Anthony , Brown Elisabeth E. , de Sanjosé Silvia
Published: April 2023

Abstract
Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations.

Methods: We conducted a pooled analysis of seven case–control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses.

Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68–1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80–1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37–1.15, I2 = 76.0%, Pheterogeneity = 0.01).

Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis.

Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology. Cancer Epidemiol Biomarkers Prev; 25(1); 217–21. ©2015 AACR.
Data from Iron in Relation to Gastric Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
Authors: Cook Michael B. , Kamangar Farin , Weinstein Stephanie J. , Albanes Demetrius , Virtamo Jarmo , Taylor Philip R. , Abnet Christian C. , Wood Richard J. , Petty Gayle , Cross Amanda J. , Dawsey Sanford M.
Published: April 2023

Abstract
Background: Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC).

Methods: We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 nonspecified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity, and C-reactive protein. Total iron-binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis.

Results: Serum iron metrics were not associated with GCC, except for a potential “n”-shaped relationship with TIBC (global P = 0.038). GNCC was inversely associated with serum ferritin (global P = 0.024), serum iron (global P = 0.060) and, possibly, transferrin saturation. TIBC appeared to share a “u”-shaped relationship with GNCC (global P = 0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations.

Conclusions: We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency.

Impact: Our findings indicate that inverse associations between iron metrics and gastric cancer are driven by associations with GNCC. Further elucidation of potential mechanisms is warranted. Cancer Epidemiol Biomarkers Prev; 21(11); 2033–42. ©2012 AACR.
Data from Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial
Authors: Liesenfeld David B. , Botma Akke , Habermann Nina , Toth Reka , Weigel Christoph , Popanda Odilia , Klika Karel D. , Potter John D. , Lampe Johanna W. , Ulrich Cornelia M.
Published: April 2023

Abstract
Background: Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk–benefit balances and biologic mechanisms need to be better defined; to further this aim, we used a metabolomics approach.

Methods: We metabolically profiled 40 healthy, nonsmoking men and women ages 20 to 45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/day over a period of 60 days. Gas and liquid chromatography–mass spectrometry were used to comprehensively profile participants' plasma samples after aspirin and placebo interventions.

Results: A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared with placebo-treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (R+S) decreased after aspirin treatment in both men and women (P = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirin-induced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid–oxoacid transhydrogenase mediated production of (R)-2-hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate.

Conclusions: Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)-2-hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention.

Impact: Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non–COX-inhibition-mediated mechanism of aspirin. Cancer Epidemiol Biomarkers Prev; 25(1); 180–7. ©2015 AACR.
Data from Molecular Subtypes of Breast Cancer: Long-term Incidence Trends and Prognostic Differences
Authors: Valla Marit , Vatten Lars Johan , Engstrøm Monica Jernberg , Haugen Olav Anton , Akslen Lars Andreas , Bjørngaard Johan Håkon , Hagen Anne Irene , Ytterhus Borgny , Bofin Anna Mary , Opdahl Signe
Published: April 2023

Abstract
Background: Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886–1977.

Methods: A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886–1928 and 1929–1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs.

Results: Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2−) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50–54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8–6.9 and 2.5; 95% CI, 1.2–5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3–0.5), Luminal B (HER2−; HR 0.5; 95% CI, 0.3–0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2–0.9).

Conclusions: We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2−) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype.

Impact: This study documents a clear secular increase in incidence and a concomitant improved prognosis for specific molecular breast cancer subtypes. Cancer Epidemiol Biomarkers Prev; 25(12); 1625–34. ©2016 AACR.
Data from Use of a Novel Nonparametric Version of DEPTH to Identify Genomic Regions Associated with Prostate Cancer Risk
Authors: MacInnis Robert J. , Schmidt Daniel F. , Makalic Enes , Severi Gianluca , FitzGerald Liesel M. , Reumann Matthias , Kapuscinski Miroslaw K. , Kowalczyk Adam , Zhou Zeyu , Goudey Benjamin , Qian Guoqi , Bui Quang M. , Park Daniel J. , Freeman Adam , Southey Melissa C. , Al Olama Ali Amin , Kote-Jarai Zsofia , Eeles Rosalind A. , Hopper John L. , Giles Graham G.
Published: April 2023

Abstract
Background: We have developed a genome-wide association study analysis method called DEPTH (DEPendency of association on the number of Top Hits) to identify genomic regions potentially associated with disease by considering overlapping groups of contiguous markers (e.g., SNPs) across the genome. DEPTH is a machine learning algorithm for feature ranking of ultra-high dimensional datasets, built from well-established statistical tools such as bootstrapping, penalized regression, and decision trees. Unlike marginal regression, which considers each SNP individually, the key idea behind DEPTH is to rank groups of SNPs in terms of their joint strength of association with the outcome. Our aim was to compare the performance of DEPTH with that of standard logistic regression analysis.

Methods: We selected 1,854 prostate cancer cases and 1,894 controls from the UK for whom 541,129 SNPs were measured using the Illumina Infinium HumanHap550 array. Confirmation was sought using 4,152 cases and 2,874 controls, ascertained from the UK and Australia, for whom 211,155 SNPs were measured using the iCOGS Illumina Infinium array.

Results: From the DEPTH analysis, we identified 14 regions associated with prostate cancer risk that had been reported previously, five of which would not have been identified by conventional logistic regression. We also identified 112 novel putative susceptibility regions.

Conclusions: DEPTH can reveal new risk-associated regions that would not have been identified using a conventional logistic regression analysis of individual SNPs.

Impact: This study demonstrates that the DEPTH algorithm could identify additional genetic susceptibility regions that merit further investigation. Cancer Epidemiol Biomarkers Prev; 25(12); 1619–24. ©2016 AACR.
Data from Changes in Epidermal Growth Factor Receptor Gene Copy Number during Oral Carcinogenesis
Authors: Bates Timothy , Kennedy Matthew , Diajil Ameena , Goodson Michaela , Thomson Peter , Doran Emma , Farrimond Heather , Thavaraj Selvam , Sloan Philip , Kist Ralf , Robinson Max
Published: April 2023

Abstract
Background: Oral squamous cell carcinoma (OSCC) is a global healthcare problem associated with poor clinical outcomes. Early detection is key to improving patient survival. OSCC may be preceded by clinically recognizable lesions, termed oral potentially malignant disorders (OPMD). As histologic assessment of OPMD does not accurately predict their clinical behavior, biomarkers are required to detect cases at risk of malignant transformation. Epidermal growth factor receptor gene copy number (EGFR GCN) is a validated biomarker in lung non–small cell carcinoma. We examined EGFR GCN in OPMD and OSCC to determine its potential as a biomarker in oral carcinogenesis.

Methods: EGFR GCN was examined by in situ hybridization (ISH) in biopsies from 78 patients with OPMD and 92 patients with early-stage (stages I and II) OSCC. EGFR ISH signals were scored by two pathologists and a category assigned by consensus. The data were correlated with patient demographics and clinical outcomes.

Results: OPMD with abnormal EGFR GCN were more likely to undergo malignant transformation than diploid cases. EGFR genomic gain was detected in a quarter of early-stage OSCC, but did not correlate with clinical outcomes.

Conclusion: These data suggest that abnormal EGFR GCN has clinical utility as a biomarker for the detection of OPMD destined to undergo malignant transformation. Prospective studies are required to verify this finding. It remains to be determined if EGFR GCN could be used to select patients for EGFR-targeted therapies.

Impact: Abnormal EGFR GCN is a potential biomarker for identifying OPMD that are at risk of malignant transformation. Cancer Epidemiol Biomarkers Prev; 25(6); 927–35. ©2016 AACR.
Data from Metabolic Syndrome and Risk of Endometrial Cancer in the United States: A Study in the SEER–Medicare Linked Database
Authors: Trabert Britton , Wentzensen Nicolas , Felix Ashley S. , Yang Hannah P. , Sherman Mark E. , Brinton Louise A.
Published: April 2023

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

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

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

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

Impact: Strategies to reduce the prevalence of metabolic syndrome factors might have a favorable effect on endometrial cancer incidence. Cancer Epidemiol Biomarkers Prev; 24(1); 261–7. ©2015 AACR.
Data from A GWAS Meta-analysis and Replication Study Identifies a Novel Locus within CLPTM1L/TERT Associated with Nasopharyngeal Carcinoma in Individuals of Chinese Ancestry
Authors: Bei Jin-Xin , Su Wen-Hui , Ng Ching-Ching , Yu Kai , Chin Yoon-Ming , Lou Pei-Jen , Hsu Wan-Lun , McKay James D. , Chen Chien-Jen , Chang Yu-Sun , Chen Li-Zhen , Chen Ming-Yuan , Cui Qian , Feng Fu-Tuo , Feng Qi-Shen , Guo Yun-Miao , Jia Wei-Hua , Khoo Alan Soo-Beng , Liu Wen-Sheng , Mo Hao-Yuan , Pua Kin-Choo , Teo Soo-Hwang , Tse Ka-Po , Xia Yun-Fei , Zhang Hongxin , Zhou Gang-Qiao , Liu Jian-Jun , Zeng Yi-Xin , Hildesheim Allan
Published: April 2023

Abstract
Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied.

Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case–control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed.

Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10−13). Our results also provide support for associations reported from published NPC GWAS—rs6774494 (P = 1.5 × 10−12; located in the MECOM gene region), rs9510787 (P = 5.0 × 10−10; located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10−8, P = 7.0 × 10−7, and P = 8.4 × 10−7, respectively; located in the CDKN2A/B gene region).

Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity.

Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(1); 188–92. ©2015 AACR.
Data from Serum C-peptide, Total and High Molecular Weight Adiponectin, and Pancreatic Cancer: Do Associations Differ by Smoking?
Authors: Nogueira Leticia M. , Newton Christina C. , Pollak Michael , Silverman Debra T. , Albanes Demetrius , Männistö Satu , Weinstein Stephanie J , Jacobs Eric J. , Stolzenberg-Solomon Rachael Z.
Published: April 2023

Abstract
Background: Studies examining associations between circulating concentrations of C-peptide and total adiponectin, two biomarkers related to obesity and insulin secretion and sensitivity and pancreatic ductal adenocarcinoma (PDA) risk have shown inconsistent results and included limited numbers of smokers.

Methods: We examined associations of these biomarkers and high molecular weight (HMW) adiponectin with PDA, overall, and by smoking status. We conducted a pooled nested case–control analysis in 3 cohorts (Prostate, Lung, Colorectal, and Ovarian Cancer Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study-II), with 758 cases (435 current smokers) and 1,052 controls (531 smokers) matched by cohort, age, sex, race, blood draw date and follow-up time. We used conditional logistic regression adjusted for age, smoking, diabetes, and body mass index to calculate ORs and 95% confidence intervals (CI).

Results: Circulating C-peptide concentration was not associated with PDA in never or former smokers, but was inversely associated with PDA in current smokers (per SD OR = 0.67; 95% CI, 0.54–0.84; Pinteraction = 0.005). HMW adiponectin was inversely associated with PDA in never smokers (OR = 0.43; 95% CI, 0.23–0.81), not associated in former smokers, and positively associated in smokers (OR = 1.23; 95% CI, 1.04–1.45; Pinteraction = 0.009). Total adiponectin was not associated with PDA in nonsmokers or current smokers.

Conclusions: Associations of biomarkers of insulin secretion and sensitivity with PDA differ by smoking status. Smoking-induced pancreatic damage may explain the associations in smokers while mechanisms related to insulin resistance associations in nonsmokers.

Impact: Future studies of these biomarkers and PDA should examine results by smoking status. Cancer Epidemiol Biomarkers Prev; 26(6); 914–22. ©2017 AACR.
Data from Primary hrHPV DNA Testing in Cervical Cancer Screening: How to Manage Screen-Positive Women? A POBASCAM Trial Substudy
Authors: Dijkstra Maaike G. , van Niekerk Dirk , Rijkaart Dorien C. , van Kemenade Folkert J. , Heideman Daniëlle A.M. , Snijders Peter J.F. , Meijer Chris J.L.M. , Berkhof Johannes
Published: April 2023

Abstract
Background: High-risk human papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV-positive women is needed in cervical cancer screening.

Methods: A cohort of 1,100 hrHPV-positive women, from a population-based screening trial (POBASCAM: n = 44,938; 29–61 years), was used to evaluate 10 triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping, and/or repeat hrHPV testing. Clinical endpoint was cervical intraepithelial neoplasia grade 3 or worse (CIN3+) detected within four years; results were adjusted for women not attending repeat testing. A triage strategy was considered acceptable, when the probability of no CIN3+ after negative triage (negative predictive value, NPV) was at least 98%, and the CIN3+ risk after positive triage (positive predictive value, PPV) was at least 20%.

Results: Triage at baseline with cytology only yielded an NPV of 94.3% [95% confidence interval (CI), 92.0–96.0] and a PPV of 39.7% (95% CI, 34.0–45.6). An increase in NPV, against a modest decrease in PPV, was obtained by triaging women with negative baseline cytology by repeat cytology (NPV 98.5% and PPV 34.0%) or by baseline HPV16/18 genotyping (NPV 98.8% and PPV 28.5%). The inclusion of both HPV16/18 genotyping at baseline and repeat cytology testing provided a high NPV (99.6%) and a moderately high PPV (25.6%).

Conclusions: Triaging hrHPV-positive women by cytology at baseline and after 6 to 12 months, possibly in combination with baseline HPV16/18 genotyping, seems acceptable for cervical cancer screening.

Impact: Implementable triage strategies are provided for primary hrHPV screening in an organized setting. Cancer Epidemiol Biomarkers Prev; 23(1); 55–63. ©2013 AACR.
Data from Comparison of Nicotine and Carcinogen Exposure with Water Pipe and Cigarette Smoking
Authors: Jacob Peyton , Abu Raddaha Ahmad H. , Dempsey Delia , Havel Christopher , Peng Margaret , Yu Lisa , Benowitz Neal L.
Published: April 2023

Abstract
Background: Smoking tobacco preparations in a water pipe (hookah) is widespread in many places of the world and is perceived by many as relatively safe. We investigated biomarkers of toxicant exposure with water pipe compared with cigarette smoking.

Methods: We conducted a crossover study to assess daily nicotine and carcinogen exposure with water pipe and cigarette smoking in 13 people who were experienced in using both products.

Results: When smoking an average of 3 water pipe sessions compared with smoking 11 cigarettes per day (cpd), water pipe use was associated with a significantly lower intake of nicotine, greater exposure to carbon monoxide (CO), and a different pattern of carcinogen exposure compared with cigarette smoking, with greater exposure to benzene, and high molecular weight polycyclic aromatic hydrocarbon (PAH), but less exposure to tobacco-specific nitrosamines, 1,3-butadiene, acrolein, acrylonitrile, propylene oxide, ethylene oxide, and low molecular weight PAHs.

Conclusions: A different pattern of carcinogen exposure might result in a different cancer risk profile between cigarette and water pipe smoking. Of particular concern is the risk of leukemia related to high levels of benzene exposure with water pipe use.

Impact: Smoking tobacco in water pipes has gained popularity in the United States and around the world. Many believe that water pipe smoking is not addictive and less harmful than cigarette smoking. We provide data on toxicant exposure that will help guide regulation and public education regarding water pipe health risk. Cancer Epidemiol Biomarkers Prev; 22(5); 765–72. ©2013 AACR.
Data from The Cost-Effectiveness of Visual Triage of Human Papillomavirus–Positive Women in Three Low- and Middle-Income Countries
Authors: Campos Nicole G. , Jeronimo Jose , Tsu Vivien , Castle Philip E. , Mvundura Mercy , Kim Jane J.
Published: April 2023

Abstract
Background: World Health Organization guidelines support human papillomavirus (HPV) testing alone (followed by treatment with cryotherapy) or in conjunction with visual inspection with acetic acid (VIA) triage testing. Our objective was to determine the cost-effectiveness of VIA triage for HPV-positive women in low-resource settings.

Methods: We calibrated mathematical simulation models of HPV infection and cervical cancer to epidemiologic data from India, Nicaragua, and Uganda. Using cost and test performance data from the START-UP demonstration projects, we assumed screening took place either once or three times in a lifetime between ages 30 and 40 years. Strategies included (i) HPV alone, followed by cryotherapy for all eligible HPV-positive women; and (ii) HPV testing with VIA triage for HPV-positive women, followed by cryotherapy for eligible women who were also VIA-positive (HPV-VIA). Model outcomes included lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs; international dollars/year of life saved).

Results: In all three countries, HPV alone was more effective than HPV-VIA. In Nicaragua and Uganda, HPV alone was also less costly than HPV-VIA; ICERs associated with screening three times in a lifetime (HPV alone) were below per capita GDP. In India, both HPV alone and HPV-VIA had ICERs below per capita GDP.

Conclusions: VIA triage of HPV-positive women is not likely to be cost-effective in settings with high cervical cancer burden. HPV alone followed by treatment may achieve greater health benefits and value for public health dollars.

Impact: This study provides early evidence on the cost-effectiveness of HPV testing followed by VIA triage versus an HPV screen-and-treat strategy. Cancer Epidemiol Biomarkers Prev; 26(10); 1500–10. ©2017 AACR.
Data from Where Can Colorectal Cancer Screening Interventions Have the Most Impact?
Authors: Siegel Rebecca L. , Sahar Liora , Robbins Anthony , Jemal Ahmedin
Published: April 2023

Abstract
Background: Although colorectal cancer death rates in the United States have declined by half since 1970, large geographic disparities persist. Spatial identification of high-risk areas can facilitate targeted screening interventions to close this gap.

Methods: We used the Getis-Ord Gi* statistic within ArcGIS to identify contemporary colorectal cancer “hotspots” (spatial clusters of counties with high rates) based on county-level mortality data from the national vital statistics system. Hotspots were compared with the remaining aggregated counties (non-hotspot United States) by plotting trends from 1970 to 2011 and calculating rate ratios (RR). Trends were quantified using joinpoint regression.

Results: Spatial mapping identified three distinct hotspots in the contemporary United States where colorectal cancer death rates were elevated. The highest rates were in the largest hotspot, which encompassed 94 counties in the Lower Mississippi Delta [Arkansas (17), Illinois (16), Kentucky (3), Louisiana (6), Mississippi (27), Missouri (15), and Tennessee (10)]. During 2009 to 2011, rates here were 40% higher than the non-hotspot United States [RR, 1.40; 95% confidence interval (CI), 1.34–1.46], despite being 18% lower during 1970 to 1972 (RR, 0.82; 95% CI, 0.78–0.86). The elevated risk was similar in blacks and whites. Notably, rates among black men in the Delta increased steadily by 3.5% per year from 1970 to 1990, and have since remained unchanged. Rates in hotspots in west central Appalachia and eastern Virginia/North Carolina were 18% and 9% higher, respectively, than the non-hotspot United States during 2009 to 2011.

Conclusions: Advanced spatial analysis revealed large pockets of the United States with excessive colorectal cancer death rates.

Impact: These well-defined areas warrant prioritized screening intervention. Cancer Epidemiol Biomarkers Prev; 24(8); 1151–6. ©2015 AACR.
Data from Colorectal Cancer Risk Following Adenoma Removal: A Large Prospective Population-Based Cohort Study
Authors: Coleman Helen G. , Loughrey Maurice B. , Murray Liam J. , Johnston Brian T. , Gavin Anna T. , Shrubsole Martha J. , Bhat Shivaram K. , Allen Patrick B. , McConnell Vivienne , Cantwell Marie M.
Published: April 2023

Abstract
Background: Randomized controlled trials have demonstrated significant reductions in colorectal cancer incidence and mortality associated with polypectomy. However, little is known about whether polypectomy is effective at reducing colorectal cancer risk in routine clinical practice. The aim of this investigation was to quantify colorectal cancer risk following polypectomy in a large prospective population-based cohort study.

Methods: Patients with incident colorectal polyps between 2000 and 2005 in Northern Ireland were identified via electronic pathology reports received to the Northern Ireland Cancer Registry. Patients were matched to the Northern Ireland Cancer Registry to detect colorectal cancer and deaths up to December 31, 2010. Colorectal cancer standardized incidence ratios (SIR) were calculated and Cox proportional hazards modeling applied to determine colorectal cancer risk.

Results: During 44,724 person-years of follow-up, 193 colorectal cancer cases were diagnosed among 6,972 adenoma patients, representing an annual progression rate of 0.43%. Colorectal cancer risk was significantly elevated in patients who had an adenoma removed (SIR, 2.85; 95% CI, 2.61–3.25) compared with the general population. Male sex, older age, rectal site, and villous architecture were associated with an increased colorectal cancer risk in adenoma patients. Further analysis suggested that not having a full colonoscopy performed at, or following, incident polypectomy contributed to the excess colorectal cancer risk.

Conclusions: Colorectal cancer risk was elevated in individuals following polypectomy for adenoma, outside of screening programs.

Impact: This finding emphasizes the need for full colonoscopy and adenoma clearance, and appropriate surveillance, after endoscopic diagnosis of adenoma. Cancer Epidemiol Biomarkers Prev; 24(9); 1373–80. ©2015 AACR.
Data from Identification and Diagnostic Performance of a Small RNA within the PCA3 and BMCC1 Gene Locus That Potentially Targets mRNA
Authors: Drayton Ross M. , Rehman Ishtiaq , Clarke Raymond , Zhao Zhongming , Pang Karl , Miah Saiful , Stoehr Robert , Hartmann Arndt , Blizard Sheila , Lavin Martin , Bryant Helen E. , Martens-Uzunova Elena S. , Jenster Guido , Hamdy Freddie C. , Gardiner Robert A. , Catto James W.F.
Published: April 2023

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

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

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

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

Impact: This short RNA is stable ex vivo, suggesting a role as a robust biomarker. We identify cytoplasmic enrichment of this RNA and potential targeting of mRNAs implicated in prostate carcinogenesis. Cancer Epidemiol Biomarkers Prev; 24(1); 268–75. ©2014 AACR.
Data from Breast Cancer Prognostic Biomarker Using Attractor Metagenes and the FGD3–SUSD3 Metagene
Authors: Ou Yang Tai-Hsien , Cheng Wei-Yi , Zheng Tian , Maurer Matthew A. , Anastassiou Dimitris
Published: April 2023

Abstract
Background: The winning model of the Sage Bionetworks/DREAM Breast Cancer Prognosis Challenge made use of several molecular features, called attractor metagenes, as well as another metagene defined by the average expression level of the two genes FGD3 and SUSD3. This is a follow-up study toward developing a breast cancer prognostic test derived from and improving upon that model.

Methods: We designed a feature selector facility calculating the prognostic scores of combinations of features, including those that we had used earlier, as well as those used in existing breast cancer biomarker assays, identifying the optimal selection of features for the test.

Results: The resulting test, called BCAM (Breast Cancer Attractor Metagenes), is universally applicable to all clinical subtypes and stages of breast cancer and does not make any use of breast cancer molecular subtype or hormonal status information, none of which provided additional prognostic value. BCAM is composed of several molecular features: the breast cancer–specific FGD3–SUSD3 metagene, four attractor metagenes present in multiple cancer types (CIN, MES, LYM, and END), three additional individual genes (CD68, DNAJB9, and CXCL12), tumor size, and the number of positive lymph nodes.

Conclusions: Our analysis leads to the unexpected and remarkable suggestion that ER, PR, and HER2 status, or molecular subtype classification, do not provide additional prognostic value when the values of the FGD3–SUSD3 and attractor metagenes are taken into consideration.

Impact: Our results suggest that BCAM's prognostic predictions show potential to outperform those resulting from existing breast cancer biomarker assays. Cancer Epidemiol Biomarkers Prev; 23(12); 2850–6. ©2014 AACR.
Data from Benign Breast Tissue Composition in Breast Cancer Patients: Association with Risk Factors, Clinical Variables, and Gene Expression
Authors: Sun Xuezheng , Sandhu Rupninder , Figueroa Jonine D. , Gierach Gretchen L. , Sherman Mark E. , Troester Melissa A.
Published: April 2023

Abstract
Background: Breast tissue composition (epithelium, non-fatty stroma, and adipose) changes qualitatively and quantitatively throughout the lifespan, and may mediate relationships between risk factors and breast cancer initiation. We sought to identify relationships between tissue composition, risk factors, tumor characteristics, and gene expression.

Methods: Participants were 146 patients from the Polish Breast Cancer Study, with data on risk factor and clinicopathological characteristics. Benign breast tissue composition was evaluated using digital image analysis of histologic sections. Whole-genome microarrays were performed on the same tissue blocks.

Results: Mean epithelial, non-fatty stromal, and adipose proportions were 8.4% (SD = 4.9%), 27.7% (SD = 24.0%), and 64.0% (SD = 24.0%), respectively. Among women <50 years old, stroma proportion decreased and adipose proportion increased with age, with approximately 2% difference per year (P < 0.01). The variation in epithelial proportion with age was modest (0.1% per year). Higher epithelial proportion was associated with obesity (7.6% in nonobese vs. 10.1% in obese; P = 0.02) and with poorly differentiated tumors (7.8% in well/moderate vs. 9.9% in poor; P = 0.05). Gene expression signatures associated with epithelial and stromal proportion were identified and validated. Stroma-associated genes were in metabolism and stem cell maintenance pathways, whereas epithelial genes were enriched for cytokine and immune response pathways.

Conclusions: Breast tissue composition was associated with age, body mass index, and tumor grade, with consequences for breast gene expression.

Impact: Breast tissue morphologic factors may influence breast cancer etiology. Composition and gene expression may act as biomarkers of breast cancer risk and progression. Cancer Epidemiol Biomarkers Prev; 23(12); 2810–8. ©2014 AACR.