bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Colorectal Cancer Screening with Blood-Based Biomarkers: Cost-Effectiveness of Methylated Septin 9 DNA versus Current Strategies
Authors: Ladabaum Uri , Allen John , Wandell Michael , Ramsey Scott
Published: April 2023

Abstract
Background: Screening reduces colorectal cancer mortality, but many persons remain unscreened. Screening with a blood test could improve screening rates. We estimated the comparative effectiveness and cost-effectiveness of colorectal cancer screening with emerging biomarkers, illustrated by a methylated Septin 9 DNA plasma assay (mSEPT9), versus established strategies.

Methods: We conducted a cost-utility analysis using a validated decision analytic model comparing mSEPT9, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), sigmoidoscopy, and colonoscopy, projecting lifetime benefits and costs.

Results: In the base case, mSEPT9 decreased colorectal cancer incidence by 35% to 41% and colorectal cancer mortality by 53% to 61% at costs of $8,400 to $11,500/quality-adjusted life year gained versus no screening. All established screening strategies were more effective than mSEPT9. FIT was cost saving, dominated mSEPT9, and was preferred among all the alternatives. Screening uptake and longitudinal adherence rates over time strongly influenced the comparisons between strategies. At the population level, mSEPT9 yielded incremental benefit at acceptable costs when it increased the fraction of the population screened more than it was substituted for other strategies.

Conclusions:mSEPT9 seems to be effective and cost-effective compared with no screening. To be cost-effective compared with established strategies, mSEPT9 or blood-based biomarkers with similar test performance characteristics would need to achieve substantially higher uptake and adherence rates than the alternatives. It remains to be proven whether colorectal cancer screening with a blood test can improve screening uptake or long-term adherence compared with established strategies.

Impact: Our study offers insights into the potential role of colorectal cancer screening with blood-based biomarkers. Cancer Epidemiol Biomarkers Prev; 22(9); 1567–76. ©2013 AACR.
Data from TGF-β Signaling Pathway and Breast Cancer Susceptibility
Authors: Scollen Serena , Luccarini Craig , Baynes Caroline , Driver Kristy , Humphreys Manjeet K. , Garcia-Closas Montserrat , Figueroa Jonine , Lissowska Jolanta , Pharoah Paul D. , Easton Douglas F. , Hesketh Robin , Metcalfe James C. , Dunning Alison M.
Published: April 2023

Abstract
Background: TGF-β acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)].

Methods: Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC).

Results: Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR−) tumors [1.18 (95% CI: 1.09–1.28), 4.1 × 10−5 (P value for heterogeneity of ORs by PR status = 2.3 × 10−4)]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis.

Conclusion: Common variation in the TGF-β ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes.

Impact: The subtype specific associations require very large studies to be confirmed. Cancer Epidemiol Biomarkers Prev; 20(6); 1112–9. ©2011 AACR.
Data from Offering Self-Sampling to Non-Attendees of Organized Primary HPV Screening: When Do Harms Outweigh the Benefits?
Authors: Rozemeijer Kirsten , de Kok Inge M.C.M , Naber Steffie K. , van Kemenade Folkert J. , Penning Corine , van Rosmalen Joost , van Ballegooijen Marjolein
Published: April 2023

Abstract
Background: Human papillomavirus (HPV) self-sampling might be a promising tool to increase effectiveness of primary HPV screening programs when offered to non-attendees. However, effectiveness could decrease if regular attendees “switch” to self-sampling, because self-sampling test characteristics may be inferior. We examined under which conditions the harms would outweigh the benefits.

Methods: The MISCAN-cervix model was used to estimate quality-adjusted life years (QALY) gained and costs of offering HPV self-sampling to non-attendees. We varied the relative CIN2+ sensitivity and specificity (self-sampling vs. regular sampling), extra attendance, risk of extra attendees, and the switching percentage.

Results: Without switching, offering self-sampling is (cost-)effective under every studied condition. If the attendance due to self-sampling increases by ≥6 percentage points, higher primary background risk women (unscreened women who will never attend regular screening) attend and the relative CIN2+ sensitivity and specificity are ≥0.95; it is (cost-)effective to offer self-sampling to non-attendees, even if all regular attendees switch. If the relative sensitivity decreases to 0.90 combined with either a 3 percentage points extra attendance or the absence of higher primary background risk women, QALYs are lost when more than 30% to 20% of the regular attendees switch.

Conclusions: Offering self-sampling will gain health effects if the relative CIN2+ sensitivity is ≥0.95, unscreened attendees are recruited, and the total attendance increases by ≥6 percentage points. Otherwise, switching of regular attendees may decrease the total effectiveness of the program.

Impact: Self-sampling needs to be implemented with great care and advantages of office-based sampling need to be emphasized to prevent switching. Cancer Epidemiol Biomarkers Prev; 24(5); 773–82. ©2014 AACR.

See related commentary by Arbyn and Castle, p. 769
Data from Pleiotropy between Genetic Markers of Obesity and Risk of Prostate Cancer
Authors: Edwards Todd L. , Giri Ayush , Motley Saundra , Duong Wynne , Fowke Jay H.
Published: April 2023

Abstract
Background: To address inconsistent findings of obesity and prostate cancer risk, we analyzed the association between prostate cancer and genetic markers of obesity and metabolism.

Methods: Analyses included 176,520 single-nucleotide polymorphisms (SNP) associated with 23 metabolic traits. We examined the association between SNPs and prostate cancer in 871 cases and 906 controls, including 427 high-grade cases with Gleason ≥ 7. Genetic risk scores (GRS) for body mass index (BMI) and waist-to-hip ratio (WHR) were also created by summing alleles associated with increasing BMI or WHR.

Results: Prostate cancer was associated with five loci, including cyclin M2, with P values less than 1 × 10−4. In addition, the WHR GRS was associated with high-grade prostate cancer versus controls [OR, 1.05; 95% confidence interval (CI), 1.00–1.11; P = 0.048] and high-grade prostate cancer versus low-grade prostate cancer (OR, 1.07; 95% CI, 1.01–1.13; P = 0.03). None of these findings exceeds the threshold for significance after correction for multiple testing.

Conclusions: Variants in genes known to be associated with metabolism and obesity may be associated with prostate cancer. We show evidence for pleiotropy between WHR GRS and prostate cancer grade. This finding is consistent with the function of several WHR genes and previously described relationships with cancer traits.

Impact: Limitations in standard obesity measures suggest alternative characterizations of obesity may be needed to understand the role of metabolic dysregulation in prostate cancer. The underlying genetics of WHR or other Metabochip SNPs, while not statistically significant beyond multiple testing thresholds within our sample size, support the metabolic hypothesis of prostate carcinogenesis and warrant further investigation in independent samples. Cancer Epidemiol Biomarkers Prev; 22(9); 1538–46. ©2013 AACR.
Data from The Impact of Race and Comorbidity on Survival in Endometrial Cancer
Authors: Olson Sara H. , Atoria Coral L. , Cote Michele L. , Cook Linda S. , Rastogi Radhai , Soslow Robert A. , Brown Carol L. , Elkin Elena B.
Published: April 2023

Abstract
Background: Poorer survival from endometrial cancer in blacks than in whites is well documented. The aims of this study were to determine whether diabetes, hypertension, or other conditions influence survival and whether accounting for these conditions reduces this racial disparity.

Methods: Using the SEER-Medicare database, we investigated the influence of diabetes, hypertension, and other comorbid conditions on survival in black and white women age ≥66 with endometrial cancer. We used Cox proportional hazards regression to evaluate the influence of comorbidities on survival for blacks and whites separately and to study survival differences between blacks and whites after adjustment for diabetes, hypertension, and other medical conditions, as well as for demographics, tumor characteristics, and treatment.

Results: In both racial subgroups, women with diabetes or other conditions had poorer overall survival, whereas hypertensive black women experienced better survival [HR, 0.74; 95% confidence interval (CI), 0.60–0.92]. For disease-specific survival, diabetes was associated with poorer survival in white women (HR, 1.19; 95% CI, 1.06–1.35) but not in blacks (HR, 0.97; 95% CI, 0.73–1.30); hypertension and other conditions were not significantly related to survival. After adjustment, black women had poorer survival than white women, with HRs of 1.16 (95% CI, 1.05–1.28) for overall and 1.27 (95% CI, 1.08–1.49) for disease-specific survival.

Conclusions: Diabetes influences disease-specific survival in white women but not in blacks. The racial disparity in survival is not explained by the presence of other health conditions.

Impact: Further research should focus on the unknown factors that lead to poorer survival in black women compared with whites. Cancer Epidemiol Biomarkers Prev; 21(5); 753–60. ©2012 AACR.
Data from Cutaneous Markers of Photo-Damage and Risk of Basal Cell Carcinoma of the Skin: A Meta-Analysis
Authors: Khalesi Mohammad , Whiteman David C. , Doi Suhail A.R. , Clark Justin , Kimlin Michael G. , Neale Rachel E.
Published: April 2023

Abstract
Epidemiologic research has shown that cutaneous markers of photo-damage are associated with risk of basal cell carcinoma (BCC). However, there has been no previous attempt to calculate pooled risk estimates. We conducted a systematic review and meta-analysis after extracting relevant studies published up to January 2013 from five electronic databases. Eligible studies were those that permitted quantitative assessment of the association between histologically confirmed BCC and actinic keratoses, solar elastosis, solar lentigines, or telangiectasia. Seven eligible studies were identified and summary odds ratios (ORs) were calculated using both random and quality effects models. Having more than ten actinic keratoses was most strongly associated with BCC, conferring up to a fivefold increase in risk (OR: 4.97; 95% CI: 3.26–7.58). Other factors, including solar elastosis, solar lentigines, and telangiectasia had weaker but positive associations with BCC with ORs around 1.5. Markers of chronic photo-damage are positively associated with BCC. The presence of actinic keratoses was the most strongly associated with BCC of the markers examined. This work highlights the relatively modest association between markers of chronic ultraviolet exposure and BCC. Cancer Epidemiol Biomarkers Prev; 22(9); 1483–9. ©2013 AACR.
Data from Summer Peaks in Uptake of Human Papillomavirus and Other Adolescent Vaccines in the United States
Authors: Moss Jennifer L. , Reiter Paul L. , Rimer Barbara K. , Ribisl Kurt M. , Brewer Noel T.
Published: April 2023

Abstract
Background: Seasonality in human papillomavirus (HPV) vaccination could have a large impact on national cancer prevention efforts. We hypothesized that uptake of HPV vaccine and other adolescent vaccines in the United States would be highest in the summer.

Methods: Data came from health care provider–verified vaccination records for 70,144 adolescents (ages 13–17 years) from the 2008 to 2012 versions of the National Immunization Survey-Teen. Using the Edwards method for testing annual trends, we examined seasonal patterns in the uptake of HPV and other recommended adolescent vaccines [tetanus, diphtheria, and pertussis (Tdap) booster and meningococcal vaccine]. HPV vaccine initiation (receipt of the first of the three-dose series) data were for female adolescents.

Results: Uptake for HPV and other adolescent vaccines peaked in the summer across years and states (all P < 0.001). Uptake was five times as frequent at the peak as at the trough for HPV vaccine, and HPV vaccine initiation was highest in June, July, and August (percent of doses delivered in these months: 38.7%). The same pattern existed for Tdap booster and meningococcal vaccine. Concomitant (same-day) vaccination of HPV vaccine with other adolescent vaccines also demonstrated summer peaks each year nationally (all P < 0.001).

Conclusion: Uptake of adolescent vaccines increased dramatically in summer months. These summer peaks are an important opportunity for interventions focused on concomitant vaccination.

Impact: The potential cancer prevention impact of HPV vaccination programs could be increased, for example, by delivering messages about concomitant vaccination during the summer, when adolescents and their parents might be most open to them. Cancer Epidemiol Biomarkers Prev; 25(2); 274–81. ©2015 AACR.
Data from Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study
Authors: Guertin Kristin A. , Li Xinmin S. , Graubard Barry I. , Albanes Demetrius , Weinstein Stephanie J. , Goedert James J. , Wang Zeneng , Hazen Stanley L. , Sinha Rashmi
Published: April 2023

Abstract
Background: Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk.

Methods: We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case–control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations.

Results: Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median ± IQR) 14 ± 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24–4.61; Ptrend < 0.0001). The prognostic value of serum choline for prediction of incident colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (all P < 0.0001). The association between serum TMAO, carnitine, or betaine and colorectal cancer risk was not statistically significant (P = 0.25, 0.71, and 0.61, respectively).

Conclusions: Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer.

Impact: Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. Cancer Epidemiol Biomarkers Prev; 26(6); 945–52. ©2017 AACR.
Data from Validation of a Coding Algorithm to Identify Bladder Cancer and Distinguish Stage in an Electronic Medical Records Database
Authors: Mamtani Ronac , Haynes Kevin , Boursi Ben , Scott Frank I. , Goldberg David S. , Keefe Stephen M. , Vaughn David J. , Malkowicz S. Bruce , Lewis James D.
Published: April 2023

Abstract
Studies on outcomes in bladder cancer rely on accurate methods to identify patients with bladder cancer and differentiate bladder cancer stage. Medical record and administrative databases are increasingly used to study cancer incidence, but few have distinguished cancer stage, and none have focused on bladder cancer. In this study, we used data from The UK Health Improvement Network (THIN) to identify patients with bladder cancer using at least one diagnostic code for bladder cancer, and distinguish muscle-invasive from non-invasive disease using a subsequent code for cystectomy. Algorithms were validated against a gold standard of physician-completed questionnaires, pathology reports, and consultant letters. Algorithm performance was evaluated by measuring positive predictive value (PPV) and corresponding 95% confidence interval (CI). Among all patients coded with bladder cancer (n = 194), PPV for any bladder cancer was 99.5% (95% CI, 97.2–99.9). PPV for incident bladder cancer was 93.8% (95% CI, 89.4–96.7). PPV for muscle-invasive bladder cancer was 70.1% (95% CI, 59.4–79.5) in patients with cystectomy (n = 95) and 83.9% (95% CI, 66.3–94.5) in those with cystectomy plus additional codes for metastases and death (n = 31). Using our codes for bladder cancer, the age- and sex-standardized incidence rate (SIR) of bladder cancer in THIN approximated that measured by cancer registries (SIR within 20%), suggesting that sensitivity was high as well. THIN is a valid and novel database for the study of bladder cancer. Our algorithm can be used to examine the epidemiology of muscle-invasive bladder cancer or outcomes following cystectomy for patients with muscle invasion. Cancer Epidemiol Biomarkers Prev; 24(1); 303–7. ©2014 AACR.
Data from Gene Methylation in Breast Ductal Fluid from BRCA1 and BRCA2 Mutation Carriers
Authors: Antill Yoland C. , Mitchell Gillian , Johnson Sandra A. , Devereux Lisa , Milner Alvin , Di Iulio Juliana , Lindeman Geoffrey J. , Kirk Judy , Phillips Kelly Anne , Campbell Ian G.
Published: April 2023

Abstract
Purpose: Genomic alterations (including gene hypermethylation) are likely to precede the phenotypic changes associated with breast tumorigenesis. From a prospective collection of ductal lavage (DL) samples from women with a known mutation in BRCA1 or BRCA2, we have assessed promoter methylation with a comparison of results with several variables, including breast cancer (BC) outcome.

Experimental Design: Hypermethylation of p16, RASSF1A, twist, and RARβ was assessed using a qualitative, real-time, nested PCR assay. Associations between methylation status and variables were tested using Fisher's exact test or logistic regression. Analyses were done at three levels: a single breast, a single duct (both over time), and each DL sample in isolation.

Results: A total of 168 samples from 93 ducts in 54 breasts have been analyzed in 34 women (16 BRCA1 and 18 BRCA2 mutation carriers). A median of 2 DL was done (range, 1–5), with 7 women developing BC on study, 1 bilateral. Methylation of p16 was associated with a known BRCA1 mutation (P = 0.001, P < 0.001, and P < 0.001 for breast, duct, and sample levels, respectively) and women with a history of contralateral BC (P = 0.001 and P < 0.001 for duct and sample levels, respectively). An association was seen for women who developed BC on study and RASSF1A methylation (P = 0.001 for sample level).

Conclusions: Genetic methylation patterns could potentially be used to predict future BC risk. In addition, p16 methylation may be a predictor of BRCA1 mutation status. Further research is required to corroborate these findings. Cancer Epidemiol Biomarkers Prev; 19(1); 265–74
Data from Usefulness of Saliva Samples for Biomarker Studies in Radiation Research
Authors: Pernot Eileen , Cardis Elisabeth , Badie Christophe
Published: April 2023

Abstract
Salivary biomarkers have important potential to facilitate breakthroughs in epidemiologic studies, management of emergency situations, and detection and surveillance of diseases by medical staff. During the last decade, an increasing number of studies on salivary biomarkers have been published as a consequence of the impressive development of new high-throughput technologies. Here, we present a review of salivary biomarkers potentially useful in ionizing radiation (IR) research, particularly in molecular epidemiologic studies. Although several salivary biomarkers of cancer and other IR-associated diseases have been identified, few salivary biomarkers of exposure and no biomarker of susceptibility or effects specific to IR have been reported so far. Further studies are therefore needed to fully assess the potential of saliva as a source of biomarkers in the radiation research field. Although the use of saliva samples is not without drawbacks, it could represent an ideal noninvasive alternative to blood, particularly in children and in the context of large molecular epidemiology studies on the effects of low doses of IR, where, given the expected limited magnitude of effects, an extensive number of samples is required to reach statistical significance.

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

Cancer Epidemiol Biomarkers Prev; 23(12); 2673–80. ©2014 AACR.
Data from Dietary Fat Intake During Adolescence and Breast Density Among Young Women
Authors: Jung Seungyoun , Goloubeva Olga , Klifa Catherine , LeBlanc Erin S. , Snetselaar Linda G. , Van Horn Linda , Dorgan Joanne F.
Published: April 2023

Abstract
Background: Lack of association between fat intake and breast cancer risk in cohort studies might be attributed to the disregard of temporal effects during adolescence when breasts develop and are particularly sensitive to stimuli. We prospectively examined associations between adolescent fat intakes and breast density.

Method: Among 177 women who participated in the Dietary Intervention Study in Children, dietary intakes at ages 10–18 years were assessed on five occasions by 24-hour recalls and averaged. We calculated geometric mean and 95% confidence intervals for MRI-measured breast density at ages 25–29 years across quartiles of fat intake using linear mixed-effect regression.

Results: Comparing women in the extreme quartiles of adolescent fat intakes, percent dense breast volume (�V) was positively associated with saturated fat (mean = 16.4% vs. 21.5%; Ptrend < 0.001). Conversely, �V was inversely associated with monounsaturated fat (25.0% vs. 15.8%; Ptrend < 0.001) and the ratio of polyunsaturated fat to saturated fat (P/S ratio; 19.1% vs. 14.3%; Ptrend < 0.001). When examining intake by pubertal stages, �V was inversely associated with intake of polyunsaturated fat (20.8% vs. 16.4%; Ptrend = 0.04), long-chain omega-3 fat (17.8% vs. 15.8%; Ptrend < 0.001), and P/S ratio (22.5% vs. 16.1%; Ptrend < 0.001) before menarche, but not after. These associations observed with �V were consistently observed with absolute dense breast volume but not with absolute nondense breast volume.

Conclusions: In our study, adolescent intakes of higher saturated fat and lower mono- and polyunsaturated fat are associated with higher breast density measured approximately 15 years later.

Impact: The fat subtype composition in adolescent diet may be important in early breast cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(6); 918–26. ©2016 AACR.
Data from Characterizing the Temporal Dynamics of Human Papillomavirus DNA Detectability Using Short-Interval Sampling
Authors: Liu Su-Hsun , Cummings Derek A.T. , Zenilman Jonathan M. , Gravitt Patti E. , Brotman Rebecca M.
Published: April 2023

Abstract
Background: Variable detection of human papillomavirus (HPV) DNA can result in misclassification of infection status, but the extent of misclassification has not been quantitatively evaluated.

Methods: In 2005–2007, 33 women of ages 22 to 53 years self-collected vaginal swabs twice per week for 16 consecutive weeks. Each of the 955 swabs collected was tested for 37 HPV types/subtypes. Assuming that a woman's underlying infection status did not change over the short study period, biases in prevalence estimates obtained from single versus multiple swabs were calculated. Using event history analysis methods, time to recurrent gain and loss of at least one HPV type was determined, separately. Baseline any-type and high risk–type HPV prevalence was 60.6% and 24.2%, respectively. Cumulative any-HPV and high-risk HPV prevalence over the 16-week period was 84.8% and 60.6%, separately.

Results: Overall, there were 319 events of detection and 313 events of loss of detection. Median times to a recurrent detection and loss of detection were 11 and seven days, respectively. Neither vaginal sex nor condom use during follow-up was associated with recurrent viral detection or loss of detection. Assuming the cumulative 16-week prevalence reflects the true prevalence of infection, the baseline any-HPV prevalence underestimated infection status by 24.2%, with a bootstrapped mean of 20.2% [95% confidence interval (CI), 8.9%–29.6%].

Conclusions: These findings suggest that a substantial proportion of HPV-infected women are misclassified as being uninfected when using a single-time DNA measurement.

Impact: Short-term variation in detectable HPV DNA needs to be considered while interpreting the natural history of infections using single samples collected at long intervals. Cancer Epidemiol Biomarkers Prev; 23(1); 200–8. ©2013 AACR.
Data from Lung Cancer Detectability by Test, Histology, Stage, and Gender: Estimates from the NLST and the PLCO Trials
Authors: ten Haaf Kevin , van Rosmalen Joost , de Koning Harry J.
Published: April 2023

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

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

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

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

Impact: This study provides detailed insights into the natural history of lung cancer and CT screening effectiveness. Cancer Epidemiol Biomarkers Prev; 24(1); 154–61. ©2014 AACR.
Data from Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients
Authors: Hu Chunling , Hart Steven N. , Bamlet William R. , Moore Raymond M. , Nandakumar Kannabiran , Eckloff Bruce W. , Lee Yean K. , Petersen Gloria M. , McWilliams Robert R. , Couch Fergus J.
Published: April 2023

Abstract
The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 25(1); 207–11. ©2015 AACR.
Data from Circulating 25-Hydroxyvitamin D3 and Survival after Diagnosis with Kidney Cancer
Authors: Muller David C. , Scelo Ghislaine , Zaridze David , Janout Vladimir , Holcatova Ivana , Navratilova Marie , Mates Dana , Midttun Øivind , Ueland Per Magne , Brennan Paul , Johansson Mattias
Published: April 2023

Abstract
Prospective cohort studies have provided some evidence that circulating vitamin D is associated with risk of, and survival from, renal cell carcinoma (RCC), but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis. We conducted a case–cohort study of 630 RCC cases, including 203 deaths, from a multicenter case–control study in Eastern Europe. Vitamin D was assessed as 25-hydroxyvitamin D3 [25(OH)D3], and we used weighted Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) by categories of season-adjusted 25(OH)D3. Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage, age, sex, and country (HR highest vs. lowest category 0.57; 95% CI, 0.34–0.97). The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease. In summary, 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates, but not specifically with RCC outcome. Cancer Epidemiol Biomarkers Prev; 24(8); 1277–81. ©2015 AACR.
Data from Body Size Throughout Adult Life Influences Postmenopausal Breast Cancer Risk among Hispanic Women: The Breast Cancer Health Disparities Study
Authors: John Esther M. , Sangaramoorthy Meera , Hines Lisa M. , Stern Mariana C. , Baumgartner Kathy B. , Giuliano Anna R. , Wolff Roger K. , Slattery Martha L.
Published: April 2023

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

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

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

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

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

See related article by John et al., p. 138
Data from The Growing Burden of Endometrial Cancer: A Major Racial Disparity Affecting Black Women
Authors: Cote Michele L. , Ruterbusch Julie J. , Olson Sara H. , Lu Karen , Ali-Fehmi Rouba
Published: April 2023

Abstract
Background: In contrast with the decreasing incidence seen for most cancers, endometrial cancer has been increasing in the United States. We examined whether the increasing incidence and mortality from endometrial cancer are equally distributed by race/ethnicity and tumor histologic subtype.

Methods: Surveillance, Epidemiology, and End Results (SEER) endometrial cancer incidence and mortality data were obtained from 2000 to 2011. Age-adjusted incidence and incidence-based mortality rates, 95% confidence intervals, and annual percent changes (APC) were calculated. Rate ratios were calculated to compare racial/ethnic groups. Five-year relative survival rates were presented to explore survival by stage at diagnosis.

Results: Incidence rates for endometrial cancers are rising across all racial/ethnic groups, with the greatest APC seen among non-Hispanic black (NHB) and Asian women (APC, 2.5 for both). NHB women have significantly higher incidence rates of aggressive endometrial cancers (clear cell, serous, high-grade endometrioid, and malignant mixed Mullerian tumors) compared with non-Hispanic white (NHW) women. Hispanic and Asian women have incidence rates equal to or lower than NHW women for all tumor subtypes. For nearly every stage and subtype, the 5-year relative survival for NHB women is significantly less than NHW women, whereas Hispanic and Asian women have the same or better survival.

Conclusions: Endometrial cancer incidence is increasing for all women, particularly the aggressive subtypes. The disparity associated with excess incidence for these aggressive histologic subtypes and poorer survival is limited to NHB women.

Impact: Increasing rates of aggressive endometrial cancers may widen the survival disparity between NHW and NHB women. Cancer Epidemiol Biomarkers Prev; 24(9); 1407–15. ©2015 AACR.
Data from Risk Stratification Using Human Papillomavirus Testing among Women with Equivocally Abnormal Cytology: Results from a State-Wide Surveillance Program
Authors: Gage Julia C. , Hunt William C. , Schiffman Mark , Katki Hormuzd A. , Cheung Li C. , Cuzick Jack , Myers Orrin , Castle Philip E. , Wheeler Cosette M.
Published: April 2023

Abstract
Background: Clinical guidelines for cervical cancer screening have incorporated comparative risks of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) for various screening outcomes to determine management. Few cohorts are large enough to distinguish CIN3+ risks among women with minor abnormalities versus negative cytology because of low incidence. The New Mexico Human Papillomavirus (HPV) Pap Registry offers a unique opportunity to evaluate cervical cancer screening in a diverse population across a broad-spectrum of health service delivery.

Methods: Kaplan–Meier and logistic–Weibull survival models were used to estimate cumulative risks of CIN3+ among women ages 21 to 64 who were screened in New Mexico between 2007 and 2011 with negative, equivocal or mildly abnormal cytology, that is, atypical squamous cells of undetermined significance (ASC-US; with or without HPV triage), or low-grade squamous intraepithelial lesions (LSIL).

Results: We identified 452,045 women meeting the selection criteria. The 3-year CIN3+ risks for women with negative, ASC-US, and LSIL cytology were 0.30%, 2.6%, and 5.2%, respectively. HPV triage of ASC-US stratified 3-year CIN3+ risks were 0.72% for HPV-negative and 7.7% for HPV-positive. Risks tended to decline after age 30 for all screening results.

Conclusions: In this state-wide population-based cohort, cytology and HPV triage of ASC-US stratified women's CIN3+ risk into similar patterns observed previously, suggesting the validity of screening guidelines for diverse populations in the United States. Absolute risk estimates should be compared across other large populations.

Impact: Strategies for HPV triage of ASC-US derived from clinical trials are upheld in large clinical practice settings and across diverse screening populations in the United States. Cancer Epidemiol Biomarkers Prev; 25(1); 36–42. ©2015 AACR.
Data from Expanding Epigenomics to Archived FFPE Tissues: An Evaluation of DNA Repair Methodologies
Authors: Siegel Erin M. , Berglund Anders E. , Riggs Bridget M. , Eschrich Steven A. , Putney Ryan M. , Ajidahun Abidemi O. , Coppola Domenico , Shibata David
Published: April 2023

Abstract
Background: Epigenome-wide association studies are emerging in the field of cancer epidemiology with the rapid development of large-scale methylation array platforms. Until recently, these methods were only valid for DNA from flash frozen (FF) tissues. Novel techniques for repairing DNA from formalin-fixed paraffin-embedded (FFPE) tissues have emerged; however, a direct comparison of FFPE DNA repair methods before analysis on genome-wide methylation array to matched FF tissues has not been conducted.

Methods: We conducted a systematic performance comparison of two DNA repair methods (REPLI-g Ligase vs. Infinium HD Restore Kit) on FFPE-DNA compared with matched FF tissues on the Infinium 450K array. A threshold of discordant methylation between FF-FFPE pairs was set at Δβ > 0.3. The correlations of β-values from FF–FFPE pairs were compared across methods and experimental conditions.

Results: The Illumina Restore kit outperformed the REPLI-g ligation method with respect to reproducibility of replicates (R2 > 0.970), highly correlated β-values between FF-FFPE (R2 > 0.888), and fewest discordant loci between FF-FFPE (≤0.61%). The performance of the Restore kit was validated in an independent set of 121 FFPE tissues.

Conclusions: The Restore kit outperformed RELPI-g ligation in restoring FFPE-derived DNA before analysis on the Infinium 450K methylation array. Our findings provide critical guidance that may significantly enhance the breadth of diseases that can be studied by methylomic profiling.

Impact: Epigenomic studies using FFPE tissues should now be considered among cancers that have not been fully characterized from an epigenomic standpoint. These findings promote novel epigenome-wide studies focused on cancer etiology, identification of novel biomarkers, and developing targeted therapies.

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

Cancer Epidemiol Biomarkers Prev; 23(12); 2622–31. ©2014 AACR.
Data from Methods for Sample Acquisition and Processing of Serial Blood and Tumor Biopsies for Multicenter Diffuse Large B-cell Lymphoma Clinical Trials
Authors: Nielsen Torsten Holm , Diaz Zuanel , Christodoulopoulos Rosa , Charbonneau Fredrick , Qureshi Samia , Rousseau Caroline , Benlimame Naciba , Camlioglu Errol , Constantin André Marc , Oros Kathleen Klein , Krumsiek Jan , Crump Michael , Morin Ryan D. , Cerchietti Leandro , Johnson Nathalie A. , Petrogiannis-Haliotis Tina , Miller Wilson H. , Assouline Sarit E. , Mann Koren K.
Published: April 2023

Abstract
Increasingly, targeted therapies are being developed to treat malignancies. To define targets, determine mechanisms of response and resistance, and develop biomarkers for the successful investigation of novel therapeutics, high-quality tumor biospecimens are critical. We have developed standard operating procedures (SOPs) to acquire and process serial blood and tumor biopsies from patients with diffuse large B-cell lymphoma enrolled in multicenter clinical trials. These SOPs allow for collection and processing of materials suitable for multiple downstream applications, including immunohistochemistry, cDNA microarrays, exome sequencing, and metabolomics. By standardizing these methods, we control preanalytic variables that ensure high reproducibility of results and facilitate the integration of datasets from such trials. This will facilitate translational research, better treatment selection, and more rapid and efficient development of new drugs.

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

Cancer Epidemiol Biomarkers Prev; 23(12); 2688–93. ©2014 AACR.
Data from The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations
Authors: Patel Yesha M. , Stram Daniel O. , Wilkens Lynne R. , Park Sung-Shim L. , Henderson Brian E. , Le Marchand Loic , Haiman Christopher A. , Murphy Sharon E.
Published: April 2023

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

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

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

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

Impact: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk. Cancer Epidemiol Biomarkers Prev; 24(1); 119–27. ©2014 AACR.
Data from Prevalence of Human Papillomavirus in Cancer of the Oropharynx by Gender
Authors: Combes Jean-Damien , Chen Alyce A. , Franceschi Silvia
Published: April 2023

Abstract
Oropharyngeal cancer (OPC) is more frequent in men than women mainly due to the heavier and longer duration of smoking in men. Human papillomavirus (HPV) has a role in the rising incidence of OPC in the United States and other high-income countries. To determine whether there is a difference in the proportion of HPV-attributable OPC between men and women, we systematically retrieved HPV prevalence data from 63 studies reporting separately on OPC by gender. The male/female (M/F) ratios of HPV prevalence in OPC across different countries and the corresponding M/F ratios of cumulative lung cancer risk (a proxy for smoking) were compared. The United States had the highest M/F ratios of HPV prevalence in OPC (1.5). The lowest M/F ratios (≤0.7) were found in Asia and some European countries (e.g., France). The countries in which the M/F ratio of HPV prevalence in OPC was ≥1.0 had the most similar lung cancer risks for men and women. When HPV prevalence data were applied to age-standardized OPC incidence rates in the United States, Australia, the United Kingdom, and France, the M/F ratio for the HPV-positive OPC incidence rates was rather stable (around 4) in all countries. In contrast, the M/F ratio for the HPV-negative OPC incidence rates reached 10.2 in France versus <3 elsewhere. We showed that HPV prevalence in OPC differs by gender and country mainly as a consequence of the vast international variation in male smoking habits. Nevertheless, HPV-positive OPC may affect men more heavily than women in different populations for reasons that are unclear. Cancer Epidemiol Biomarkers Prev; 23(12); 2954–8. ©2014 AACR.
Data from Genetic Associations in Classical Hodgkin Lymphoma: A Systematic Review and Insights into Susceptibility Mechanisms
Authors: Kushekhar Kushi , van den Berg Anke , Nolte Ilja , Hepkema Bouke , Visser Lydia , Diepstra Arjan
Published: April 2023

Abstract
Both targeted and genome-wide studies have revealed genetic associations for susceptibility, prognosis, and treatment-induced secondary malignancies and toxicities in classical Hodgkin lymphoma (cHL). This review gives a systematic and comprehensive overview of significant associations and places them into a biologic context. The strongest susceptibility polymorphisms have been found for the human leukocyte antigen (HLA) genes. These associations are specific for cHL overall or for subgroups based on tumor cell Epstein–Barr virus (EBV) status. These findings strongly suggest that EBV-specific immune responses influence cHL susceptibility in EBV+ cHL and that immune responses targeting other tumor-associated antigens are important in EBV− cHL. Accordingly, most of the numerous other susceptibility loci map to genes that affect functionality of the immune system, underscoring the crucial role of the immune system in cHL development. The number of association studies on cHL prognosis is limited with one consistent association for the drug-metabolizing UGT1A1 gene. PRDM1 is associated with radiation-induced secondary malignancies and a small number of genes are associated with treatment-related toxicities. In conclusion, most loci showing genetic associations in cHL harbor genes with a potential functional relevance for cHL susceptibility. Cancer Epidemiol Biomarkers Prev; 23(12); 2737–47. ©2014 AACR.