bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Validation Study of Genes with Hypermethylated Promoter Regions Associated with Prostate Cancer Recurrence
Authors: Stott-Miller Marni , Zhao Shanshan , Wright Jonathan L. , Kolb Suzanne , Bibikova Marina , Klotzle Brandy , Ostrander Elaine A. , Fan Jian-Bing , Feng Ziding , Stanford Janet L.
Published: April 2023

Abstract
Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.

Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.

Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10−4). DNA methylation profiles did not differ by recurrence status for the other genes.

Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence.

Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. Cancer Epidemiol Biomarkers Prev; 23(7); 1331–9. ©2014 AACR.
Data from Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations
Authors: Cook Michael B. , Stanczyk Frank Z. , Wood Shannon N. , Pfeiffer Ruth M. , Hafi Muhannad , Veneroso Carmela C. , Lynch Barlow , Falk Roni T. , Zhou Cindy Ke , Niwa Shelley , Emanuel Eric , Gao Yu-Tang , Hemstreet George P. , Zolfghari Ladan , Carroll Peter R. , Manyak Michael J. , Sesterhann Isabell A. , Levine Paul H. , Hsing Ann W.
Published: April 2023

Abstract
Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.

Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.

Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.

Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.

Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.
Data from Prostate Stem Cell Antigen Polymorphisms and Susceptibility to Gastric Cancer: A Systematic Review and Meta-analysis
Authors: Wang Tao , Zhang Lina , Li Haixin , Wang Bangmao , Chen Kexin
Published: April 2023

Abstract
Background: Many studies have reported that prostate stem cell antigen (PSCA) polymorphisms (rs2294008 and/or 2976392) are significantly associated with gastric cancer (GC) risk, although the published results are inconsistent. We conducted a systematic review and meta-analysis for relevant literatures to quantitatively evaluate the relationship between PSCA polymorphisms and GC susceptibility.

Methods: Extensive searches were conducted in three databases up to November 1, 2011. ORs and 95% CIs were used to assess the strength of the associations. The data were further stratified by ethnicity, histopathology, subsite, and study design. All of the associations were evaluated with dominant model and recessive model, respectively. Heterogeneity and publication bias were also assessed by Q test, I2, and funnel plot accordingly.

Results: Nine articles including 11 case–control data sets were included, with 10,746 GC cases and 9,158 controls for rs2294008 and 6,060 cases and 4,824 controls for rs2976392. The results showed that risk allele carriers were significantly associated with GC risk compared with nonrisk allele homozygotes. In stratification analyses, these associations remained significant for majority of subgroups except for Caucasians and noncardia tumor in dominant model, and cardia tumor in both dominant and recessive model. Random model was used when heterogeneity among studies was detected. No publication bias was observed.

Conclusions: The two loci of PSCA (rs2294008 and rs2976392) were both significantly associated with GC susceptibility and in linkage disequilibrium.

Impact: More prospective studies on PSCA polymorphisms at multicenters with sufficient sample size and less heterogeneity will be needed for further validations. Cancer Epidemiol Biomarkers Prev; 21(5); 843–50. ©2012 AACR.
Data from Hepatitis B Virus Infection and Risk of Nasopharyngeal Carcinoma in Southern China
Authors: Ye Yan-Fang , Xiang Yan-Qun , Fang Fang , Gao Rui , Zhang Li-Fang , Xie Shang-Hang , Liu Zhiwei , Du Jin-Lin , Chen Sui-Hong , Hong Ming-Huang , Qian Chao-Nan , Ye Weimin , Zeng Yi-Xin , Liu Qing , Cao Su-Mei
Published: April 2023

Abstract
Background: Whether or not hepatitis B virus (HBV) infection plays a role in the development of nasopharyngeal carcinoma (NPC) is largely unknown. Our study aimed to assess the association between HBV infection and the risk of NPC in Southern China.

Methods: We conducted a case–control study including 711 NPC cases and two groups of controls. The first control group consisted of 656 individuals with other benign tumors unrelated to HBV infection and the second group consisted of 680 healthy population controls. Multivariable ORs and corresponding 95% confidence intervals (CI) for NPC were estimated by logistic regression.

Results: Patients with NPC had higher prevalence of antibodies against hepatitis B core antigen–positive [anti-HBc-(+); 47.26%] compared with either benign tumor controls (39.33%; P < 0.01) or healthy controls (41.18%; P = 0.04). In multivariable models adjusting for a set of risk factors for NPC, anti-HBc-(+) was significantly associated with a higher risk of NPC [adjusted OR (AOR), 1.40; 95% CI, 1.12–1.74 compared with the benign tumor controls and AOR, 1.48; 95% CI, 1.05–2.08 compared with the healthy controls]. The association was not modified by hepatitis B surface antigen (HBsAg) status. Finally, compared with the healthy controls, individuals with both anti-HBc-(+) and EBV antibodies had largely increased risk of NPC (AOR, 141.82; 95% CI, 68.73–292.62).

Conclusion: Our study suggests that HBV infection is associated with NPC risk in Southern China.

Impact: Prevention for HBV infection may play a role in the development of NPC. Cancer Epidemiol Biomarkers Prev; 24(11); 1766–73. ©2015 AACR.
Data from Physicians, Clinics, and Neighborhoods: Multiple Levels of Influence on Colorectal Cancer Screening
Authors: Pruitt Sandi L. , Leonard Tammy , Zhang Song , Schootman Mario , Halm Ethan A. , Gupta Samir
Published: April 2023

Abstract
Background: We (i) described variability in colorectal cancer (CRC) test use across multiple levels, including physician, clinic, and neighborhood; and (ii) compared the performance of novel cross-classified models versus traditional hierarchical models.

Methods: We examined multilevel variation in CRC test use among patients not up-to-date with screening in a large, urban safety net health system (2011–2012). Outcomes included: (i) fecal occult blood test (FOBT) or (ii) colonoscopy and were ascertained using claims data during a 1-year follow-up. We compared Bayesian (i) cross-classified four-level logistic models nesting patients within separate, nonoverlapping “levels” (physicians, clinics, and census tracts) versus (ii) three hierarchical two-level models using deviance information criterion. Models were adjusted for covariates (patient sociodemographic factors, driving time to clinic, and census tract poverty rate).

Results: Of 3,195 patients, 157 (4.9%) completed FOBT and 292 (9.1%) completed colonoscopy during the study year. Patients attended 19 clinics, saw 177 physicians, and resided in 332 census tracts. Significant variability was observed across all levels in both hierarchical and cross-classified models that was unexplained by measured covariates. For colonoscopy, variance was similar across all levels. For FOBT, physicians, followed by clinics, demonstrated the largest variability. Model fit using cross-classified models was superior or similar to 2-level hierarchical models.

Conclusions: Significant and substantial variability was observed across neighborhood, physician, and clinic levels in CRC test use, suggesting the importance of factors at each of these levels on CRC testing.

Impact: Future multilevel research and intervention should consider the simultaneous influences of multiple levels, including clinic, physician, and neighborhood. Cancer Epidemiol Biomarkers Prev; 23(7); 1346–55. ©2014 AACR.
Data from DNA Methylation-Derived Neutrophil-to-Lymphocyte Ratio: An Epigenetic Tool to Explore Cancer Inflammation and Outcomes
Authors: Koestler Devin C. , Usset Joseph , Christensen Brock C. , Marsit Carmen J. , Karagas Margaret R. , Kelsey Karl T. , Wiencke John K.
Published: April 2023

Abstract
Background: The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a cytologic marker of both inflammation and poor outcomes in patients with cancer. DNA methylation is a key element of the epigenetic program defining different leukocyte subtypes and may provide an alternative to cytology in assessing leukocyte profiles. Our aim was to create a bioinformatic tool to estimate NLR using DNA methylation, and to assess its diagnostic and prognostic performance in human populations.

Methods: We developed a DNA methylation–derived NLR (mdNLR) index based on normal isolated leukocyte methylation libraries and established cell-mixture deconvolution algorithms. The method was applied to cancer case–control studies of the bladder, head and neck, ovary, and breast, as well as publicly available data on cancer-free subjects.

Results: Across cancer studies, mdNLR scores were either elevated in cases relative to controls, or associated with increased hazard of death. High mdNLR values (>5) were strong indicators of poor survival. In addition, mdNLR scores were elevated in males, in nonHispanic white versus Hispanic ethnicity, and increased with age. We also observed a significant interaction between cigarette smoking history and mdNLR on cancer survival.

Conclusions: These results mean that our current understanding of mature leukocyte methylomes is sufficient to allow researchers and clinicians to apply epigenetically based analyses of NLR in clinical and epidemiologic studies of cancer risk and survival.

Impact: As cytologic measurements of NLR are not always possible (i.e., archival blood), mdNLR, which is computed from DNA methylation signatures alone, has the potential to expand the scope of epigenome-wide association studies. Cancer Epidemiol Biomarkers Prev; 26(3); 328–38. ©2016 AACR.
Data from Impact of Pre-analytic Blood Sample Collection Factors on Metabolomics
Authors: Townsend Mary K. , Bao Ying , Poole Elizabeth M. , Bertrand Kimberly A. , Kraft Peter , Wolpin Brian M. , Clish Clary B. , Tworoger Shelley S.
Published: April 2023

Abstract
Background: Many epidemiologic studies are using metabolomics to discover markers of carcinogenesis. However, limited data are available on the influence of pre-analytic blood collection factors on metabolite measurement.

Methods: We quantified 166 metabolites in archived plasma from 423 Health Professionals Follow-up Study and Nurses' Health Study participants using liquid chromatography–tandem mass spectrometry (LC-MS). We compared multivariable-adjusted geometric mean metabolite LC-MS peak areas across fasting time, season of blood collection, and time of day of blood collection categories.

Results: The majority of metabolites (160 of 166 metabolites) had geometric mean peak areas that were within 15% comparing samples donated after fasting 9 to 12 versus ≥13 hours; greater differences were observed in samples donated after fasting ≤4 hours. Metabolite peak areas generally were similar across season of blood collection, although levels of certain metabolites (e.g., bile acids and purines/pyrimidines) tended to be different in the summer versus winter months. After adjusting for fasting status, geometric mean peak areas for bile acids and vitamins, but not other metabolites, differed by time of day of blood collection.

Conclusion: Fasting, season of blood collection, and time of day of blood collection were not important sources of variability in measurements of most metabolites in our study. However, considering blood collection variables in the design or analysis of studies may be important for certain specific metabolites, particularly bile acids, purines/pyrimidines, and vitamins.

Impact: These results may be useful for investigators formulating analysis plans for epidemiologic metabolomics studies, including determining which metabolites to a priori exclude from analyses. Cancer Epidemiol Biomarkers Prev; 25(5); 823–9. ©2016 AACR.
Data from What Predicts an Advanced-Stage Diagnosis of Breast Cancer? Sorting Out the Influence of Method of Detection, Access to Care, and Biologic Factors
Authors: Lipscomb Joseph , Fleming Steven T. , Trentham-Dietz Amy , Kimmick Gretchen , Wu Xiao-Cheng , Morris Cyllene R. , Zhang Kun , Smith Robert A. , Anderson Roger T. , Sabatino Susan A.
Published: April 2023

Abstract
Background: Multiple studies have yielded important findings regarding the determinants of an advanced-stage diagnosis of breast cancer. We seek to advance this line of inquiry through a broadened conceptual framework and accompanying statistical modeling strategy that recognize the dual importance of access-to-care and biologic factors on stage.

Methods: The Centers for Disease Control and Prevention–sponsored Breast and Prostate Cancer Data Quality and Patterns of Care Study yielded a seven-state, cancer registry–derived population-based sample of 9,142 women diagnosed with a first primary in situ or invasive breast cancer in 2004. The likelihood of advanced-stage cancer (American Joint Committee on Cancer IIIB, IIIC, or IV) was investigated through multivariable regression modeling, with base-case analyses using the method of instrumental variables (IV) to detect and correct for possible selection bias. The robustness of base-case findings was examined through extensive sensitivity analyses.

Results: Advanced-stage disease was negatively associated with detection by mammography (P < 0.001) and with age < 50 (P < 0.001), and positively related to black race (P = 0.07), not being privately insured [Medicaid (P = 0.01), Medicare (P = 0.04), uninsured (P = 0.07)], being single (P = 0.06), body mass index > 40 (P = 0.001), a HER2 type tumor (P < 0.001), and tumor grade not well differentiated (P < 0.001). This IV model detected and adjusted for significant selection effects associated with method of detection (P = 0.02). Sensitivity analyses generally supported these base-case results.

Conclusions: Through our comprehensive modeling strategy and sensitivity analyses, we provide new estimates of the magnitude and robustness of the determinants of advanced-stage breast cancer.

Impact: Statistical approaches frequently used to address observational data biases in treatment-outcome studies can be applied similarly in analyses of the determinants of stage at diagnosis. Cancer Epidemiol Biomarkers Prev; 25(4); 613–23. ©2016 AACR.
Data from Six Serum-Based miRNAs as Potential Diagnostic Biomarkers for Gastric Cancer
Authors: Huang Zebo , Zhu Danxia , Wu Lirong , He Mingfeng , Zhou Xin , Zhang Lan , Zhang Huo , Wang Weiwei , Zhu Jun , Cheng Wenfang , Chen Yan , Fan Yong , Qi Lianwen , Yin Yin , Zhu Wei , Shu Yongqian , Liu Ping
Published: April 2023

Abstract
Background: Circulating miRNAs in serum may serve as promising diagnostic biomarkers for patients with gastric cancer.

Methods: Using qRT-PCR-based Exiqon panel, we identified 58 differentially expressed miRNAs from three gastric cancer pool samples and one normal control (NC) pool in the initial screening phase. Identified miRNAs were further validated in the training (49 gastric cancer vs. 47 NCs) and validation phases (154 gastric cancer vs. 120 NCs) using qRT-PCR. The expression levels of the miRNAs were also determined in tissues, arterial serum, and exosomes.

Results: Consequently, six serum miRNAs (miR10b-5p, miR132-3p, miR185-5p, miR195-5p, miR-20a3p, and miR296-5p) were significantly overexpressed in gastric cancer compared with NCs. The areas under the receiver operating characteristic curve of the six-miRNA panel were 0.764 and 0.702 for the training and validation phases, respectively. miR10b-5p and miR296-5p were significantly upregulated in gastric cancer tissues (n = 188). In addition, patients who did not receive adjuvant chemotherapy with high expression of miR10b-5p or miR296-5p in tissues tended to suffer worse overall survival. Furthermore, the expression levels of miR10b-5p, miR195-5p, miR20a-3p, and miR296-5p were significantly elevated in exosomes from gastric cancer serum samples (n = 30).

Conclusions: We identified a six-miRNA panel in serum for the detection of gastric cancer.

Impact: Our findings provide a novel serum miRNA signature for gastric cancer diagnosis, and will serve as the basis of the application of circulating miRNAs in clinical for the detection of gastric cancer in the future. Cancer Epidemiol Biomarkers Prev; 26(2); 188–96. ©2016 AACR.
Data from Thyroid-Stimulating Hormone, Thyroid Hormones, and Risk of Papillary Thyroid Cancer: A Nested Case–Control Study
Authors: Huang Huang , Rusiecki Jennifer , Zhao Nan , Chen Yingtai , Ma Shuangge , Yu Herbert , Ward Mary H. , Udelsman Robert , Zhang Yawei
Published: April 2023

Abstract
Background: The effects of thyroid-stimulating hormone (TSH) and thyroid hormones on the development of human papillary thyroid cancer (PTC) remain poorly understood.

Methods: The study population consisted of 741 (341 women, 400 men) histologically confirmed PTC cases and 741 matched controls with prediagnostic serum samples stored in the Department of Defense Serum Repository. Concentrations of TSH, total T3, total T4, and free T4 were measured in serum samples. Conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI).

Results: The median time between blood draw and PTC diagnosis was 1,454 days. Compared with the middle tertile of TSH levels within the normal range, serum TSH levels below the normal range were associated with an elevated risk of PTC among women (OR, 3.74; 95% CI, 1.53–9.19) but not men. TSH levels above the normal range were associated with an increased risk of PTC among men (OR, 1.96; 95% CI, 1.04–3.66) but not women. The risk of PTC decreased with increasing TSH levels within the normal range among both men and women (Ptrend = 0.0005 and 0.041, respectively).

Conclusions: We found a significantly increased risk of PTC associated with TSH levels below the normal range among women and with TSH levels above the normal range among men. An inverse association between PTC and TSH levels within the normal range was observed among both men and women.

Impact: These results could have significant clinical implications for physicians who are managing patients with abnormal thyroid functions and those with thyroidectomy. Cancer Epidemiol Biomarkers Prev; 26(8); 1209–18. ©2017 AACR.
Data from Bias Explains Most of the Parent-of-Origin Effect on Breast Cancer Risk in BRCA1/2 Mutation Carriers
Authors: Vos Janet R. , Oosterwijk Jan C. , Aalfs Cora M. , Rookus Matti A. , Adank Muriel A. , van der Hout Annemarie H. , van Asperen Christi J. , Gómez Garcia Encarna B. , Mensenkamp Arjen R. , Jager Agnes , Ausems Margreet G.E.M. , Mourits Marian J. , de Bock Geertruida H.
Published: April 2023

Abstract
Background:Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias.

Methods: A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history.

Results: The mutation was of paternal origin in 330 (42%, P < 0.001) BRCA1 and 222 (42%, P < 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19–2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95–2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25–1.71) and 1.14 (95% CI, 0.42–3.15), respectively.

Conclusion: A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear.

Impact: There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251–8. ©2016 AACR.
Data from microRNA Biomarker Discovery and High-Throughput DNA Sequencing Are Possible Using Long-term Archived Serum Samples
Authors: Rounge Trine B. , Lauritzen Marianne , Langseth Hilde , Enerly Espen , Lyle Robert , Gislefoss Randi E.
Published: April 2023

Abstract
Background: The impacts of long-term storage and varying preanalytical factors on the quality and quantity of DNA and miRNA from archived serum have not been fully assessed. Preanalytical and analytical variations and degradation may introduce bias in representation of DNA and miRNA and may result in loss or corruption of quantitative data.

Methods: We have evaluated DNA and miRNA quantity, quality, and variability in samples stored up to 40 years using one of the oldest prospective serum collections in the world, the Janus Serumbank, a biorepository dedicated to cancer research.

Results: miRNAs are present and stable in archived serum samples frozen at −25°C for at least 40 years. Long-time storage did not reduce miRNA yields; however, varying preanalytical conditions had a significant effect and should be taken into consideration during project design. Of note, 500 μL serum yielded sufficient miRNA for qPCR and small RNA sequencing and on average 650 unique miRNAs were detected in samples from presumably healthy donors. Of note, 500 μL serum yielded sufficient DNA for whole-genome sequencing and subsequent SNP calling, giving a uniform representation of the genomes.

Conclusions: DNA and miRNA are stable during long-term storage, making large prospectively collected serum repositories an invaluable source for miRNA and DNA biomarker discovery.

Impact: Large-scale biomarker studies with long follow-up time are possible utilizing biorepositories with archived serum and state-of-the-art technology. Cancer Epidemiol Biomarkers Prev; 24(9); 1381–7. ©2015 AACR.
Data from A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer
Authors: Scarbrough Peter M. , Weber Rachel Palmieri , Iversen Edwin S. , Brhane Yonathan , Amos Christopher I. , Kraft Peter , Hung Rayjean J. , Sellers Thomas A. , Witte John S. , Pharoah Paul , Henderson Brian E. , Gruber Stephen B. , Hunter David J. , Garber Judy E. , Joshi Amit D. , McDonnell Kevin , Easton Doug F. , Eeles Ros , Kote-Jarai Zsofia , Muir Kenneth , Doherty Jennifer A. , Schildkraut Joellen M.
Published: April 2023

Abstract
Background: DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility.

Methods: We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling.

Results: We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10−6), MSH5 (P < 5.09 × 10−6), and BRCA2 (P = 5.70 × 10−6). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways.

Conclusions: Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways.

Impact: Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria. Cancer Epidemiol Biomarkers Prev; 25(1); 193–200. ©2015 AACR.
Data from Targeted, Deep Sequencing Reveals Full Methylation Profiles of Multiple HPV Types and Potential Biomarkers for Cervical Cancer Progression
Authors: Liu Pengyuan , Iden Marissa , Fye Samantha , Huang Yi-Wen , Hopp Elizabeth , Chu Chen , Lu Yan , Rader Janet S.
Published: April 2023

Abstract
Background: Invasive cervical cancer (ICC) and its premalignant phase (cervical intraepithelial neoplasia; CIN1-3) are distinguished by gynecologic and pathologic examination, yet no current methodologies can predict precancerous lesions that are destined to progress to ICC. Thus, development of reliable assays to assess patient prognosis is much needed.

Methods: Human papillomavirus (HPV) DNA methylation is significantly altered in cervical disease. Using an HPV enrichment approach and next-generation DNA sequencing, methylation status was characterized in a case–case comparison of CIN (n = 2 CIN1; n = 2 CIN2; n = 20 CIN3) and ICC (n = 37) samples. Pyrosequencing validated methylation changes at CpGs of interest in a larger sample cohort (n = 61 CIN3; 50 ICC).

Results: Global viral methylation, across HPV types, was significantly higher in ICC than CIN3. Average L1 gene methylation in 13 different HPV types best distinguished CIN3 from ICC. Methylation levels at individual CpG sites as a quantitative classifier achieved a sensitivity and specificity of >95% for detecting ICC in HPV 16 samples. Pyrosequencing confirmed significantly higher methylation of these CpGs in E1 of HPV 16 in ICC compared with CIN3.

Conclusions: Global HPV methylation is significantly higher in ICC than CIN3, with L1 gene methylation levels performing best for distinguishing CIN3 from ICC. Methylation levels at CpGs in the E1 gene of HPV 16 (972, 978, 1870, and 1958) can distinguish between CIN3 and ICC.

Impact: Higher methylation at specific E1 CpGs may associate with increased likelihood of progression to ICC in HPV 16–positive CIN3 lesions. Cancer Epidemiol Biomarkers Prev; 26(4); 642–50. ©2017 AACR.
Data from Young Adult and Usual Adult Body Mass Index and Multiple Myeloma Risk: A Pooled Analysis in the International Multiple Myeloma Consortium (IMMC)
Authors: Birmann Brenda M. , Andreotti Gabriella , De Roos Anneclaire J. , Camp Nicola J. , Chiu Brian C.H. , Spinelli John J. , Becker Nikolaus , Benhaim-Luzon Véronique , Bhatti Parveen , Boffetta Paolo , Brennan Paul , Brown Elizabeth E. , Cocco Pierluigi , Costas Laura , Cozen Wendy , de Sanjosé Silvia , Foretová Lenka , Giles Graham G. , Maynadié Marc , Moysich Kirsten , Nieters Alexandra , Staines Anthony , Tricot Guido , Weisenburger Dennis , Zhang Yawei , Baris Dalsu , Purdue Mark P.
Published: April 2023

Abstract
Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case–control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI.

Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls.

Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04–1.14; P = 0.007]. We observed significant heterogeneity by study design (P = 0.04), noting the BMI–multiple myeloma association only for population-based studies (Ptrend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m2; OR, 1.2; 95% CI, 1.1–1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI (Pinteraction <0.0001); we noted statistically significant associations with multiple myeloma for persons overweight (25–<30 kg/m2) or obese (30+ kg/m2) in both younger and usual adulthood (vs. individuals consistently <25 kg/m2), but not for those overweight or obese at only one time period.

Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood.

Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876–85. ©2017 AACR.
Data from Biomarker Discovery for Heterogeneous Diseases
Authors: Wallstrom Garrick , Anderson Karen S. , LaBaer Joshua
Published: April 2023

Abstract
Background: Modern genomic and proteomic studies reveal that many diseases are heterogeneous, comprising multiple different subtypes. The common notion that one biomarker can be predictive for all patients may need to be replaced by an understanding that each subtype has its own set of unique biomarkers, affecting how discovery studies are designed and analyzed.

Methods: We used Monte Carlo simulation to measure and compare the performance of eight selection methods with homogeneous and heterogeneous diseases using both single-stage and two-stage designs. We also applied the selection methods in an actual proteomic biomarker screening study of heterogeneous breast cancer cases.

Results: Different selection methods were optimal, and more than two-fold larger sample sizes were needed for heterogeneous diseases compared with homogeneous diseases. We also found that for larger studies, two-stage designs can achieve nearly the same statistical power as single-stage designs at significantly reduced cost.

Conclusions: We found that disease heterogeneity profoundly affected biomarker performance. We report sample size requirements and provide guidance on the design and analysis of biomarker discovery studies for both homogeneous and heterogeneous diseases.

Impact: We have shown that studies to identify biomarkers for the early detection of heterogeneous disease require different statistical selection methods and larger sample sizes than if the disease were homogeneous. These findings provide a methodologic platform for biomarker discovery of heterogeneous diseases. Cancer Epidemiol Biomarkers Prev; 22(5); 747–55. ©2013 AACR.
Data from Distinct Genetic and Epigenetic Signatures of Colorectal Cancers According to Ethnic Origin
Authors: Nieminen Taina T. , Shoman Soheir , Eissa Saad , Peltomäki Päivi , Abdel-Rahman Wael M.
Published: April 2023

Abstract
Background: The outcome of colorectal cancer varies depending on ethnic origin. Egyptian colorectal carcinoma is surprisingly young-age disease with high proportion of rectal and advanced stage cancers.

Methods: We characterized 69 sporadic Egyptian colorectal cancers for promoter methylation at 24 tumor suppressor genes, microsatellite instability, and expression of mismatch repair, p53, and β-catenin proteins. Data were compared with 80 Western colorectal carcinoma of sporadic and familial origin from Finland.

Results: Egyptian colorectal carcinomas showed significantly higher methylation of the microsatellite stable (MSS) tumors as reflected by the average number of methylated genes per case (P = 0.00002) and tumor suppressor gene methylator phenotype (TSGMP), defined here as methylation of ≥5 genes, (P = 0.0001) compared with the sporadic Western cancers. The TSGMP was associated with advanced stage in the Egyptian cancers (P = 0.0016). Four genes were differentially methylated between Egyptian and Western cases, of which the association of CDKN2B/p15 methylation with Egyptian origin was outstanding (P = 4.83E-10). Egyptian carcinoma also showed significantly lower frequency of nuclear β-catenin localization than the sporadic Western cancers (P = 0.00006) but similar to that of the familial Western subset designated as familial colorectal cancer type X.

Conclusions: We show novel pathway in colon carcinogenesis marked by high methylation of MSS cancers, remarkable CDKN2B/p15 methylation, and low frequency of Wnt signaling activation.

Impact: Our findings highlight the possible effect of environmental exposures in carcinogenesis through DNA methylation and should have applications in prevention, molecular diagnosis, prognosis, and treatment. Cancer Epidemiol Biomarkers Prev; 21(1); 202–11. ©2011 AACR.
Data from Factors Associated with False Positive Results on Screening Mammography in a Population of Predominantly Hispanic Women
Authors: McGuinness Julia E. , Ueng William , Trivedi Meghna S. , Yi Hae Seung , David Raven , Vanegas Alejandro , Vargas Jennifer , Sandoval Rossy , Kukafka Rita , Crew Katherine D.
Published: April 2023

Abstract
Background: Potential harms of screening mammography include false positive results, such as recall breast imaging or biopsies.

Methods: We recruited women undergoing screening mammography at Columbia University Medical Center in New York, New York. They completed a questionnaire on breast cancer risk factors and permitted access to their medical records. Breast cancer risk status was determined using the Gail model and a family history screener. High risk was defined as a 5-year invasive breast cancer risk of ≥1.67% or eligible for BRCA genetic testing. False positive results were defined as recall breast imaging (BIRADS score of 0, 3, 4, or 5) and/or biopsies that did not yield breast cancer.

Results: From November 2014 to October 2015, 2,361 women were enrolled and 2,019 were evaluable, of whom 76% were Hispanic and 10% non-Hispanic white. Fewer Hispanic women met high-risk criteria for breast cancer than non-Hispanic whites (18.0% vs. 68.1%), but Hispanics more frequently engaged in annual screening (71.9% vs. 60.8%). Higher breast density (heterogeneously/extremely dense vs. mostly fat/scattered fibroglandular densities) and more frequent screening (annual vs. biennial) were significantly associated with false positive results [odds ratio (OR), 1.64; 95% confidence interval (CI), 1.32–2.04 and OR, 2.18; 95% CI, 1.70–2.80, respectively].

Conclusions: We observed that women who screened more frequently or had higher breast density were at greater risk for false positive results. In addition, Hispanic women were screening more frequently despite having a lower risk of breast cancer compared with whites.

Impact: Our results highlight the need for risk-stratified screening to potentially minimize the harms of screening mammography. Cancer Epidemiol Biomarkers Prev; 27(4); 446–53. ©2018 AACR.
Data from Contributions of Subtypes of Non-Hodgkin Lymphoma to Mortality Trends
Authors: Howlader Nadia , Morton Lindsay M. , Feuer Eric J. , Besson Caroline , Engels Eric A.
Published: April 2023

Abstract
Background: Non-Hodgkin lymphoma (NHL) comprises distinct tumor subtypes. Although mortality from NHL overall has changed dramatically in the United States over time, little is known about trends for subtypes, because death certificates do not record this information.

Methods: Using data from U.S. Surveillance, Epidemiology, and End Results (SEER) areas, we assessed NHL mortality rates and mapped NHL deaths to incident NHL cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific NHL subtypes (incidence-based mortality; IBM). We also describe NHL incidence and survival after NHL diagnosis by calendar year. We used Joinpoint to identify years when IBM and incidence rate trends changed slope.

Results: Overall NHL mortality rates increased during 1975–1997, peaking at 10.9 per 100,000 person-years, then decreased subsequently in 1997–2011. Overall IBM rates mirror this trend during 1990–2011. For B-cell NHL subtypes, IBM rates decreased beginning in the mid-1990s, with yearly declines of −3.0% for diffuse large B-cell lymphoma (DLBCL), −2.7% for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and −5.3% for follicular lymphoma. Incidence rates for these subtypes did not decrease until after 2003. Corresponding 5-year cancer-specific survival increased dramatically over time for DLBCL (from 37%–66%), CLL/SLL (69%–84%), and follicular lymphoma (69%–82%). IBM for peripheral T-cell lymphoma was flat during 2006–2011, although incidence increased.

Conclusions: Mortality due to three common B-cell NHL subtypes has fallen over time in the United States.

Impact: This decline reflects better survival after NHL diagnosis, likely from improved therapies, because the decline in NHL incidence occurred later. Cancer Epidemiol Biomarkers Prev; 25(1); 174–9. ©2015 AACR.
Data from CpG Site–Specific Hypermethylation of p16INK4α in Peripheral Blood Lymphocytes of PAH-Exposed Workers
Authors: Yang Ping , Ma Junxiang , Zhang Bo , Duan Huawei , He Zhini , Zeng Junling , Zeng Xiaowen , Li Daochuan , Wang Qing , Xiao Yongmei , Liu Caixia , Xiao Qin , Chen Liping , Zhu Xiaonian , Xing Xiumei , Li Zhifang , Zhang Shixin , Zhang Zhengbao , Ma Lu , Wang Erman , Zhuang Zhixiong , Zheng Yuxin , Chen Wen
Published: April 2023

Abstract
Background: Sufficient epidemiologic evidence shows an etiologic link between polycyclic aromatic hydrocarbons (PAH) exposure and lung cancer risk. While the genetic modifications have been found in PAH-exposed population, it is unclear whether gene-specific methylation involves in the process of PAH-associated biologic consequence.

Methods: Sixty-nine PAH-exposed workers and 59 control subjects were recruited. Using bisulfite sequencing, we examined the methylation status of p16INK4α promoter in peripheral blood lymphocytes (PBL) from PAH-exposed workers and in benzo(a)pyrene (BaP)-transformed human bronchial epithelial (HBE) cells. The relationships between p16INK4α methylation and the level of urinary 1-hydroxypyrene (1-OHP) or the frequency of cytokinesis block micronucleus (CBMN) were analyzed.

Results: Compared with the control group, PAH-exposed workers exhibited higher levels of urinary 1-OHP (10.62 vs. 2.52 μg/L), p16INK4α methylation (7.95% vs. 1.14% for 22 “hot” CpG sites), and CBMN (7.28% vs. 2.92%) in PBLs. p16INK4α hypermethylation in PAH-exposed workers exhibited CpG site specificity. Among the 35 CpG sites we analyzed, 22 were significantly hypermethylated. These 22 hypermethylated CpG sites were positively correlated to levels of urinary 1-OHP and CBMN in PBLs. Moreover, the hypermethylation and suppression of p16 expression was also found in BaP-transformed HBER cells.

Conclusion: PAH exposure induced CpG site–specific hypermethylation of p16INK4α gene. The degree of p16INK4α methylation was associated with the levels of DNA damage and internal exposure.

Impact:p16INK4α hypermethylation might be an essential biomarker for the exposure to PAHs and for early diagnosis of cancer. Cancer Epidemiol Biomarkers Prev; 21(1); 182–90. ©2011 AACR.
Data from Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment
Authors: Masson-Lecomte Alexandra , López de Maturana Evangelina , Goddard Michael E. , Picornell Antoni , Rava Marta , González-Neira Anna , Márquez Mirari , Carrato Alfredo , Tardon Adonina , Lloreta Josep , Garcia-Closas Montserrat , Silverman Debra , Rothman Nathaniel , Kogevinas Manolis , Allory Yves , Chanock Stephen J. , Real Francisco X. , Malats Núria
Published: April 2023

Abstract
Background: Increasing evidence points to the role of tumor immunologic environment on urothelial bladder cancer prognosis. This effect might be partly dependent on the host genetic context. We evaluated the association of SNPs in inflammation-related genes with non–muscle-invasive bladder cancer (NMIBC) risk-of-recurrence and risk-of-progression.

Methods: We considered 822 NMIBC included in the SBC/EPICURO Study followed-up >10 years. We selected 1,679 SNPs belonging to 251 inflammatory genes. The association of SNPs with risk-of-recurrence and risk-of-progression was assessed using Cox regression single-marker (SMM) and multimarker methods (MMM) Bayes A and Bayesian LASSO. Discriminative abilities of the models were calculated using the c index and validated with bootstrap cross-validation procedures.

Results: While no SNP was found to be associated with risk-of-recurrence using SMM, three SNPs in TNIP1, CD5, and JAK3 showed very strong association with posterior probabilities >90% using MMM. Regarding risk-of-progression, one SNP in CD3G was significantly associated using SMM (HR, 2.69; P = 1.55 × 10−5) and two SNPs in MASP1 and AIRE, showed a posterior probability ≥80% with MMM. Validated discriminative abilities of the models without and with the SNPs were 58.4% versus 60.5% and 72.1% versus 72.8% for risk-of-recurrence and risk-of-progression, respectively.

Conclusions: Using innovative analytic approaches, we demonstrated that SNPs in inflammatory-related genes were associated with NMIBC prognosis and that they improve the discriminative ability of prognostic clinical models for NMIBC.

Impact: This study provides proof of concept for the joint effect of genetic variants in improving the discriminative ability of clinical prognostic models. The approach may be extended to other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1144–50. ©2016 AACR.
Data from Time to Colonoscopy after Positive Fecal Blood Test in Four U.S. Health Care Systems
Authors: Chubak Jessica , Garcia Michael P. , Burnett-Hartman Andrea N. , Zheng Yingye , Corley Douglas A. , Halm Ethan A. , Singal Amit G. , Klabunde Carrie N. , Doubeni Chyke A. , Kamineni Aruna , Levin Theodore R. , Schottinger Joanne E. , Green Beverly B. , Quinn Virginia P. , Rutter Carolyn M.
Published: April 2023

Abstract
Background: To reduce colorectal cancer mortality, positive fecal blood tests must be followed by colonoscopy.

Methods: We identified 62,384 individuals ages 50 to 89 years with a positive fecal blood test between January 1, 2011 and December 31, 2012 in four health care systems within the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. We estimated the probability of follow-up colonoscopy and 95% confidence intervals (CI) using the Kaplan–Meier method. Overall differences in cumulative incidence of follow-up across health care systems were assessed with the log-rank test. HRs and 95% CIs were estimated from multivariate Cox proportional hazards models.

Results: Most patients who received a colonoscopy did so within 6 months of their positive fecal blood test, although follow-up rates varied across health care systems (P <0.001). Median days to colonoscopy ranged from 41 (95% CI, 40–41) to 174 (95% CI, 123–343); percent followed-up by 12 months ranged from 58.1% (95% CI, 51.6%–63.7%) to 83.8% (95% CI, 83.4%–84.3%) and differences across health care systems were also observed at 1, 2, 3, and 6 months. Increasing age and comorbidity score were associated with lower follow-up rates.

Conclusion: Individual characteristics and health care system were associated with colonoscopy after positive fecal blood tests. Patterns were consistent across health care systems, but proportions of patients receiving follow-up varied. These findings suggest that there is room to improve follow-up of positive colorectal cancer screening tests.

Impact: Understanding the timing of colonoscopy after positive fecal blood tests and characteristics associated with lack of follow-up may inform future efforts to improve follow-up. Cancer Epidemiol Biomarkers Prev; 25(2); 344–50. ©2016 AACR.