bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Activation of YAP1 by N6-Methyladenosine–Modified circCPSF6 Drives Malignancy in Hepatocellular Carcinoma
Authors: Chen Yunhao , Ling Zhenan , Cai Xianlei , Xu Yongfang , Lv Zhen , Man Da , Ge Jiangzhen , Yu Chengkuan , Zhang Deguo , Zhang Yanpeng , Xie Haiyang , Zhou Lin , Wu Jian , Zheng Shusen
Published: March 2023

Abstract
Circular RNAs (circRNA) and N6-methyladenosine (m6A) modification are extensively involved in the progression of diverse tumors, including hepatocellular carcinoma (HCC). However, the cross-talk between circRNAs and m6A remains elusive in the pathogenesis of HCC. Here we investigated m6A-mediated regulation of circRNAs in HCC. m6A-related circRNAs were identified by integrating information from two published studies, revealing circular cleavage and polyadenylation specific factor 6 (circCPSF6) as a novel m6A-modified circRNA. circCPSF6 was dominated by ALKBH5-mediated demethylation, followed by the recognization and destabilization by YTHDF2. Meanwhile, circCPSF6 was upregulated in HCC specimens, and elevated circCPSF6 expression served as an independent prognostic factor for worse survival of patients with HCC. Loss-of-function assays demonstrated that circCPSF6 maintained cell proliferation and tumorigenicity and reinforced cell motility and tumor metastasis. circCPSF6 triggered expression of YAP1, further activating its downstream cascade. Mechanistically, circCPSF6 competitively bound PCBP2, blunting its binding to YAP1 mRNA, thereby sustaining the stability of YAP1. Functionally, removal of YAP1 reversed the effects of circCPSF6 in vitro and in vivo. Aberrant activation of the circCPSF6-YAP1 axis promoted HCC malignancy. These findings offer novel insights into the regulation of circRNAs by m6A modifications and the role of this epigenetic reprogramming in HCC.
Significance:
This study advances the understanding of the interplay between m6A methylation and circRNAs in hepatocellular carcinoma, highlighting the potential of circCPSF6 as a therapeutic target.
Data from Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers
Authors: Liao Chengheng , Glodowski Cherise Ryan , Fan Cheng , Liu Juan , Mott Kevin R. , Kaushik Akash , Vu Hieu , Locasale Jason W. , McBrayer Samuel K. , DeBerardinis Ralph J. , Perou Charles M. , Zhang Qing
Published: March 2023

Abstract
Metabolic dysregulation is a prominent feature in breast cancer, but it remains poorly characterized in patient tumors. In this study, untargeted metabolomics analysis of triple-negative breast cancer (TNBC) and patient with estrogen receptor (ER)–positive breast cancer samples, as well as TNBC patient-derived xenografts (PDX), revealed two major metabolic groups independent of breast cancer histologic subtypes: a “Nucleotide/Carbohydrate-Enriched” group and a “Lipid/Fatty Acid-Enriched” group. Cell lines grown in vivo more faithfully recapitulated the metabolic profiles of patient tumors compared with those grown in vitro. Integrated metabolic and gene expression analyses identified genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof of principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell lines or PDX xenografts with a pyrimidine biosynthesis inhibitor or a glutaminase inhibitor led to therapeutic efficacy. In multiple in vivo models of TNBC, treatment with the pyrimidine biosynthesis inhibitor conferred better therapeutic outcomes than chemotherapeutic agents. This study provides a metabolic stratification of breast tumor samples that can guide the selection of effective therapeutic strategies targeting breast cancer subsets. In addition, we have developed a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study to facilitate future research.
Significance:
A multiomics strategy that integrates metabolic and gene expression profiling in patient tumor samples and animal models identifies effective pharmacologic approaches to target rapidly proliferating breast tumor subtypes.
Data from Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer
Authors: Wei Ruozheng , Zhou Yuning , Li Chang , Rychahou Piotr , Zhang Shulin , Titlow William B. , Bauman Greg , Wu Yuanyuan , Liu Jinpeng , Wang Chi , Weiss Heidi L. , Evers B. Mark , Wang Qingding
Published: March 2023

Abstract
The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression.
Significance:
This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival.

See related commentary by Montrose and Galluzzi, p. 1464
Data from HSP90 Mediates IFNγ-Induced Adaptive Resistance to Anti-PD-1 Immunotherapy
Authors: Liu Ke , Huang Jun , Liu Jiao , Li Changfeng , Kroemer Guido , Tang Daolin , Kang Rui
Published: March 2023

Abstract
Constitutive or acquired resistance is a major problem limiting the clinical success of anticancer immunotherapies targeting the PD-1/PD-L1 interaction. Here, we report that the molecular chaperone HSP90 is a key mediator of IFNγ-induced adaptive immune resistance. An unbiased screen of 17 cancer cell lines or primary cancer cells identified novel metabolic agents, especially HSP90 inhibitors, that blocked the upregulation of immune checkpoints (IDO1 and PD-L1) induced by IFNγ. Subsequent quantitative mass spectrometry combined with functional rescue analysis revealed that IFNγ-induced immune checkpoint expression requires increased protein stability of the transcription factor STAT1, mediated by the HSP90–SUGT1 chaperone complex. Expression of dominant-negative HSP90 (D88N) resulted in inhibition of STAT1-mediated IFNγ signaling. The upregulation of IDO1 in cancer cells acted as an immunosuppressive feedback mechanism to limit the proliferation and function of cytotoxic CD8+ T lymphocytes through iron-dependent kynurenine production and subsequent TSPAN5-mediated kynurenine secretion. The effectiveness and safety of combinations of anti-PD-1 immunotherapy with iron chelation or pharmacologic inhibitors of HSP90 or IDO1 was confirmed in xenograft, orthotopic, and transgenic mouse models of pancreatic cancer. These findings support the rationale for future clinical trials in which widely used immunotherapies are combined with additional molecules that intercept resistance by iron chelation, IDO1 inhibition, or HSP90 neutralization.
Significance:
This study reveals an HSP90-centric, iron-modulated mechanism that confers immunosuppression, offering potential therapeutic targets for interfering with acquired resistance to the most prevalent anticancer immunotherapies.
Data from Proteomic Mapping and Targeting of Mitotic Pericentriolar Material in Tumors Bearing Centrosome Amplification
Authors: Xie Bingteng , Pu Yang , Yang Fan , Chen Wei , Yue Wei , Ma Jihong , Zhang Na , Jiang Yuening , Wu Jiegen , Lin Yihan , Liang Xin , Wang Chu , Zou Peng , Li Mo
Published: March 2023

Abstract
Recent work has made it clear that pericentriolar material (PCM), the matrix of proteins surrounding centrioles, contributes to most functions of centrosomes. Given the occurrence of centrosome amplification in most solid tumors and the unconventional survival of these tumor cells, it is tempting to hypothesize that gel-like mitotic PCM would cluster extra centrosomes to defend against mitotic errors and increase tumor cell survival. However, because PCM lacks an encompassing membrane, is highly dynamic, and is physically connected to centrioles, few methods can decode the components of this microscale matrix. In this study, we took advantage of differential labeling between two sets of APEX2-centrosome reactions to design a strategy for acquiring the PCM proteome in living undisturbed cells without synchronization treatment, which identified 392 PCM proteins. Localization of ubiquitination promotion proteins away from PCM was a predominant mechanism to maintain the large size of PCM for centrosome clustering during mitosis in cancer cells. Depletion of PCM gene kinesin family member 20A (KIF20A) caused centrosome clustering failure and apoptosis in cancer cells in vitro and in vivo. Thus, our study suggests a strategy for targeting a wide range of tumors exhibiting centrosome amplification and provides a proteomic resource for future mining of PCM proteins.
Significance:
This study identifies the proteome of pericentriolar material and reveals therapeutic vulnerabilities in tumors bearing centrosome amplification.
Data from TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance
Authors: Li Yongxu , Wang Tiepeng , Wan Quan , Wang Qing , Chen Zhenzhong , Gao Yuan , Ye Yuchen , Lin Jiusheng , Zhao Bihuan , Wang Huaile , Yang Jinming , Zhao Kai , Lu Na
Published: March 2023

Abstract
Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes.
Significance:
The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.
Supplementary Figure 6 from Collaborative Cancer Epidemiology in the 21st Century: The Model of Cancer Consortia
Authors: Burgio Michael R. , Ioannidis John P.A. , Kaminski Brett M. , DeRycke Eric , Rogers Scott , Khoury Muin J. , Seminara Daniela
Published: April 2023

PDF - 27KB, Percentage of CEC associated papers by scientific area.
Supplementary Figures and tables from Circulating Cancer-Associated Macrophage-Like Cells Differentiate Malignant Breast Cancer and Benign Breast Conditions
Authors: Adams Daniel L. , Adams Diane K. , Alpaugh R. Katherine , Cristofanilli Massimo , Martin Stuart S. , Chumsri Saranya , Tang Cha-Mei , Marks Jeffrey R.
Published: April 2023

Supplementary Figure 1. Enumeration of CTC subtypes from Study A and Study B. Supplementary Figure 2. CAML enumeration from blood samples taken pre or post biopsy. Supplementary Figure 2. CAML enumeration from blood samples taken pre or post biopsy. Supplementary Figure 2. CAML enumeration from blood samples taken pre or post biopsy. Supplementary Figure 2. CAML enumeration from blood samples taken pre or post biopsy.
Supplementary Figure 2 from Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications
Authors: Sampson Joshua N. , Boca Simina M. , Shu Xiao Ou , Stolzenberg-Solomon Rachael Z. , Matthews Charles E. , Hsing Ann W. , Tan Yu Ting , Ji Bu-Tian , Chow Wong-Ho , Cai Qiuyin , Liu Da Ke , Yang Gong , Xiang Yong Bing , Zheng Wei , Sinha Rashmi , Cross Amanda J. , Moore Steven C.
Published: April 2023

PDF file - 16K, The correlation of the (BIV) measured from PLCO and SPA.
Supplementary Figure 34 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

PDF file - 91K
Supplementary Table 2 from Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility
Authors: FitzGerald Liesel M. , Kumar Akash , Boyle Evan A. , Zhang Yuzheng , McIntosh Laura M. , Kolb Suzanne , Stott-Miller Marni , Smith Tiffany , Karyadi Danielle M. , Ostrander Elaine A. , Hsu Li , Shendure Jay , Stanford Janet L.
Published: April 2023

PDF - 61K, Information on the 22 insertion/deletions identified by whole-exome sequencing.
Supplementary Tables 1 - 3 from Serum Levels of the Chemokine CXCL13, Genetic Variation in CXCL13 and Its Receptor CXCR5, and HIV-Associated Non-Hodgkin B-Cell Lymphoma Risk
Authors: Hussain Shehnaz K. , Zhu Weiming , Chang Shen-Chih , Breen Elizabeth Crabb , Vendrame Elena , Magpantay Larry , Widney Dan , Conn Daniel , Sehl Mary , Jacobson Lisa P. , Bream Jay H. , Wolinsky Steven , Rinaldo Charles R. , Ambinder Richard F. , Detels Roger , Zhang Zuo-Feng , Martínez-Maza Otoniel
Published: April 2023

PDF file - 106K, Spearman's correlation coefficients calculated for each time-window, separately in cases and controls; Association Between CXCL13 and CXCR5 tagSNPs and CXCL13 Serum Levels; Association between CXCL13 serum levels and HIV-associated non-Hodgkin lymphoma risk at three time-windows, stratified by SNP genotypes.
Supplementary Figure 1 from Biomarker Discovery for Heterogeneous Diseases
Authors: Wallstrom Garrick , Anderson Karen S. , LaBaer Joshua
Published: April 2023

PDF file - 5559K, Figure S1. Estimated power for the first stage of a two-stage design with normal samples for a (a) homogeneous disease and (b) heterogeneous disease.
Supplementary Figure S2 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

Supplementary Figure S2. Distribution of mean Î”Î² for each experimental condition by normalization: (a) DASEN and (a) minfi-Illumina. Normal distribution of mean Î”Î² peaked approximately at 0 for DASEN and <0 for minfi-Illumina.
Data from Blood Vitamin D Levels in Relation to Genetic Estimation of African Ancestry
Authors: Signorello Lisa B. , Williams Scott M. , Zheng Wei , Smith Jeffrey R. , Long Jirong , Cai Qiuyin , Hargreaves Margaret K. , Hollis Bruce W. , Blot William J.
Published: March 2023

Abstract
Background: African-Americans generally have lower circulating levels of 25 hydroxyvitamin D [25(OH)D] than Whites, attributed to skin pigmentation and dietary habits. Little is known about the genetic determinants of 25(OH)D levels nor whether the degree of African ancestry associates with circulating 25(OH)D.

Methods: With the use of a panel of 276 ancestry informative genetic markers, we estimated African and European admixture for a sample of 758 African-American and non-Hispanic White Southern Community Cohort Study participants. For African-Americans, cut points of <85%, 85% to 95%, and ≥95% defined low, medium, and high African ancestry, respectively. We estimated the association between African ancestry and 25(OH)D and also explored whether vitamin D exposure (sunlight, diet) had varying effects on 25(OH)D levels dependent on ancestry level.

Results: The mean serum 25(OH)D levels among Whites and among African-Americans of low, medium, and high African ancestry were 27.2, 19.5, 18.3, and 16.5 ng/mL, respectively. Serum 25(OH)D was estimated to decrease by 1.0 to 1.1 ng/mL per 10% increase in African ancestry. The effect of high vitamin D exposure from sunlight and diet was 46% lower among African-Americans with high African ancestry than among those with low/medium ancestry.

Conclusions: We found novel evidence that the level of African ancestry may play a role in clinical vitamin D status.

Impact: This is the first study to describe how 25(OH)D levels vary in relation to genetic estimation of African ancestry. Further study is warranted to replicate these findings and uncover the potential pathways involved. Cancer Epidemiol Biomarkers Prev; 19(9); 2325–31. ©2010 AACR.
Data from National Trends and Disparities in Cervical Cancer Screening among Commercially Insured Women, 2001–2010
Authors: Wharam J. Frank , Zhang Fang , Xu Xin , Landon Bruce E. , Ross-Degnan Dennis
Published: March 2023

Abstract
Background: Previous surveys reported declining cervical cancer screening rates from 2000 to 2010, but trends by key demographic and age groups are less clear.

Methods: We examined 3-year Papanicolaou (Pap) test rates among 4.2 million women enrolled in a large national health plan during 2001 to 2010. We calculated and plotted adjusted 3-year rates stratified by age and key neighborhood-level socioeconomic characteristics including poverty level and race/ethnicity (white, black, Hispanic, and mixed ethnicity neighborhood). We fitted trends in 2001–2010 screening rates and socioeconomic disparities as annual percentage changes (APC) using joinpoint analysis.

Results: Women ages 21 to 29 years had estimated 3-year Pap testing rates of 81.3% to 81.4% over the decade. Estimated disparities by low–high poverty level were 3.1% and 2.0% in 2001–2003 and 2008–2010, respectively, a nonsignificant decline. Initial white–black disparities were 4.0% and declined significantly from 2005–2007 to 2008–2010 to 2.8% at an APC of −0.65% (P = 0.021). White–Hispanic disparities declined from 4.3% to 0.8% over the decade, a −0.50% APC (P = 0.024). Among women ages 30 to 64 years, estimated 3-year Pap testing rates trended down from 76.1% to 71.8% over the decade [−0.94% APC (P < 0.001) until 2005–2007]. This pattern was similar among women from most categories of poverty and race/ethnicity.

Conclusions: Among commercially insured women ages 21 to 29 years, 3-year Pap testing rates remained stable at 81% over the decade; disparities were small and improved for Hispanic women to a greater degree than for black women. Among women ages 30 to 64 years, 3-year Pap testing rates declined from 2001 to 2010.

Impact: Cervical cancer screening should be promoted to achieve Healthy People 2020 goals. Cancer Epidemiol Biomarkers Prev; 23(11); 2366–73. ©2014 AACR.
Data from Gene–Environment Interaction Involving Recently Identified Colorectal Cancer Susceptibility Loci
Authors: Kantor Elizabeth D. , Hutter Carolyn M. , Minnier Jessica , Berndt Sonja I. , Brenner Hermann , Caan Bette J. , Campbell Peter T. , Carlson Christopher S. , Casey Graham , Chan Andrew T. , Chang-Claude Jenny , Chanock Stephen J. , Cotterchio Michelle , Du Mengmeng , Duggan David , Fuchs Charles S. , Giovannucci Edward L. , Gong Jian , Harrison Tabitha A. , Hayes Richard B. , Henderson Brian E. , Hoffmeister Michael , Hopper John L. , Jenkins Mark A. , Jiao Shuo , Kolonel Laurence N. , Le Marchand Loic , Lemire Mathieu , Ma Jing , Newcomb Polly A. , Ochs-Balcom Heather M. , Pflugeisen Bethann M. , Potter John D. , Rudolph Anja , Schoen Robert E. , Seminara Daniela , Slattery Martha L. , Stelling Deanna L. , Thomas Fridtjof , Thornquist Mark , Ulrich Cornelia M. , Warnick Greg S. , Zanke Brent W. , Peters Ulrike , Hsu Li , White Emily
Published: March 2023

Abstract
Background: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene–environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279.

Methods: Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons.

Results: None of the permutation-adjusted P values reached statistical significance.

Conclusions: The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors.

Impact: Results suggest no evidence of strong gene–environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time. Cancer Epidemiol Biomarkers Prev; 23(9); 1824–33. ©2014 AACR.
Data from Increased Lung and Bladder Cancer Incidence in Adults after In Utero and Early-Life Arsenic Exposure
Authors: Steinmaus Craig , Ferreccio Catterina , Acevedo Johanna , Yuan Yan , Liaw Jane , Durán Viviana , Cuevas Susana , García José , Meza Rodrigo , Valdés Rodrigo , Valdés Gustavo , Benítez Hugo , VanderLinde Vania , Villagra Vania , Cantor Kenneth P. , Moore Lee E. , Perez Saida G. , Steinmaus Scott , Smith Allan H.
Published: March 2023

Abstract
Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer.

Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls.

Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110, 110 to 800, and >800 μg/L were 1.00, 1.88 [95% confidence interval (CI), 0.96–3.71], and 5.24 (3.05–9.00; Ptrend < 0.001) for lung cancer, and 1.00, 2.94 (1.29–6.70), and 8.11 (4.31–15.25; Ptrend < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed.

Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure.

Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease. Cancer Epidemiol Biomarkers Prev; 23(8); 1529–38. ©2014 AACR.
Data from Genetic Variants of Toll-Like Receptor 2 and 5, Helicobacter Pylori Infection, and Risk of Gastric Cancer and Its Precursors in a Chinese Population
Authors: Zeng Hong-Mei , Pan Kai-Feng , Zhang Yang , Zhang Lian , Ma Jun-Ling , Zhou Tong , Su Hui-Juan , Li Wen-Qing , Li Ji-You , Gerhard Markus , Classen Meinhard , You Wei-Cheng
Published: March 2023

Abstract
Background: Genetic polymorphisms of Toll-like receptors (TLR) may influence the outcome of Helicobacter pylori infection and play important roles in gastric carcinogenesis. To screen the genetic variants of TLR2 and TLR5, and evaluate their associations with gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, Shandong Province, China.

Methods: Genetic variants were identified by PCR-based denaturing high-performance liquid chromatography and PCR-restriction fragment length polymorphism analysis in 248 GC cases, 846 subjects with advanced gastric lesions including 350 dysplasia and 496 intestinal metaplasia, and 496 superficial gastritis/mild chronic atrophic gastritis controls.

Results: Nine allelic variants each were detected within the promoter and exons of TLR2 and TLR5. Among those, TLR2 c. −196 to −174 del carriers (ins/del+del/del) showed a significantly decreased risk of GC (adjusted OR, 0.66; 95% CI: 0.48–0.90), whereas TLR5 rs5744174 C carriers (TC+CC) had an increased risk of GC (OR, 1.43; 95% CI: 1.03–1.97). Further analysis indicated an elevated risk of GC in subjects with the TLR5 rs5744174 TC+CC genotype and H. pylori infection (OR, 3.35; 95% CI: 2.13–5.26), and a significant interaction between rs5744174 and H. pylori infection was observed (OR, 2.15; 95% CI: 1.12–4.16).

Conclusion: These findings suggest that TLR2 c. −196 to −174 ins > del, TLR5 rs5744174 and interaction between rs5744174 and H. pylori infection were associated with the development of GC.

Impact:TLR2 and TLR5 polymorphisms may play important roles in the process of H. pylori-related gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 20(12); 2594–602. ©2011 AACR.
Data from Replication of Breast Cancer GWAS Susceptibility Loci in the Women's Health Initiative African American SHARe Study
Authors: Hutter Carolyn M. , Young Alicia M. , Ochs-Balcom Heather M. , Carty Cara L. , Wang Tao , Chen Christina T.L. , Rohan Thomas E. , Kooperberg Charles , Peters Ulrike
Published: March 2023

Abstract
Background: Genome-wide association studies (GWAS) have identified loci associated with risk of breast cancer. These studies have primarily been conducted in populations of European descent. To fully understand the impact of these loci, it is important to study groups with other genetic ancestries, including African American women.

Methods: We examined 22 single-nucleotide polymorphisms (SNP), previously identified in GWAS of breast cancer risk in European and Asian descent women (index SNPs), and SNPs in the surrounding regions in a study of 7,800 African American women (including 316 women with incident invasive breast cancer) from the Women's Health Initiative SNP Health Association Resource.

Results: Two index SNPs were associated with breast cancer: rs3803662 at 16q12.2/TOX3 (Hazard ratio [HR] for the T allele = 0.79, 95% CI: 0.67–0.92, P = 0.003) and rs10941679 at 5p12 (HR for the G allele = 1.31, 95% CI: 1.06–1.63, P = 0.014). When we expanded to regions, the 3p24.1 region showed an association with breast cancer risk (permutation based P = 0.027) and three regions (10p15.1, 10q26.13/FGFR2, and 16q12.2/TOX3) showed a trend toward association.

Conclusion: Our findings provide evidence that some breast cancer GWAS regions may be associated with breast cancer in African American women. Larger, more comprehensive studies are needed to fully assess generalizability of published GWAS findings and to identify potential novel associations in African American populations.

Impact: Both replication and lack of replication of published GWAS findings in other ancestral groups provides important information of the genetic etiology of this disease and may impact translation of GWAS findings to clinical and public health settings. Cancer Epidemiol Biomarkers Prev; 20(9); 1950–9. ©2011 AACR.
Data from Fecal MicroRNAs as Novel Biomarkers for Colon Cancer Screening
Authors: Link Alexander , Balaguer Francesc , Shen Yan , Nagasaka Takeshi , Lozano Juan José , Boland C. Richard , Goel Ajay
Published: March 2023

Abstract
Introduction: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, but currently available noninvasive screening programs have achieved only a modest decrease in mortality. MicroRNAs (miRNA) play an important role in a wide array of biological processes and are commonly dysregulated in neoplasia. We aimed to evaluate the feasibility of fecal miRNAs as biomarkers for colorectal neoplasia screening.

Materials and Methods: Total RNA was extracted from freshly collected stool samples from 8 healthy volunteers and 29 samples collected via fecal occult blood testing from subjects with normal colonoscopies, colon adenomas, and CRCs. miRNA expression analyses were done with TaqMan quantitative reverse transcription-PCR for a subset of miRNAs. Illumina miRNA microarray profiling was done to evaluate the differences in expression patterns between normal colonic mucosa tissues and stool samples from healthy subjects.

Results: We efficiently extracted miRNAs from stool specimens using our developed protocol. Data from independent experiments showed high reproducibility for miRNA extraction and expression. miRNA expression patterns were similar in stool specimens among healthy volunteers, and reproducible in stool samples that were collected serially in time from the same individuals. miRNA expression profiles from 29 patients showed higher expression of miR-21 and miR-106a in patients with adenomas and CRCs compared with individuals free of colorectal neoplasia.

Conclusion: Our data indicate that miRNAs could be extracted from stool easily and reproducibly. The stools of patients with colorectal neoplasms have unique and identifiable patterns of miRNA expression.

Impact: Fecal miRNAs may be an excellent candidate for the development of a noninvasive screening test for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 19(7); 1766–74. ©2010 AACR.
Data from A Novel Approach to Predict the Likelihood of Specific Ovarian Tumor Pathology Based on Serum CA-125: A Multicenter Observational Study
Authors: Van Calster Ben , Valentin Lil , Van Holsbeke Caroline , Zhang Jing , Jurkovic Davor , Lissoni Andrea Alberto , Testa Antonia Carla , Czekierdowski Artur , Fischerová Daniela , Domali Ekaterini , Van de Putte Gregg , Vergote Ignace , Van Huffel Sabine , Bourne Tom , Timmerman Dirk
Published: March 2023

Abstract
Background: The CA-125 tumor marker has limitations when used to distinguish between benign and malignant ovarian masses. We therefore establish likelihood curves of six subgroups of ovarian pathology based on CA-125 and menopausal status.

Methods: This cross-sectional study conducted by the International Ovarian Tumor Analysis group involved 3,511 patients presenting with a persistent adnexal mass that underwent surgical intervention. CA-125 distributions for six tumor subgroups (endometriomas and abscesses, other benign tumors, borderline tumors, stage I invasive cancers, stage II–IV invasive cancers, and metastatic tumors) were estimated using kernel density estimation with stratification for menopausal status. Likelihood curves for the tumor subgroups were derived from the distributions.

Results: Endometriomas and abscesses were the only benign pathologies with median CA-125 levels above 20 U/mL (43 and 45, respectively). Borderline and invasive stage I tumors had relatively low median CA-125 levels (29 and 81 U/mL, respectively). The CA-125 distributions of stage II–IV invasive cancers and benign tumors other than endometriomas or abscesses were well separated; the distributions of the other subgroups overlapped substantially. This held for premenopausal and postmenopausal patients. Likelihood curves and reference tables comprehensibly show how subgroup likelihoods change with CA-125 and menopausal status.

Conclusions and Impact: Our results confirm the limited clinical value of CA-125 for preoperative discrimination between benign and malignant ovarian pathology. We have shown that CA-125 may be used in a different way. By using likelihood reference tables, we believe clinicians will be better able to interpret preoperative serum CA-125 results in patients with adnexal masses. Cancer Epidemiol Biomarkers Prev; 20(11); 2420–8. ©2011 AACR.
Data from A Genome-Wide Survey over the ChIP-On-Chip Identified Androgen Receptor-Binding Genomic Regions Identifies a Novel Prostate Cancer Susceptibility Locus at 12q13.13
Authors: Feng Junjie , Sun Jielin , Kim Seong-Tae , Lu Yizhen , Wang Zhong , Zhang Zheng , Gronberg Henrik , Isaacs William B. , Zheng S. Lilly , Xu Jianfeng
Published: March 2023

Abstract
Background: The molecular mechanisms for the genome-wide association studies (GWAS)-identified prostate cancer (PCa) risk-associated single-nucleotide polymorphisms (SNP) remain largely unexplained. One recent finding that the PCa risk SNPs are enriched in genomic regions containing androgen receptor (AR)-binding sites has suggested altered AR signaling as a potentially important mechanism.

Methods: To explore novel associations by leveraging this knowledge, we utilized a meta-analysis previously done over SNPs harbored in ChIP-on-chip identified AR-binding genomic regions using the GWAS data from the Johns Hopkins Hospital (JHH) and the Cancer Genetic Markers of Susceptibility (CGEMS) study, and subsequently evaluated the top associations in a third population from the CAncer of the Prostate in Sweden (CAPS) study.

Results: One SNP (rs4919743: G>A), located at the KRT8 locus at 12q13.13 which encodes a keratin protein (K8) long used as a prostate epithelial malignancy marker and implicated in the tumorigenesis of several cancer types, was identified to be associated with PCa risk. The frequency of its minor “A” allele was consistently higher in PCa cases than in controls in all three study populations, with a combined OR of 1.22 (95% CI: 1.13–1.32) and an overall P value of 4.50 × 10−7 (Bonferroni corrected, P = 0.006).

Conclusion: We have identified a novel genetic locus that is associated with PCa risk.

Impact: This study illustrated the great potential of prior biological knowledge in facilitating the search for novel disease-associated genetic loci. This finding warrants further replication in other studies. Cancer Epidemiol Biomarkers Prev; 20(11); 2396–403. ©2011 AACR.
Data from A Variable Age of Onset Segregation Model for Linkage Analysis, with Correction for Ascertainment, Applied to Glioma
Authors: Sun Xiangqing , Vengoechea Jaime , Elston Robert , Chen Yanwen , Amos Christopher I. , Armstrong Georgina , Bernstein Jonine L. , Claus Elizabeth , Davis Faith , Houlston Richard S. , Il'yasova Dora , Jenkins Robert B. , Johansen Christoffer , Lai Rose , Lau Ching C. , Liu Yanhong , McCarthy Bridget J. , Olson Sara H. , Sadetzki Siegal , Schildkraut Joellen , Shete Sanjay , Yu Robert , Vick Nicholas A. , Merrell Ryan , Wrensch Margaret , Yang Ping , Melin Beatrice , Bondy Melissa L. , Barnholtz-Sloan Jill S.
Published: March 2023

Abstract
Background: We propose a 2-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.

Methods: First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N = 281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N = 74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are reestimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.

Results: Using the best-fitting segregation models in model-based multipoint linkage analysis, we identified 2 separate peaks on chromosome 17; the first agreed with a region identified by Shete and colleagues who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD).

Conclusions: Our approach was able to narrow the linkage peak previously published for glioma.

Impact: We provide a practical solution to model-based linkage analysis for disease affection status with variable age of onset for the kinds of pedigree data often collected for linkage analysis. Cancer Epidemiol Biomarkers Prev; 21(12); 2242–51. ©2012 AACR.
Data from Stool DNA Test of Methylated Syndecan-2 for the Early Detection of Colorectal Neoplasia
Authors: Niu Feng , Wen Jialing , Fu Xinhui , Li Chujun , Zhao Rongsong , Wu Shan , Yu Hao , Liu Xianglin , Zhao Xia , Liu Side , Wang Xinying , Wang Jianping , Zou Hongzhi
Published: March 2023

Abstract
Background: Although the incidence of colorectal cancer is steadily increasing, screening for colorectal cancer with conventional approaches is not routinely performed in China. Noninvasive screening methods are attractive options to resolve this issue. Syndecan-2 (SDC2) is frequently methylated in colorectal cancer. However, the value of a stool test of methylated SDC2 for the detection of colorectal cancer is unknown.

Methods: Methylation status of SDC2 was tested in cell lines and 398 colorectal tissue samples and further evaluated with 497 stool samples, including 196 from colorectal cancer patients, 122 from adenoma patients, and 179 from normal individuals, using real-time methylation-specific PCR. The impacts of one quantitative partial stool sampling device and 17 potentially interfering substances on the performance of fecal methylated SDC2 were also analyzed. SDC2 expression was also measured.

Results: SDC2 methylation level was higher in 96.8% (120/124) of colorectal cancer tissues compared with paired adjacent normal epithelia. Stool test of methylated SDC2 detected 81.1% (159/196) of colorectal cancer and 58.2% (71/122) of adenomas at a specificity of 93.3% (167/179). No significant difference was found between partial and whole stool collection on colorectal cancer detection (P > 0.05, R2 = 0.80). Among 17 interfering substances, only berberine at high concentrations inhibited fecal detection of methylated SDC2. SDC2 was overexpressed in colorectal cancer tissues compared with normal epithelia.

Conclusions: Fecal methylated SDC2 is a valuable biomarker for the noninvasive detection of colorectal neoplasms.

Impact: Stool DNA test of methylated SDC2 would serve as an alternative method for screening colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 26(9); 1411–9. ©2017 AACR.
Data from Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer
Authors: Win Aung Ko , Jenkins Mark A. , Dowty James G. , Antoniou Antonis C. , Lee Andrew , Giles Graham G. , Buchanan Daniel D. , Clendenning Mark , Rosty Christophe , Ahnen Dennis J. , Thibodeau Stephen N. , Casey Graham , Gallinger Steven , Le Marchand Loïc , Haile Robert W. , Potter John D. , Zheng Yingye , Lindor Noralane M. , Newcomb Polly A. , Hopper John L. , MacInnis Robert J.
Published: March 2023

Abstract
Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.

Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.

Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).

Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.

Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.
Data from Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk
Authors: Delahanty Ryan J. , Xiang Yong-Bing , Spurdle Amanda , Beeghly-Fadiel Alicia , Long Jirong , Thompson Deborah , Tomlinson Ian , Yu Herbert , Lambrechts Diether , Dörk Thilo , Goodman Marc T. , Zheng Ying , Salvesen Helga B. , Bao Ping-Ping , Amant Frederic , Beckmann Matthias W. , Coenegrachts Lieve , Coosemans An , Dubrowinskaja Natalia , Dunning Alison , Runnebaum Ingo B. , Easton Douglas , Ekici Arif B. , Fasching Peter A. , Halle Mari K. , Hein Alexander , Howarth Kimberly , Gorman Maggie , Kaydarova Dylyara , Krakstad Camilla , Lose Felicity , Lu Lingeng , Lurie Galina , O'Mara Tracy , Matsuno Rayna K. , Pharoah Paul , Risch Harvey , Corssen Madeleine , Trovik Jone , Turmanov Nurzhan , Wen Wanqing , Lu Wei , Cai Qiuyin , Zheng Wei , Shu Xiao-Ou
Published: March 2023

Abstract
Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.

Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.

Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.

Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.

Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.
Data from Association of Prostate Cancer Risk Variants with TMPRSS2:ERG Status: Evidence for Distinct Molecular Subtypes
Authors: Penney Kathryn L. , Pettersson Andreas , Shui Irene M. , Graff Rebecca E. , Kraft Peter , Lis Rosina T. , Sesso Howard D. , Loda Massimo , Mucci Lorelei A.
Published: March 2023

Abstract
Background: Numerous genetic variants have been confirmed as prostate cancer risk factors. These variants may confer susceptibility to the development of specific molecular alterations during tumor initiation and progression. The TMPRSS2:ERG gene fusion occurs in roughly 50% of prostate cancers. Genetic risk variants may influence the development of this fusion. We sought to determine whether prostate cancer risk variants are differentially associated with TMPRSS2:ERG fusion–positive and negative cancer.

Methods: In the Health Professionals Follow-up Study and Physicians' Health Study Tumor Cohort, we evaluated the associations of 39 prostate cancer risk SNPs with TMPRSS2:ERG fusion status, measured by ERG protein expression. Logistic regression was performed to generate OR and 95% confidence intervals. The primary outcome was ERG+ (n = 227) versus ERG− (n = 260) prostate cancer. A secondary outcome was ERG+ or ERG− cancer versus controls without cancer.

Results: Six of 39 SNPs were significantly associated (P < 0.05) with ERG+ versus ERG− disease. Three SNPs were exclusively associated with the risk of ERG+, one with risk of ERG−, and two with associations trending in opposite directions for ERG+ and ERG−. Only two significant SNPs would be expected by chance.

Conclusions: Prostate cancer genetic risk variants are differentially associated with the development of ERG+ and ERG− prostate cancer.

Impact: Our findings suggest the molecular process of prostate carcinogenesis may be distinct for men with different underlying genetic predisposition. When examining risk factors for prostate cancer, the integration of molecular subtypes may enhance understanding of the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 25(5); 745–9. ©2016 AACR.