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Pancreatic Neoplasms: HELP
Articles by Chen Wu
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, Chen Wu wrote the following 18 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Excessive miR-25-3p maturation via N 2019

Zhang, Jialiang / Bai, Ruihong / Li, Mei / Ye, Huilin / Wu, Chen / Wang, Chengfeng / Li, Shengping / Tan, Liping / Mai, Dongmei / Li, Guolin / Pan, Ling / Zheng, Yanfen / Su, Jiachun / Ye, Ying / Fu, Zhiqiang / Zheng, Shangyou / Zuo, Zhixiang / Liu, Zexian / Zhao, Qi / Che, Xu / Xie, Dan / Jia, Weihua / Zeng, Mu-Sheng / Tan, Wen / Chen, Rufu / Xu, Rui-Hua / Zheng, Jian / Lin, Dongxin. ·Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. · Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China. · Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. · Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · CAMS Key Laboratory of Genetics and Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Abdominal Surgery, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. · Department of Pancreaticobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. chenrf63@163.com. · Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. xurh@sysucc.org.cn. · Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. zhengjian@sysucc.org.cn. · Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. lindx@sysucc.org.cn. · Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. lindx@sysucc.org.cn. · CAMS Key Laboratory of Genetics and Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. lindx@sysucc.org.cn. ·Nat Commun · Pubmed #31015415.

ABSTRACT: N

2 Article Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations. 2018

Chang, Jiang / Tian, Jianbo / Zhu, Ying / Zhong, Rong / Zhai, Kan / Li, Jiaoyuan / Ke, Juntao / Han, QiangQiang / Lou, Jiao / Chen, Wei / Zhu, Beibei / Shen, Na / Zhang, Yi / Gong, Yajie / Yang, Yang / Zou, Danyi / Peng, Xiating / Zhang, Zhi / Zhang, Xuemei / Huang, Kun / Yang, Ming / Wang, Li / Wu, Chen / Lin, Dongxin / Miao, Xiaoping. ·Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, 430030, Wuhan, China. · Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. · Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, 100020, Beijing, China. · Wuhan GeneCreate Biological Engineering Co., Ltd, 430075, Wuhan, China. · Department of Chemotherapy and Radiotherapy, Tangshan Gongren Hospital, 063210, Tangshan, China. · Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, 063210, Tangshan, China. · Tongji School of Pharmacy, Huazhong University of Science and Technology, 430030, Wuhan, China. · Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 250117, Jinan, China. · Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 100730, Beijing, China. · Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. chenwu@cicams.ac.cn. · Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. lindx@cicams.ac.cn. · Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, 430030, Wuhan, China. miaoxp@hust.edu.cn. ·Nat Commun · Pubmed #30206226.

ABSTRACT: Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 × 10

3 Article Functional role of BTB and CNC Homology 1 gene in pancreatic cancer and its association with survival in patients treated with gemcitabine. 2018

Huang, Xudong / Zheng, Jian / Li, Jun / Che, Xu / Tan, Wenle / Tan, Wen / Shao, Mingming / Cheng, Xinxin / Du, Zhongli / Zhao, Yanjie / Wang, Chengfeng / Wu, Chen / Lin, Dongxin. ·Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. · Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. · Department of Abdominal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. ·Theranostics · Pubmed #29930735.

ABSTRACT: Genetic variation (rs372883C/T) in the 3'-untranslated region of BTB and CNC homology 1 (

4 Article Integrative analysis of gene expression profiles reveals specific signaling pathways associated with pancreatic duct adenocarcinoma. 2018

Li, Jun / Tan, Wenle / Peng, Linna / Zhang, Jialiang / Huang, Xudong / Cui, Qionghua / Zheng, Jian / Tan, Wen / Wu, Chen / Lin, Dongxin. ·Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P.R. China. · Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P.R. China. · Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P.R. China. lindx@cicams.ac.cn. · Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P.R. China. lindx@cicams.ac.cn. · Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210009, P.R. China. lindx@cicams.ac.cn. ·Cancer Commun (Lond) · Pubmed #29764514.

ABSTRACT: BACKGROUND: Pancreatic duct adenocarcinoma (PDAC) remains a major health problem because conventional cancer treatments are relatively ineffective against it. Microarray studies have linked many genes to pancreatic cancer, but the available data have not been extensively mined for potential insights into PDAC. This study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancreatic cancer deposited in the gene expression omnibus database. METHODS: Pathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene (GSE71989, GSE15471, GSE16515, GSE32676, GSE41368 and GSE28735) expression profiles. Genes potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the expression of one candidate gene (CKS2) and its association with survival was examined in 102 patients with PDAC from our hospital. Effects of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and CFPAC-1. RESULTS: The KEGG signaling pathway called "pathway in cancer" may play an important role in pancreatic cancer development and progression. Five genes (BIRC5, CKS2, ITGA3, ITGA6 and RALA) in this pathway were significantly associated with survival time in patients with PDAC. CKS2 was overexpressed in PDAC samples from our hospital, and higher CKS2 expression in these patients was associated with shorter survival time. CKS2 knockdown substantially inhibited PDAC cell proliferation in vitro. CONCLUSIONS: Analysis integrating existing microarray datasets allowed identification of the "pathway in cancer" as an important signaling pathway in PDAC. This integrative approach may be powerful for identifying genes and pathways involved in cancer.

5 Article Effects of obatoclax combined with gemcitabine on the biological activity of pancreatic cancer cells under hypoxic conditions. 2018

Hou, Xin-Fang / Li, Shuai / Wu, Chen / Li, Ke / Xu, Shu-Ning / Wang, Ju-Feng. ·Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China. ·Mol Med Rep · Pubmed #29749486.

ABSTRACT: The present study aimed to investigate the effects of obatoclax (OBX) combined with gemcitabine (GEM) treatment on the proliferation, migration, invasion and epithelial‑mesenchymal transition (EMT) related proteins of pancreatic cancer cell line BxPC‑3 under hypoxic conditions. Protein expression levels of hypoxia‑inducible factor 1α (HIF‑1α) in BxPC‑3 pancreatic cancer cells under normoxic and hypoxic conditions were detected by western blotting. Cells were divided into four groups: Normoxia group, hypoxia group, OBX group and OBX + GEM group. The proliferation activity of BxPC‑3 cells was detected by Cell Counting kit‑8. The migratory and invasive abilities of BxPC‑3 cells were detected by the scratch test and Matrigel assay, respectively. The protein expression levels of vimentin, E‑cadherin and p53 in BxPC‑3 cells were also detected by western blotting. HIF‑1α expression under hypoxic conditions was significantly increased compared with expression under normoxic conditions. Under hypoxic conditions, OBX treatment reduced cell activity, decreased cell migration and invasion, promoted the expression of E‑cadherin and p53. In the OBX + GEM group, BxPC‑3 cell activity decreased significantly, cell migration and invasion decreased significantly, the expression of vimentin was significantly reduced and the expression of E‑cadherin and p53 further increased. In conclusion, the present results demonstrated that under hypoxic conditions, OBX combined with a small dose of GEM may be able to inhibit the growth, migration and invasion of pancreatic cancer cells, possibly via inhibition of EMT process. These results may provide a promising strategy for pancreatic cancer therapy.

6 Article Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. 2016

Zheng, Jian / Huang, Xudong / Tan, Wen / Yu, Dianke / Du, Zhongli / Chang, Jiang / Wei, Lixuan / Han, Yaling / Wang, Chengfeng / Che, Xu / Zhou, Yifeng / Miao, Xiaoping / Jiang, Guoliang / Yu, Xianjun / Yang, Xianghong / Cao, Guangwen / Zuo, Chaohui / Li, Zhaoshen / Wang, Chunyou / Cheung, Siu Tim / Jia, Yongfeng / Zheng, Xiongwei / Shen, Hongbing / Wu, Chen / Lin, Dongxin. ·State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Genetics, Medical College of Soochow University, Suzhou, China. · School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. · Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China. · Department of Pancreas and Hepatobiliary Surgery, Cancer Hospital, Fudan University, Shanghai, China. · Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China. · Department of Epidemiology, Second Military Medical University, Shanghai, China. · Department of Gastroduodenal and Pancreatic Surgery, Hunan Province Tumor Hospital, Changsha, China. · Department of Gastroenterology, First Affiliated Hospital, Second Military Medical University, Shanghai, China. · Union Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. · Department of Surgery, University of Hong Kong, Hong Kong, China. · Department of Pathology, Affiliated Hospital, Inner Mongolia School of Medicine, Huhhot, China. · Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou, China. · Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China. · Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. ·Nat Genet · Pubmed #27213290.

ABSTRACT: Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.

7 Article Circulating Metabolites and Survival Among Patients With Pancreatic Cancer. 2016

Yuan, Chen / Clish, Clary B / Wu, Chen / Mayers, Jared R / Kraft, Peter / Townsend, Mary K / Zhang, Mingfeng / Tworoger, Shelley S / Bao, Ying / Qian, Zhi Rong / Rubinson, Douglas A / Ng, Kimmie / Giovannucci, Edward L / Ogino, Shuji / Stampfer, Meir J / Gaziano, John Michael / Ma, Jing / Sesso, Howard D / Anderson, Garnet L / Cochrane, Barbara B / Manson, JoAnn E / Torrence, Margaret E / Kimmelman, Alec C / Amundadottir, Laufey T / Vander Heiden, Matthew G / Fuchs, Charles S / Wolpin, Brian M. ·Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CY, ZRQ, DAR, KN, SO, MGVH, CSF, BMW) · Broad Institute of MIT and Harvard University, Cambridge, MA (CBC, MGVH) · Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China (CW) · Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (JRM, MET, MGVH) · Department of Epidemiology (PK, SST, ELG, SO, MJS, JM, HDS, JEM), Department of Biostatistics (PK), and Department of Nutrition (ELG, MJS), Harvard School of Public Health, Boston, MA · Department of Pathology (SO), and Channing Division of Network Medicine (MKT, SST, YB, ELG, MJS, JM, JEM, CSF) and Division of Preventive Medicine (JMG, HDS, JEM), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (MZ, LTA) · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA (JMG) · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (GLA) · University of Washington School of Nursing, Seattle, WA (BBC) · Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA (ACK). ·J Natl Cancer Inst · Pubmed #26755275.

ABSTRACT: BACKGROUND: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown. METHODS: We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple-hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single-nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two-sided. RESULTS: Two metabolites in the tricarboxylic acid (TCA) cycle--isocitrate and aconitate--were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, Ptrend < .001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, Ptrend < .001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P trend < .001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate. CONCLUSIONS: Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer.

8 Article Survival among patients with pancreatic cancer and long-standing or recent-onset diabetes mellitus. 2015

Yuan, Chen / Rubinson, Douglas A / Qian, Zhi Rong / Wu, Chen / Kraft, Peter / Bao, Ying / Ogino, Shuji / Ng, Kimmie / Clancy, Thomas E / Swanson, Richard S / Gorman, Megan J / Brais, Lauren K / Li, Tingting / Stampfer, Meir J / Hu, Frank B / Giovannucci, Edward L / Kulke, Matthew H / Fuchs, Charles S / Wolpin, Brian M. ·Chen Yuan, Douglas A. Rubinson, Zhi Rong Qian, Shuji Ogino, Kimmie Ng, Megan J. Gorman, Lauren K. Brais, Tingting Li, Matthew H. Kulke, Charles S. Fuchs, and Brian M. Wolpin, Dana-Farber Cancer Institute · Chen Wu, Peter Kraft, Shuji Ogino, Meir J. Stampfer, Frank B. Hu, and Edward L. Giovannucci, Harvard School of Public Health · and Ying Bao, Shuji Ogino, Kimmie Ng, Thomas E. Clancy, Richard S. Swanson, Meir J. Stampfer, Frank B. Hu, Edward L. Giovannucci, Matthew H. Kulke, Charles S. Fuchs, and Brian M. Wolpin, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ·J Clin Oncol · Pubmed #25403204.

ABSTRACT: PURPOSE: Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown. PATIENTS AND METHODS: We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage. RESULTS: In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival. CONCLUSION: Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies.

9 Article Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. 2014

Mayers, Jared R / Wu, Chen / Clish, Clary B / Kraft, Peter / Torrence, Margaret E / Fiske, Brian P / Yuan, Chen / Bao, Ying / Townsend, Mary K / Tworoger, Shelley S / Davidson, Shawn M / Papagiannakopoulos, Thales / Yang, Annan / Dayton, Talya L / Ogino, Shuji / Stampfer, Meir J / Giovannucci, Edward L / Qian, Zhi Rong / Rubinson, Douglas A / Ma, Jing / Sesso, Howard D / Gaziano, John Michael / Cochrane, Barbara B / Liu, Simin / Wactawski-Wende, Jean / Manson, JoAnn E / Pollak, Michael N / Kimmelman, Alec C / Souza, Amanda / Pierce, Kerry / Wang, Thomas J / Gerszten, Robert E / Fuchs, Charles S / Vander Heiden, Matthew G / Wolpin, Brian M. ·Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA. · Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. · Department of Epidemiology, Harvard School of Public Health, Boston, MA. · Broad Institute of MIT and Harvard University, Cambridge, MA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. · Division of Genomic Stability and DNA repair, Department of Radiation Oncology, Dana- Farber Cancer Institute, Boston, MA 02215. · Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. · Department of Nutrition, Harvard School of Public Health, Boston, MA. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System. · University of Washington School of Nursing, Seattle, WA. · Departments of Epidemiology and Medicine, Brown University, Providence, RI. · Department of Social and Preventive Medicine, University at Buffalo, SUNY, Buffalo, NY. · Departments of Oncology and Medicine, McGill University, Montreal, QC, Canada. · Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN. · Cardiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA. · Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA. ·Nat Med · Pubmed #25261994.

ABSTRACT: Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

10 Article Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. 2014

Wolpin, Brian M / Rizzato, Cosmeri / Kraft, Peter / Kooperberg, Charles / Petersen, Gloria M / Wang, Zhaoming / Arslan, Alan A / Beane-Freeman, Laura / Bracci, Paige M / Buring, Julie / Canzian, Federico / Duell, Eric J / Gallinger, Steven / Giles, Graham G / Goodman, Gary E / Goodman, Phyllis J / Jacobs, Eric J / Kamineni, Aruna / Klein, Alison P / Kolonel, Laurence N / Kulke, Matthew H / Li, Donghui / Malats, Núria / Olson, Sara H / Risch, Harvey A / Sesso, Howard D / Visvanathan, Kala / White, Emily / Zheng, Wei / Abnet, Christian C / Albanes, Demetrius / Andreotti, Gabriella / Austin, Melissa A / Barfield, Richard / Basso, Daniela / Berndt, Sonja I / Boutron-Ruault, Marie-Christine / Brotzman, Michelle / Büchler, Markus W / Bueno-de-Mesquita, H Bas / Bugert, Peter / Burdette, Laurie / Campa, Daniele / Caporaso, Neil E / Capurso, Gabriele / Chung, Charles / Cotterchio, Michelle / Costello, Eithne / Elena, Joanne / Funel, Niccola / Gaziano, J Michael / Giese, Nathalia A / Giovannucci, Edward L / Goggins, Michael / Gorman, Megan J / Gross, Myron / Haiman, Christopher A / Hassan, Manal / Helzlsouer, Kathy J / Henderson, Brian E / Holly, Elizabeth A / Hu, Nan / Hunter, David J / Innocenti, Federico / Jenab, Mazda / Kaaks, Rudolf / Key, Timothy J / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Krogh, Vittorio / Kupcinskas, Juozas / Kurtz, Robert C / LaCroix, Andrea / Landi, Maria T / Landi, Stefano / Le Marchand, Loic / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Nakamura, Yusuke / Oberg, Ann L / Owzar, Kouros / Patel, Alpa V / Peeters, Petra H M / Peters, Ulrike / Pezzilli, Raffaele / Piepoli, Ada / Porta, Miquel / Real, Francisco X / Riboli, Elio / Rothman, Nathaniel / Scarpa, Aldo / Shu, Xiao-Ou / Silverman, Debra T / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Taylor, Philip R / Theodoropoulos, George E / Thornquist, Mark / Tjønneland, Anne / Tobias, Geoffrey S / Trichopoulos, Dimitrios / Vodicka, Pavel / Wactawski-Wende, Jean / Wentzensen, Nicolas / Wu, Chen / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Hoover, Robert / Hartge, Patricia / Fuchs, Charles / Chanock, Stephen J / Stolzenberg-Solomon, Rachael S / Amundadottir, Laufey T. ·1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3]. · 1] Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2]. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. [3]. · 1] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2]. · 1] Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. [2]. · 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. · 1] Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA. [2] Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. [3] New York University Cancer Institute, New York, New York, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. · 1] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. [3] Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. · Group Health Research Institute, Seattle, Washington, USA. · 1] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland, USA. · The Cancer Research Center of Hawaii (retired), Honolulu, Hawaii, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. · 1] Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington, USA. · 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy. · 1] INSERM, Centre for Research in Epidemiology and Population Health (CESP), Nutrition, Hormones and Women's Health Team, Villejuif, France. [2] University Paris Sud, UMRS 1018, Villejuif, France. [3] Institut Gustave Roussy (IGR), Villejuif, France. · Westat, Rockville, Maryland, USA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · 1] National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. [2] Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands. [3] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. · Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim, Germany. · Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · 1] Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · 1] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Massachusetts Veteran's Epidemiology, Research and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. · 1] Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. [3] Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. · Preventive Medicine, University of Southern California, Los Angeles, California, USA. · Prevention and Research Center, Mercy Medical Center, Baltimore, Maryland, USA. · Cancer Prevention, University of Southern California, Los Angeles, California, USA. · 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard School of Public Health, Boston, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. · The University of North Carolina Eshelman School of Pharmacy, Center for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, North Carolina, USA. · International Agency for Research on Cancer, Lyon, France. · Cancer Epidemiology Unit, University of Oxford, Oxford, UK. · School of Clinical Medicine, University of Cambridge, Cambridge, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA. · 1] Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. [2] Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. [3] Department of Nutrition, National School of Public Health, Athens, Greece. · Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Biology, University of Pisa, Pisa, Italy. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. · Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. · Alliance Statistics and Data Center, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Alliance Statistics and Data Center, Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA. · 1] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Gastroenterology, Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, Italy. · 1] Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. [2] Department of Epidemiology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. [3] CIBERESP, Madrid, Spain. · 1] Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. [2] Departament de Ciències i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Toxicogenomics Unit, Center for Toxicology and Safety, National Institute of Public Health, Prague, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · 1st Propaideutic Surgical Department, Hippocration University Hospital, Athens, Greece. · Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [3] Hellenic Health Foundation, Athens, Greece. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic. · Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · 1] Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. [2] New York University Cancer Institute, New York, New York, USA. · 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2]. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3]. · 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [3]. ·Nat Genet · Pubmed #25086665.

ABSTRACT: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

11 Article A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk. 2014

He, Meian / Wu, Chen / Xu, Jianfeng / Guo, Huan / Yang, Handong / Zhang, Xiaomin / Sun, Jielin / Yu, Dianke / Zhou, Li / Peng, Tao / He, Yunfeng / Gao, Yong / Yuan, Jing / Deng, Qifei / Dai, Xiayun / Tan, Aihua / Feng, Yingying / Zhang, Haiying / Min, Xinwen / Yang, Xiaobo / Zhu, Jiang / Zhai, Kan / Chang, Jiang / Qin, Xue / Tan, Wen / Hu, Yanling / Lang, Mingjian / Tao, Sha / Li, Yuanfeng / Li, Yi / Feng, Junjie / Li, Dongfeng / Kim, Seong-Tae / Zhang, Shijun / Zhang, Hongxing / Zheng, S Lilly / Gui, Lixuan / Wang, Youjie / Wei, Sheng / Wang, Feng / Fang, Weimin / Liang, Yuan / Zhai, Yun / Chen, Weihong / Miao, Xiaoping / Zhou, Gangqiao / Hu, Frank B / Lin, Dongxin / Mo, Zengnan / Wu, Tangchun. ·MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, , Wuhan, Hubei, China. ·Gut · Pubmed #23300138.

ABSTRACT: OBJECTIVE: Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. DESIGN: We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). RESULTS: The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10(-13)-3.30×10(-290)); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10(-22)-5.81×10(-209)); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10(-18) and 1.28×10(-14)). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). CONCLUSIONS: This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

12 Article Genome-wide association study of survival in patients with pancreatic adenocarcinoma. 2014

Wu, Chen / Kraft, Peter / Stolzenberg-Solomon, Rachael / Steplowski, Emily / Brotzman, Michelle / Xu, Mousheng / Mudgal, Poorva / Amundadottir, Laufey / Arslan, Alan A / Bueno-de-Mesquita, H Bas / Gross, Myron / Helzlsouer, Kathy / Jacobs, Eric J / Kooperberg, Charles / Petersen, Gloria M / Zheng, Wei / Albanes, Demetrius / Boutron-Ruault, Marie-Christine / Buring, Julie E / Canzian, Federico / Cao, Guangwen / Duell, Eric J / Elena, Joanne W / Gaziano, J Michael / Giovannucci, Edward L / Hallmans, Goran / Hutchinson, Amy / Hunter, David J / Jenab, Mazda / Jiang, Guoliang / Khaw, Kay-Tee / LaCroix, Andrea / Li, Zhaoshen / Mendelsohn, Julie B / Panico, Salvatore / Patel, Alpa V / Qian, Zhi Rong / Riboli, Elio / Sesso, Howard / Shen, Hongbing / Shu, Xiao-Ou / Tjonneland, Anne / Tobias, Geoffrey S / Trichopoulos, Dimitrios / Virtamo, Jarmo / Visvanathan, Kala / Wactawski-Wende, Jean / Wang, Chengfeng / Yu, Kai / Zeleniuch-Jacquotte, Anne / Chanock, Stephen / Hoover, Robert / Hartge, Patricia / Fuchs, Charles S / Lin, Dongxin / Wolpin, Brian M. ·Department of Epidemiology, Harvard School of Public Health, , Boston, Massachusetts, USA. ·Gut · Pubmed #23180869.

ABSTRACT: BACKGROUND AND OBJECTIVE: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. METHODS: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). RESULTS: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. CONCLUSIONS: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

13 Article Prediagnostic body mass index and pancreatic cancer survival. 2013

Yuan, Chen / Bao, Ying / Wu, Chen / Kraft, Peter / Ogino, Shuji / Ng, Kimmie / Qian, Zhi Rong / Rubinson, Douglas A / Stampfer, Meir J / Giovannucci, Edward L / Wolpin, Brian M. ·Chen Yuan, Shuji Ogino, Kimmie Ng, Zhi Rong Qian, Douglas A. Rubinson, and Brian M. Wolpin, Dana-Farber Cancer Institute · Ying Bao, Shuji Ogino, Kimmie Ng, Meir J. Stampfer, Edward L. Giovannucci, and Brian M. Wolpin, Brigham and Women's Hospital, Harvard Medical School · and Chen Wu, Peter Kraft, Shuji Ogino, Meir J. Stampfer, and Edward L. Giovannucci, Harvard School of Public Health, Boston, MA. ·J Clin Oncol · Pubmed #24145341.

ABSTRACT: PURPOSE: Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival. PATIENTS AND METHODS: We analyzed survival by prediagnostic BMI assessed in 1986 among 902 patients from two large prospective cohorts diagnosed from 1988 to 2010. We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and stage. We evaluated the temporal association of BMI with survival by grouping reported BMI by 2-year lag-time intervals before diagnosis. RESULTS: The multivariable-adjusted HR for death was 1.53 (95% CI, 1.11 to 2.09) comparing patients with BMI ≥ 35 kg/m(2) with those with BMI < 25 kg/m(2) (P trend = .001), which was similar after adjustment for stage. The association of BMI with survival was stronger with longer lag times between reported BMI and cancer diagnosis. Among patients with BMI collected 18 to 20 years before diagnosis, HR for death was 2.31 (95% CI, 1.48 to 3.61; P trend < .001), comparing obese with healthy-weight patients. No statistically significant differences were seen by cohort, smoking status, or stage, although the association was stronger among never-smokers (HR, 1.61; 95% CI, 1.01 to 2.57; P trend = .002) than ever-smokers (HR, 1.36; 95% CI, 0.86 to 2.15; P trend = .63), comparing BMI ≥ 35 kg/m(2) with BMI < 25 kg/m(2). Higher prediagnostic BMI was associated with more advanced stage at diagnosis, with 72.5% of obese patients presenting with metastatic disease versus 59.4% of healthy-weight patients (P = .02). CONCLUSION: Higher prediagnostic BMI was associated with statistically significantly decreased survival among patients with pancreatic cancer from two large prospective cohorts.

14 Article Hyperglycemia, insulin resistance, impaired pancreatic β-cell function, and risk of pancreatic cancer. 2013

Wolpin, Brian M / Bao, Ying / Qian, Zhi Rong / Wu, Chen / Kraft, Peter / Ogino, Shuji / Stampfer, Meir J / Sato, Kaori / Ma, Jing / Buring, Julie E / Sesso, Howard D / Lee, I-Min / Gaziano, John Michael / McTiernan, Anne / Phillips, Lawrence S / Cochrane, Barbara B / Pollak, Michael N / Manson, JoAnn E / Giovannucci, Edward L / Fuchs, Charles S. ·Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA. bwolpin@partners.org ·J Natl Cancer Inst · Pubmed #23847240.

ABSTRACT: BACKGROUND: Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction. METHODS: This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided. RESULTS: The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001). CONCLUSIONS: Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.

15 Article Inflammatory plasma markers and pancreatic cancer risk: a prospective study of five U.S. cohorts. 2013

Bao, Ying / Giovannucci, Edward L / Kraft, Peter / Qian, Zhi Rong / Wu, Chen / Ogino, Shuji / Gaziano, J Michael / Stampfer, Meir J / Ma, Jing / Buring, Julie E / Sesso, Howard D / Lee, I-Min / Rifai, Nader / Pollak, Michael N / Jiao, Li / Lessin, Lawrence / Cochrane, Barbara B / Manson, Joann E / Fuchs, Charles S / Wolpin, Brian M. ·Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. ying.bao@channing.harvard.edu ·Cancer Epidemiol Biomarkers Prev · Pubmed #23462920.

ABSTRACT: Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1,094 controls from Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL-6, and TNF-αR2 and the risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 [95% confidence interval (CI), 0.74-1.63; Ptrend = 0.81] for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL-6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, prediagnostic levels of circulating CRP, IL-6, and TNF-αR2 were not associated with the risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.

16 Article Identification of common variants in BRCA2 and MAP2K4 for susceptibility to sporadic pancreatic cancer. 2013

Huang, Liming / Wu, Chen / Yu, Dianke / Wang, Chengfeng / Che, Xu / Miao, Xiaoping / Zhai, Kan / Chang, Jiang / Jiang, Guoliang / Yang, Xianghong / Cao, Guangwen / Hu, Zhibin / Zhou, Yongjian / Zuo, Chaohui / Wang, Chunyou / Zhang, Xianghong / Zhou, Yifeng / Yu, Xianjun / Dai, Wanjin / Li, Zhaoshen / Shen, Hongbing / Liu, Luming / Chen, Yanling / Zhang, Sheng / Wang, Xiaoqi / Liu, Yu / Sun, Menghong / Cao, Wei / Gao, Jun / Ma, Ying / Zheng, Xiongwei / Cheung, Siu Tim / Jia, Yongfeng / Tan, Wen / Wu, Tangchun / Lin, Dongxin. ·State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. ·Carcinogenesis · Pubmed #23299404.

ABSTRACT: Germline mutations in genes that cause hereditary syndromes are highly predisposed to familial pancreatic cancer. However, genetic susceptibility to sporadic pancreatic cancer is largely uncovered. We conducted a two-stage association study on pancreatic cancer that included 981 cases and 1991 controls in the first stage followed by a second stage (2603 cases and 2877 controls). Using an approach based on candidate genes whose roles in pancreatic cancer have been well known, we identified two new susceptibility loci. rs11571836 located in the BRCA2 3'-untranslated region was significantly associated with lower expression of BRCA2 transcript and increased pancreatic cancer risk [odds ratio = 1.30, 95% confidence interval = 1.14-1.47, P = 7.64 × 10(-5)] in a recessive manner. rs12939944 located in the MAP2K4 intron was associated with decreased risk (odds ratio = 0.82, 95% confidence interval = 0.74-0.91, P = 0.0001) in a dominant manner. Our results demonstrate for the first time that common variants in BRCA2 and MAP2K4 are susceptibility to sporadic pancreatic cancer.

17 Article Copy number variation at 6q13 functions as a long-range regulator and is associated with pancreatic cancer risk. 2012

Huang, Liming / Yu, Dianke / Wu, Chen / Zhai, Kan / Jiang, Guoliang / Cao, Guangwen / Wang, Chunyou / Liu, Yu / Sun, Menghong / Li, Zhaoshen / Tan, Wen / Lin, Dongxin. ·State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. ·Carcinogenesis · Pubmed #22016467.

ABSTRACT: Copy number variations (CNVs) have been recognized to contribute to phenotypic variations and to be associated with susceptibility to certain complex diseases. This study examined the functional significance of CNVR2966.1 at 6q13 and its association with pancreatic cancer susceptibility. The CNVR2966.1 was found to be a 10,379 bp nucleotides deletion/insertion within the uniform boundaries chromosome 6: 74 648 791-74 659 169. Luciferase reporter gene assays revealed an active regulator in CNVR2966.1, which was demonstrated by circular chromosome conformation capture assays to physically interact with the upstream functional sequence of CDKN2B. CDKN2B transcription levels in pancreatic tissues were therefore significantly higher in individuals with two copies of CNVR2966.1 than in those with low copy number of CNVR2966.1. The risk of pancreatic cancer observed in 1027 cases and 1031 controls was significantly associated with copy number of CNVR2966.1, with the odds ratio being 1.31 (95% confidence interval = 1.08-1.60; P = 0.007) for one copy genotype compared with two copies genotype. These results suggest that CNVR2966.1 is associated with pancreatic cancer risk probably owing to its effect on long-range regulation of CDKN2B.

18 Article Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. 2011

Wu, Chen / Miao, Xiaoping / Huang, Liming / Che, Xu / Jiang, Guoliang / Yu, Dianke / Yang, Xianghong / Cao, Guangwen / Hu, Zhibin / Zhou, Yongjian / Zuo, Chaohui / Wang, Chunyou / Zhang, Xianghong / Zhou, Yifeng / Yu, Xianjun / Dai, Wanjin / Li, Zhaoshen / Shen, Hongbing / Liu, Luming / Chen, Yanling / Zhang, Sheng / Wang, Xiaoqi / Zhai, Kan / Chang, Jiang / Liu, Yu / Sun, Menghong / Cao, Wei / Gao, Jun / Ma, Ying / Zheng, Xiongwei / Cheung, Siu Tim / Jia, Yongfeng / Xu, Jian / Tan, Wen / Zhao, Ping / Wu, Tangchun / Wang, Chengfeng / Lin, Dongxin. ·State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. ·Nat Genet · Pubmed #22158540.

ABSTRACT: Pancreatic cancer has the lowest survival rate among human cancers, and there are no effective markers for its screening and early diagnosis. To identify genetic susceptibility markers for this cancer, we carried out a genome-wide association study on 981 individuals with pancreatic cancer (cases) and 1,991 cancer-free controls of Chinese descent using 666,141 autosomal SNPs. Promising associations were replicated in an additional 2,603 pancreatic cancer cases and 2,877 controls recruited from 25 hospitals in 16 provinces or cities in China. We identified five new susceptibility loci at chromosomes 21q21.3, 5p13.1, 21q22.3, 22q13.32 and 10q26.11 (P = 2.24 × 10(-13) to P = 4.18 × 10(-10)) in addition to 13q22.1 previously reported in populations of European ancestry. These results advance our understanding of the development of pancreatic cancer and highlight potential targets for the prevention or treatment of this cancer.