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101. The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium

Author

Anna González-Neira, Qin Wang, Daniel C. Tessier, John J. Spinelli, Valerie Gaborieau, Keitaro Matsuo, Paul D.P. Pharoah, Catherine S. Healey, Motoki Iwasaki, Don M. Conroy, Shoichiro Tsugane, Artitaya Lophatananon, Ji Yeob Choi, Mikael Hartman, Alison M. Dunning, Chiu-Chen Tseng, Nur Aishah Taib, Roger L. Milne, Sue K. Park, Anna H. Wu, Kenneth Muir, Kyriaki Michailidou, Tomotaka Ugai, Kristan J. Aronson, Douglas F. Easton, Soo Hwang Teo, Sung-Won Kim, Chen-Yang Shen, Suleeporn Sangrajrang, Ava Kwong, Tsun Chan, Daniel Vincent, Esther M. John, Manjeet K. Bolla, Joe Dennis, Pei Ei Wu, Wei Zheng, Ching Wan Chan, Hidemi Ito, Xiao-Ou Shu, Daehee Kang, Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Adult, medicine.medical_specialty, lcsh:QH426-470, Alcohol Drinking, Estrogen receptor, aldehyde dehydrogenase‐2, Single-nucleotide polymorphism, Breast Neoplasms, 030105 genetics & heredity, Polymorphism, Single Nucleotide, aldehyde dehydrogenase-2, Alcohol Drinking/epidemiology, 03 medical and health sciences, Breast cancer, breast cancer, Asian People, single nucleotide polymorphism, Internal medicine, Epidemiology, Genotype, Genetics, medicine, Humans, Asian Continental Ancestry Group/genetics, Gene–environment interaction, Aldehyde Dehydrogenase, Mitochondrial/genetics, Molecular Biology, Genetics (clinical), ALDH2, Aged, business.industry, Breast Neoplasms/epidemiology, Aldehyde Dehydrogenase, Mitochondrial, Odds ratio, Original Articles, Middle Aged, medicine.disease, 3. Good health, lcsh:Genetics, 030104 developmental biology, Original Article, Female, Gene-Environment Interaction, business, acetaldehyde
Abstract

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium.METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

Published
2019
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102. A high-resolution HLA imputation system for the Taiwanese population: a study of the Taiwan Biobank

Author

Hsuan-Yu Chen, Chen-Yang Shen, Shu Fen Liao, Katsushi Tokunaga, Ya-Hsuan Chang, Seik-Soon Khor, Yu Ju Lin, Mei Hsuan Lee, Pei-Ei Wu, Xiuwen Zheng, Yu Han Huang, and Hou-Wei Chu

Subjects
0301 basic medicine, Genotype, Population, Taiwan, Human leukocyte antigen, Disease, Biology, 030226 pharmacology & pharmacy, Polymorphism, Single Nucleotide, HLA-DQ alpha-Chains, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Databases, Genetic, Genetics, HLA-DQ beta-Chains, Humans, Allele frequency net database, Allele, education, Pharmacology, education.field_of_study, Whole Genome Sequencing, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Biobank, 030104 developmental biology, Genetics, Population, Phenotype, Molecular Medicine, Imputation (genetics), SNP array, HLA-DRB1 Chains
Abstract

An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.

Published
2019

104. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author

Elinor J. Sawyer, Maria Kabisch, Louise A. Brinton, Joe Dennis, Frederik Marmé, Sofia Khan, Michael Lush, Soo-Hwang Teo, Giuseppe Floris, Thilo Dörk, Pascal Guénel, Chiu-Chen Tseng, Anja Rudolph, Arto Mannermaa, Vessela N. Kristensen, Manjeet K. Bolla, Daehee Kang, Peter A. Fasching, Qin Wang, Caroline Seynaeve, Sara Margolin, Hidemi Ito, Xingyi Guo, John W.M. Martens, Mikael Hartman, Matthias W. Beckmann, Bernard Thienpont, Kyriaki Michailidou, Ming-Feng Hou, Diether Lambrechts, Simon S. Cross, Heli Nevanlinna, Graham G. Giles, Robert A.E.M. Tollenaar, Alison M. Dunning, Anna H. Wu, Cheng Har Yip, Artitaya Lophatananon, William J. Blot, Irene L. Andrulis, Kenneth Muir, Stig E. Bojesen, Chia-Ni Hsiung, Arnaud Droit, Per Hall, Douglas F. Easton, Hui Cai, Jonathan Beesley, Hatef Darabi, Pilar Zamora, Paolo Peterlongo, Jiajun Shi, Wei Zheng, Antoinette Hollestelle, Alicia Beeghly-Fadiel, Siddhartha Kar, Mervi Grip, Jirong Long, Melissa C. Southey, Javier Benitez, Sander Canisius, Zhiguo Zhao, Annika Lindblom, Susan L. Neuhausen, Ji Yeob Choi, Robert Winqvist, Catriona McLean, Valerie Gaborieau, Keitaro Matsuo, Georgia Chenevix-Trench, Suleeporn Sangrajrang, Hoda Anton-Culver, Diana Torres, Jingmei Li, Julia A. Knight, Anna Jakubowska, Paul D.P. Pharoah, Ans M.W. van den Ouweland, Nichola Johnson, Montserrat Garcia-Closas, Thomas Brüning, Veli-Matti Kosma, Matha J. Shrubsole, Anthony J. Swerdlow, Xiao-Ou Shu, Ying Zheng, Henrik Flyger, Hermann Brenner, Angela Cox, Florentia Fostira, Maartje J. Hooning, Antonis C. Antoniou, Kamila Czene, Wanqing Wen, Volker Arndt, Siranoush Manoukian, Hui Miao, Anne Lise Børresen-Dale, Jenny Chang-Claude, Christopher A. Haiman, Janet E. Olson, Annegien Broeks, Peter Devilee, Qiuyin Cai, kConFab Investigators, Ching-Yu Cheng, Chen-Yang Shen, Nick Orr, Roger L. Milne, Loic Le Marchand, Ian Tomlinson, Thomas C. Putti, Alfons Meindl, Thérèse Truong, Amanda E. Toland, John L. Hopper, Fergus J. Couch, Olivia Fletcher, Marjanka K. Schmidt, Ute Hamann, Maya Ghoussaini, Yanfeng Zhang, Rita K. Schmutzler, Barbara Burwinkel, Jacques Simard, Silje Nord, Hiltrud Brauch, Natalia Bogdanova, and Jan Lubinski

Subjects
0301 basic medicine, Genetics, Cancer Research, Linkage disequilibrium, Haplotype, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Breast cancer, Oncology, Genotype, medicine, Genetic association
Abstract

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Published
2016
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105. Structural analysis of functional group and mechanism investigation of caking property of coking coal

Author

Xiang Li, Chen-yang Shen, Liang-hui Bu, Zhuang Yang, and Zhi-hong Qin

Subjects
Chemistry, business.industry, Hydrogen bond, 020209 energy, technology, industry, and agriculture, 02 engineering and technology, Branching (polymer chemistry), complex mixtures, Caking, Chemical engineering, Close relationship, 0202 electrical engineering, electronic engineering, information engineering, Organic chemistry, Molecule, Coal, Fourier transform infrared spectroscopy, business, Structural unit
Abstract

Eleven coking coals were used in this study and FT-IR and the caking index tests were carried out. The peak separation and quantitative calculation of FT-IR spectra were performed by using Peakfit software, and the relationship between caking property and typical functional groups of coal was investigated. The results showed that there was a close relationship between caking property and FT-IR spectra of coal, especially in the regions of 3000–2800 and 3700–3000 cm −1 . The component with aliphatic structure was a major determinant of coal caking property. Usually, the shorter chain length or the higher branching degree of coal aliphatic structure was, the higher caking property will be. The caking property was codetermined by aliphatic structure and hydrogen bond (including −OH or −NH) and there was a synergic relationship between them. When the condensed degree of structural unit was low and the amount of bridge bonds was higher, the plastic mass based on structural unit with moderate molecular weight can be generated regardless of the coal molecule size. The most dominant sort of binding forces in coal was hydrogen bond. An associative structure even super molecular structure, which was broken and changed into plastic mass during the state of metaplast, was formed when a number of hydrogen bonds were associated together. The existence of plastic mass was beneficial to the transformation of metaplast into semi-coke and further acquisition of well caking property.

Published
2016
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106. Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

Author

Yu-Feng Huang, Nai-Chuan Chang, Mohit K. Midha, Alice L. Yu, Chen-Yang Shen, Kuo Ping Chiu, King-Jen Chang, Tan-Chi Fan, Yu-Tai Wang, Chien-Jen Chen, Tzu-Han Chen, Hsiao-Hsiang Yang, and Wen-Hung Kuo

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Oncology and Carcinogenesis, early onset breast cancer, lcsh:RC254-282, Article, Germline, early onset breast cancer (EOBC), 03 medical and health sciences, missense mutations, nonsynonymous mutations, 0302 clinical medicine, Breast cancer, Germline mutation, Clinical Research, Internal medicine, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Medicine, Missense mutation, Copy-number variation, Aetiology, Cancer, business.industry, Prevention, Mortality rate, Human Genome, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, somatic mutations, germline mutations, business, Biotechnology, Cohort study
Abstract

Early onset breast cancer (EOBC), diagnosed at age ~40 or younger, is associated with a poorer prognosis and higher mortality rate compared to breast cancer diagnosed at age 50 or older. EOBC poses a serious threat to public health and requires in-depth investigation. We studied a cohort comprising 90 Taiwanese female patients, aiming to unravel the underlying mechanisms of EOBC etiopathogenesis. Sequence data generated by whole-exome sequencing (WES) and whole-genome sequencing (WGS) from white blood cell (WBC)&ndash, tumor pairs were analyzed to identify somatic missense mutations, copy number variations (CNVs) and germline missense mutations. Similar to regular breast cancer, the key somatic mutation-susceptibility genes of EOBC include TP53 (40% prevalence), PIK3CA (37%), GATA3 (17%) and KMT2C (17%), which are frequently reported in breast cancer, however, the structural protein-coding genes MUC17 (19%), FLG (16%) and NEBL (11%) show a significantly higher prevalence in EOBC. Furthermore, the top 2 genes harboring EOBC germline mutations, MUC16 (19%) and KRT18 (19%), encode structural proteins. Compared to conventional breast cancer, an unexpectedly higher number of EOBC susceptibility genes encode structural proteins. We suspect that mutations in structural proteins may increase physical permeability to environmental hormones and carcinogens and cause breast cancer to occur at a young age.

Published
2020
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107. Intracellular expression of IFN-λ4 leads to ER stress, enhanced IRF1 signaling and decreased proliferation in hepatic cells that might protect HCV+ patients from liver cirrhosis

Author

Olusegun O Onabajo, Fang Wang, Mei-Hsuan Lee, Oscar Florez-Vargas, Adeola Obajemu, Mauro A Castro, Joselin Vargas, Shu-Fen Liao, Yu-Han Huang, Chen-Yang Shen, Rouf Banday, Thomas O’Brien, A. Gordon Robertson, and Ludmila Prokunina-Olsson

Subjects
Immunology, Immunology and Allergy
Abstract

Several genetic variants in the human IFNL3/IFNL4 locus have been associated with reduced hepatic fibrosis despite poor clearance of HCV infection. We expanded this analysis to cirrhosis, a more advanced stage of fibrosis. In 2931 individuals with chronic HCV, the IFNL4 genotype that generates IFN-λ4 was associated with protection from cirrhosis (OR=0.65, p=0.012, adjusted for age and sex). The IFNL4 genotype affects the production of IFN-λ4 and, additionally, may affect expression levels of IFN-λ3, making it difficult to delineate the individual contribution of these IFNs. To address this, we established HepG2-based cell models engineered to inducibly express either IFN-λ3 or IFN-λ4. Using RNA-seq based expression profile generated in these hepatic cell lines, we explored the global transcriptome of liver tumors (n=373) from The Cancer Genome Atlas to identify transcription factor networks affected by these IFNs in the liver. Several networks, including IRF1, were upregulated by IFN-λ4 more strongly than by IFN-λ3. Intracellular expression of IFN-λ4 but not of IFN-λ3 also led to potent IRF1-dependent antiproliferative effects. Live cell imaging revealed that IFN-λ4 was poorly secreted, mainly accumulated in lysosomes, and caused apoptosis, suggesting increased ER-stress via the misfolded protein response. Knockdown of DNA damage-inducible transcript 3 (DDIT3), an ER-stress response effector, significantly attenuated the antiproliferative effects of IFN-λ4. This novel interplay of enhanced IRF1 signaling coupled with intracellular accumulation and induction of ER stress by IFN-λ4 may have complex consequences on liver homeostasis during chronic HCV infection but also mediate anti-cirrhotic phenotypes.

Published
2020
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108. Genetic Evidence for the Association between Schizophrenia and Breast Cancer

Author

Jirong Long, Pei-Ei Wu, Jenny Chang-Claude, Chen-Yang Shen, Qiuyin Cai, Lang Wu, Jiajun Shi, Wei Zheng, Hermann Brenner, Shuyang Wang, Emmanouil Saloustros, Xiang Shu, Xiao-Ou Shu, and Wanqing Wen

Subjects
Oncology, medicine.medical_specialty, lcsh:Medicine, Single-nucleotide polymorphism, Genome-wide association study, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Internal medicine, Mendelian randomization, Medicine, Estrogen Receptor Status, 030304 developmental biology, Genetic association, 0303 health sciences, instrumental variables, genome-wide association study, business.industry, lcsh:R, Odds ratio, medicine.disease, Confidence interval, 3. Good health, schizophrenia, business, 030217 neurology & neurosurgery
Abstract

Objective: To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study. Methods: The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the United Kingdom Clozapine Clinic. The association between these SNPs determined schizophrenia and breast cancer risk was estimated in approximately 229,000 European descent females from the Breast Cancer Association Consortium using the inverse-variance weighted and the weighted median MR methods. Results: We found that the genetically-predicted risk of schizophrenia was associated with increased breast cancer risk (under a random-effects model: odds ratio per 1 unit increase in log odds of schizophrenia = 1.04, 95% confidence interval: 1.02–1.06, p = 5.6 × 10−5). Similar significant associations were observed in analyses using a weighted median model and sensitivity analysis excluding six SNPs with genotype imputation score of less than 0.8, as well as analyses stratified by estrogen receptor status of breast cancer. Conclusion: Our findings implicate a modest increased risk for breast cancer in genetically determined schizophrenic females.

Published
2018

109. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author

Maya Ghoussaini, Stacey L. Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal·lari, Kinjal Desai, Siddhartha Kar, Kristine M. Hillman, Susanne Kaufmann, Dylan M. Glubb, Jonathan Beesley, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ed Dicks, Qi Guo, Marjanka K. Schmidt, Mitul Shah, Robert Luben, Judith Brown, Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J. Van’t Veer, Emiel J. Th Rutgers, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji-Yeob Choi, Sue K. Park, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H. Wu, Chiu-chen Tseng, David Van Den Berg, Daniel O. Stram, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Qiuyin Cai, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S. C. Lee, Tien Y. Wong, Maartje J. Hooning, John W. M. Martens, J. Margriet Collée, Carolien H. M. van Deurzen, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Miroslav K. Kapuscinski, Chen-Yang Shen, Pei-Ei Wu, Jyh-Cherng Yu, Shou-Tung Chen, Grethe Grenaker Alnæs, Anne-Lise Borresen-Dale, Graham G. Giles, Roger L. Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A. Fasching, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L. Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Ines de Santiago, Jason Carroll, Carlos Caldas, Melissa A. Brown, Mathieu Lupien, Vessela N. Kristensen, Paul D. P. Pharoah, Georgia Chenevix-Trench, Juliet D. French, Douglas F. Easton, and Alison M. Dunning

Subjects
Oncology, medicine.medical_specialty, Multidisciplinary, business.industry, Published Erratum, MEDLINE, General Physics and Astronomy, Locus (genetics), General Chemistry, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, medicine, 030212 general & internal medicine, business
Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology., Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Published
2018

110. SUMOylation of XRCC1 activated by poly (ADP-ribosyl)ation regulates DNA repair

Author

Hsiu Ming Shih, Wei-Ting Chen, Wen Cheng Chou, Che Chang Chang, Chen-Yang Shen, Yen Sung Huang, Chun Chen Ho, Chia-Ni Hsiung, Pei Ei Wu, Ying Mei Lin, and Ling Yueh Hu

Subjects
0301 basic medicine, Protein sumoylation, DNA Repair, DNA repair, SUMO protein, Poly (ADP-Ribose) Polymerase-1, DNA polymerase beta, Biology, Genomic Instability, 03 medical and health sciences, XRCC1, chemistry.chemical_compound, Poly ADP Ribosylation, 0302 clinical medicine, PARP1, Genetics, Humans, Molecular Biology, Genetics (clinical), Polymerase, DNA Polymerase beta, Sumoylation, General Medicine, Base excision repair, Methyl Methanesulfonate, Cell biology, DNA-Binding Proteins, Alcohol Oxidoreductases, 030104 developmental biology, X-ray Repair Cross Complementing Protein 1, chemistry, 030220 oncology & carcinogenesis, biology.protein, DNA Damage, Protein Binding
Abstract

XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here, we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation. A SUMOylation-defective mutant of XRCC1 had lower binding activity for DNA polymerase beta (POLB) and was linked to a lower capacity for repair of MMS-induced DNA damages. Our study therefore identified a pathway in which DNA damage-induced poly(ADP-ribosyl)ation (PARylation) promotes SUMOylation of XRCC1, which leads to more efficient recruitment of POLB to complete BER.

Published
2018

111. Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1α in erk-responsive lung cancer

Author

Pei-Ei Wu, Ling-Yueh Hu, Chen-Yang Shen, Yi-Hsien Hsieh, Chia-Wei Chang, Chun-Wen Cheng, Chung-Chin Yao, Chung-Chih Weng, and Po-Ming Chen

Subjects
Pathology, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Lung Neoplasms, Time Factors, HIF-1α, Mice, Nude, Antineoplastic Agents, Vimentin, Biology, Transfection, Metastasis, Cell Movement, Cell Line, Tumor, microRNA, medicine, Animals, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, FOXO3a, Neoplasm Metastasis, Extracellular Signal-Regulated MAP Kinases, Lung cancer, 3' Untranslated Regions, Protein Kinase Inhibitors, A549 cell, Mice, Inbred BALB C, Binding Sites, Forkhead Box Protein O3, EMT, miR-622, Cancer, Forkhead Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Tumor Burden, Enzyme Activation, Gene Expression Regulation, Neoplastic, lung cancer, MicroRNAs, Oncology, Cancer cell, Cancer research, biology.protein, Heterografts, Female, Research Paper, Signal Transduction
Abstract

Metastatic spread of cancer cells portends a poor prognosis and mortality for lung cancer patients. Hypoxia-inducible factor-1α (HIF-1α) enhances tumor cell motility by activating the epithelial-to-mesenchymal transition (EMT), which is considered a prerequisite for metastasis. Recent studies of microRNA involvement in cancer invasion and metastasis have highlighted the role of such RNAs in tumor development. However, little work has been done to identify tumor suppressor microRNAs that target HIF-1α to down-modulate the EMT and thereby counteract the aggressiveness and metastasis of lung cancer cells. Here, we identified the 3'-untranslated region of HIF-1α mRNA as a target of miR-622 and established that miR-622-mediated down-modulation of HIF-1α correlates with decreased levels of mesenchymal proteins, including Snail, β-catenin, and vimentin. Functional analyses revealed that increased miR-622 expression inhibited lung cancer cell migration and invasion in vitro. miR-622 also inhibited the genesis of metastatic lung nodules as demonstrated in a lung cancer xenograft model in which nude mice were transplanted with A549 cells expressing miR-622. Mechanistic analyses showed that overexpression of EGF decreased the miR-622 level in A549 cells, and this reduction could be rescued by administrating U0126, an inhibitor of ERK. Moreover, miR-622 overexpression mediated by the transcription factor FOXO3a decreased the invasiveness of lung tumor cells by inhibiting HIF-1α via inactivation of ERK signaling in U0126-treated A549 cells. These findings highlight the pivotal role of the FOXO3a/miR-622 axis in inhibiting HIF-1α to interfere with tumor metastasis, and this information may contribute to development of novel therapeutic strategies for treating aggressive lung cancer.

Published
2015
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112. Fasudil, a Rho-kinase inhibitor, prevents intima-media thickening in a partially ligated carotid artery mouse model: Effects of fasudil in flow-induced vascular remodeling

Author

Chen-yang Shen, Wei Li, Qingle Li, Xiaoming Zhang, Fu Gao, Yan-Kui Li, Xiangyu Zhang, and Tao Zhang

Subjects
Neointima, Male, Cancer Research, medicine.medical_specialty, Vascular smooth muscle, Myosin light-chain kinase, Myocytes, Smooth Muscle, Inflammation, Biology, Vascular Remodeling, Biochemistry, Carotid Intima-Media Thickness, Muscle, Smooth, Vascular, Proinflammatory cytokine, flow-induced vascular remodeling, Mice, Internal medicine, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Genetics, medicine, Animals, Molecular Biology, Rho-associated protein kinase, Protein Kinase Inhibitors, Cell Proliferation, rho-Associated Kinases, Fasudil, Hemodynamics, Anatomy, Articles, Rho-associated kinase pathway, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Carotid Arteries, Oncology, Rho kinase inhibitor, cardiovascular system, Molecular Medicine, medicine.symptom, fasudil, Signal Transduction
Abstract

Vascular remodeling in response to hemodynamic alterations is a physiological process that requires coordinated signaling between endothelial, inflammatory and vascular smooth muscle cells (VSMCs). Extensive experimental and clinical studies have indicated the critical role of the Ras homolog gene family, member A/Rho‑associated kinase (ROCK) signaling pathway in the pathogenesis of cardiovascular disease, where ROCK activation has been demonstrated to promote inflammation and remodeling through inducing the expression of proinflammatory cytokines and adhesion molecules in endothelial cells and VSMCs. However, the role of ROCK in flow‑induced vascular remodeling has not been fully defined. The current study aimed to investigate the effect of the ROCK signaling pathway in flow‑induced vascular remodeling by comparing the responses to partial carotid artery ligation in mice treated with fasudil (a ROCK inhibitor) and untreated mice. Intima‑media thickness and neointima formation were evaluated by morphology. VSMC proliferation and inflammation of the vessel wall were assessed by immunohistochemistry. In addition, the expression levels of ROCK and the downstream effectors of ROCK, myosin light chain (MLC) and phosphorylated‑MLC (p‑MLC), were quantified by western blot analysis. Following a reduction in blood flow, ROCK1 and p‑MLC expression increased in the untreated left common carotid arteries (LCA). Fasudil‑treated mice developed a significantly smaller intima‑media thickness compared with the untreated mice. Quantitative immunohistochemistry of the fasudil‑treated LCA indicated that there was a reduction in proliferation when compared with untreated vessels. There were fewer CD45+ cells observed in the fasudil‑treated LCA compared with the untreated LCA. In conclusion, the expression of ROCK was enhanced in flow‑induced carotid artery remodeling and ROCK inhibition as a result of fasudil treatment may attenuate flow‑induced carotid artery remodeling.

Published
2015

113. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Author

Christopher A. Haiman, Pascal Guénel, Hidemi Ito, Susan L. Neuhausen, Christy G. Woolcott, Graham G. Giles, Anthony J. Swerdlow, Per Hall, Kamila Czene, Artitaya Lophatananon, Åslaug Helland, Yu-Tang Gao, Vessela N. Kristensen, Manjeet K. Bolla, Anna H. Wu, Jacques Simard, John L. Hopper, Robert Luben, Julia A. Knight, Mark S. Goldberg, Thilo Dörk, Kay-Tee Khaw, Christopher G. Scott, Giuseppe Floris, Jennifer Stone, Madeleine M.A. Tilanus-Linthorst, Stig E. Bojesen, Daehee Kang, Qin Wang, Angela Cox, Fergus J. Couch, Jonathan Beesley, Maartje J. Hooning, Natalia Bogdanova, Brian E. Henderson, Paolo Peterlongo, Rulla M. Tamimi, Soo Hwang Teo, Diether Lambrechts, Ute Hamann, Wei Zheng, Volker Arndt, Juliet D. French, Stacey L. Edwards, Julian Peto, Ian Tomlinson, Ji Yeob Choi, Elinor J. Sawyer, Melissa C. Southey, Annegien Broeks, Arif B. Ekici, Heli Nevanlinna, Celine M. Vachon, Thérèse Truong, Amanda E. Toland, Javier Benitez, Barbara Burwinkel, Xiao-Ou Shu, Robert Winqvist, Pierre Antoine Dugué, Karen McCue, Mikael Hartman, Minouk J. Schoemaker, Keitaro Matsuo, Norbert Arnold, Deborah J. Thompson, Paolo Radice, Anna Jakubowska, Marjanka K. Schmidt, Hermann Brenner, Hoda Anton-Culver, Argyrios Ziogas, Jenny Chang-Claude, Alicia Beeghly-Fadiel, Veli-Matti Kosma, Hatef Darabi, Drakoulis Yannoukakos, Maya Ghoussaini, Rodney J. Scott, Maria Kabisch, Chen-Yang Shen, Suleeporn Sangrajrang, Montserrat Garcia-Closas, James McKay, Alfons Meindl, Christoph Engel, Joe Dennis, Chiu-Chen Tseng, Catriona McLean, Arja Jukkola-Vuorinen, Peter A. Fasching, Katharina Heusinger, Georgia Chenevix-Trench, Robert A.E.M. Tollenaar, Kyriaki Michailidou, Rita K. Schmutzler, Shivaani Mariapun, Silje Nord, Hiltrud Brauch, Peter Devilee, Isabel dos-Santos-Silva, Douglas F. Easton, Frederik Marmé, Vilde D. Haakensen, Wei-Yen Lim, Keith Humphreys, Siddhartha Kar, Anja Rudolph, Arto Mannermaa, Jan Lubinski, Anna González-Neira, Sara Margolin, Matthias W. Beckmann, Simon S. Cross, Anne Lise Børresen-Dale, Jonine D. Figueroa, Alison M. Dunning, Kenneth Muir, Sander Canisius, Jingmei Li, Carmel Apicella, Jyh-Cherng Yu, Gertraud Maskarinec, Roger L. Milne, Henrik Flyger, Irene L. Andrulis, Annika Lindblom, Sofia Khan, Diana Torres, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Surgery, Cardiothoracic Surgery, Pulmonary Medicine, Thompson, Deborah [0000-0003-1465-5799], Ghoussaini, Maya [0000-0002-2415-2143], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Genotype, Quantitative Trait Loci, Autophagy-Related Proteins, Estrogen receptor, Breast Neoplasms, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Odds Ratio, medicine, Genetics, Humans, SNP, Genetics(clinical), Luciferases, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Chromosomes, Human, Pair 10, Haplotype, Age Factors, Chromosome Mapping, medicine.disease, 3. Good health, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, 030220 oncology & carcinogenesis, Trans-Activators, Regression Analysis, Female, Genome-Wide Association Study, Transcription Factors
Abstract

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Published
2015
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114. The humanNANOS3gene contributes to lung tumour invasion by inducing epithelial-mesenchymal transition

Author

Katrien Staes, Christine Gilles, Philippe Birembaut, Christine Terryn, Chen-Yang Shen, Claire Kileztky, Frans van Roy, B. Nawrocki-Raby, Véronique Dalstein, Anne-Pascaline Martin, Vanessa Andries, Simon Grelet, Myriam Polette, and Chun-Wen Cheng

Subjects
0303 health sciences, Cell, Vimentin, Transfection, Biology, medicine.disease, 3. Good health, Pathology and Forensic Medicine, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, microRNA, medicine, biology.protein, Gene silencing, Epithelial–mesenchymal transition, Lung cancer, Post-transcriptional regulation, 030304 developmental biology
Abstract

We have explored the role of the human NANOS3 gene in lung tumour progression. We show that NANOS3 is over-expressed by invasive lung cancer cells and is a prognostic marker for non-small cell lung carcinomas (NSCLCs). NANOS3 gene expression is restricted in testis and brain and is regulated by epigenetic events. It is up-regulated in cultured cells undergoing epithelial - mesenchymal transition (EMT). NANOS3 over-expression in human NSCLC cell lines enhances their invasiveness by up-regulating EMT, whereas its silencing induces mesenchymal - epithelial transition. NANOS3 represses E-cadherin at the transcriptional level and up-regulates vimentin post-transcriptionally. Also, we show that NANOS3 binds mRNAs encoding vimentin and regulates the length of their poly(A) tail. Finally, NANOS3 can also protect vimentin mRNA from microRNA-mediated repression. We thus demonstrate a role for NANOS3 in the acquisition of invasiveness by human lung tumour cells and propose a new mechanism of post-transcriptional regulation of EMT.

Published
2015
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115. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Vesa Kataja, Aida Karina Dieffenbach, Chia-Ni Hsiung, Catherine S. Healey, Gie Hooi Tan, Soo Hwang Teo, Domenico Palli, Frederik Marme, Katri Pylkäs, Roger L. Milne, Jaana M. Hartikainen, Gord Glendon, Susan L. Slager, Chen-Yang Shen, Fredrick R. Schumacher, Daniel F. Schmidt, Suleeporn Sangrajrang, Kee Seng Chia, Lorna Gibson, Pascal Guénel, Alice S. Whittemore, Jenny Chang-Claude, Yu Tang Gao, Hidemi Ito, Simon S. Cross, Sofia Khan, Marie Sanchez, Daniel Vincent, Daniel Herrero, Nicola Miller, Antoinette Hollestelle, Caroline M. Seynaeve, Christopher A. Haiman, Hermann Brenner, Kay-Tee Khaw, Loris Bernard, Habibul Ahsan, Melissa C. Southey, David Van Den Berg, Martha J. Shrubsole, Daniel O. Stram, William Blot, Mel Maranian, Robert Winqvist, Keitaro Matsuo, John W. M. Martens, Heli Nevanlinna, Mia M. Gaudet, Anna Jakubowska, Christine D. Berg, Paul D.P. Pharoah, Jacques Simard, Manjeet K. Bolla, Dieter Flesch-Janys, Mark S. Goldberg, Paul Brennan, Ching Wan Chan, Sune F. Nielsen, Sara Lindström, Mitul Shah, Matthias W. Beckmann, Craig Luccarini, Jonathan Beesley, Kyriaki Michailidou, Paolo Peterlongo, Marc J. Gunter, Anna González-Neira, Ji Yeob Choi, Per Hall, Sarah Stewart-Brown, Keith Humphreys, Hui Cai, Kathleen E. Malone, Elinor J. Sawyer, Louise A. Brinton, Marjanka K. Schmidt, Xiao-Ou Shu, Barbara Perkins, Lotte Maxild Mortensen, Chiu-Chen Tseng, Hanne Meijers-Heijboer, Minouk J. Schoemaker, Keun-Young Yoo, Julia A. Knight, Alan Ashworth, Stig E. Bojesen, Kamila Czene, Artitaya Lophatananon, Graham G. Giles, S. Ahmed, Kazuo Tajima, Douglas F. Easton, Maria Kabisch, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Irene L. Andrulis, Clare Turnbull, Caroline Baynes, Christine B. Ambrosone, Jan Lubinski, Muriel A. Adank, A. Meindl, Taru A. Muranen, Siranoush Manoukian, Susan M. Gapstur, Natalia Bogdanova, Alexander Hein, Annika Lindblom, Nazneen Rahman, Annegien Broeks, Lothar Haeberle, Federico Canzian, G Pita, Ming-Feng Hou, Hiroji Iwata, Drakoulis Yannoukakos, Diana Torres, Vessela N. Kristensen, Peter Devilee, Qiuyin Cai, Christi J Asperen, John L. Hopper, Diether Lambrechts, Michael Lush, Hans Wildiers, Joe Dennis, Sandra L. Halverson, Carl Blomqvist, Erik Van Limbergen, Malin Sund, Daehee Kang, Grethe I. Grenaker Alnæs, Marilie D. Gammon, Ursula Eilber, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Kirsimari Aaltonen, Olivia Fletcher, Jonine D. Figueroa, Angela Cox, Pei Ei Wu, Maartje J. Hooning, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Malcolm W.R. Reed, Emily Hallberg, Sara Margolin, Volker Arndt, Montserrat Garcia-Closas, Francois Bacot, Rita K. Schmutzler, Julian Peto, David J. Hunter, Thomas Brüning, Katarzyna Jaworska, Christof Sohn, Børge G. Nordestgaard, Enes Makalic, Hatef Darabi, Barbara Burwinkel, Petra P.H. Peeters, J. Margriet Collée, Rongxi Yang, Robert N. Hoover, Eiliv Lund, Fergus J. Couch, Ute Hamann, Jirong Long, Wei Zheng, Sabine Behrens, Giske Ursin, Muhammad G. Kibriya, Claire Mulot, Laure Dossus, Helen Tsimiklis, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Alison M. Dunning, Lisa B. Signorello, Valerie Gaborieau, Kenneth Muir, Anthony J. Swerdlow, Javier Benitez, Judith S. Brand, Sander Canisius, Hoda Anton-Culver, Veli-Matti Kosma, Thilo Dörk, Sten Cornelissen, Christa Stegmaier, Cheng Har Yip, Brian E. Henderson, Harald Surowy, Jingmei Li, Nur Aishah Taib, W. Ryan Diver, Carmel Apicella, Janet E. Olson, Kristiina Aittomäki, Celine M. Vachon, Regina M. Santella, Dimitrios Trichopoulos, Jianjun Liu, Nick Orr, Martine Dumont, Christian Sutter, Sue K. Park, Mikael Hartman, Susan L. Neuhausen, Hui Miao, M. Pilar Zamora, Anna H. Wu, Rob B. van der Luijt, Isabel dos-Santos-Silva, Graham Casey, Henrik Flyger, M. Rosario Alonso, Nuria Álvarez, Michael J. Kerin, Loic Le Marchand, Jose Ignacio Arias Perez, Mikael Eriksson, Esther M. John, Quinten Waisfisz, Qin Wang, Daniel C. Tessier, Paolo Radice, Robert A.E.M. Tollenaar, James McKay, Silje Nord, Hiltrud Brauch, José María Huerta, Stephen J. Chanock, Mervi Grip, Patrick Neven, Senno Verhoef, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, and CCA - Oncogenesis

Subjects
Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, Cohort Studies, brca1, Breast cancer, Research Support, N.I.H., Extramural, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, common variants, Journal Article, estrogen, chek2-asterisk-1100delc, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Non-U.S. Gov't, genotype imputation, risk, Genetic association, Research Support, Non-U.S. Gov't, Chromatin binding, Extramural, Cancer, Microarray Analysis, confer susceptibility, medicine.disease, 3. Good health, ovarian-cancer, Genetic Loci, Case-Control Studies, alleles, Female, Imputation (genetics), Genome-Wide Association Study, metaanalysis
Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Published
2015
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116. Open and Endovascular Treatment of Trans-Atlantic Inter-Society Consensus II D Aortoiliac Occlusive Lesions: What Determines the Rate of Restenosis?

Author

Yang Jiao, Miltiadis Krokidis, Yun-Feng Liu, Chen-yang Shen, Yongbao Zhang, Qingle Li, and Xiaoming Zhang

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, lcsh:Medicine, Arterial Occlusive Diseases, Femoral artery, Revascularization, Trans-Atlantic Inter-Society Consensus II, Iliac Artery, Aortoiliac Occlusive Lesions, Restenosis, Risk Factors, medicine.artery, medicine, Humans, Popliteal Artery, Risk factor, Survival analysis, Aged, Retrospective Studies, business.industry, Proportional hazards model, Risk Factor, Endovascular Procedures, lcsh:R, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Reconstruction, Popliteal artery, Surgery, Femoral Artery, Treatment Outcome, Female, Original Article, business, Angioplasty, Balloon
Abstract

Background: Open surgery is the preferred approach for the treatment of type D lesions according to the Trans-Atlantic Inter-Society Consensus (TASC) II guideline, but endovascular solutions also appear to be a valid option in selected patients. The study aimed to identify the risk factors of restenosis after open and endovascular reconstruction of symptomatic TASC II D aortoiliac occlusive lesions (AIOLs). Methods: Fifty-six patients (82 limbs) who underwent open repair and endovascular treatment (ET) for symptomatic TASC ΙΙ D AIOLs between March 2005 and December 2012 were retrospectively reviewed. Baseline characteristics, preoperative and postoperative imaging, and operation procedure reports were reviewed and analyzed. Restenosis after revascularization was assessed by duplex ultrasound or computed tomography angiogram. Kaplan-Meier survival analysis, Log-rank test, and multivariate Cox regression were used to evaluate the relevance between risk factors and patency. Results: The mean duration of follow-up was 42.8 ± 23.5 months (ranging from 3 to 90 months). Primary patency rates at 1-, 3-, 5-, and 7-year were 93.6%, 89.3%, 87.0%, and 70.3%, respectively. Restenosis after revascularization occurred in 11 limbs. Kaplan-Meier survival analysis and the Log-rank test revealed that diabetes, Rutherford classification ≥5 th and concurrent femoropopliteal TASC II type C/D lesions were significantly related to the duration of primary patency. According to the result of Cox regression, diabetes and femoropopliteal TASC ΙΙ type C/D lesions were identified as the risk factors for restenosis after revascularization. Conclusion: This study demonstrated that diabetes and femoropopliteal TASC ΙΙ type C/D lesions are risk factors associated with restenosis after open and ET of TASC II D AIOLs.

Published
2015

117. Aircraft noise, hearing ability, and annoyance

Author

Trong-Neng Wu, Jim Shoung Lai, Chen-Yang Shen, Tai-Sheng Yu, and Po-Ya Chang

Subjects
Jet planes -- Noise, Noise pollution -- Health aspects, Hearing loss -- Risk factors, Environmental issues, Health
Abstract

. The relationship between aircraft noise, loss of hearing and annoyance was explored in a study in two schools located near an international airport in Taiwan. Sixthgrade students (N = 242) were recruited from two schools and were classified into high-and low-noise-exposure groups, based on environmental noise measurements. Personal-equivalent 24-h noise exposure was measured to determine noise exposure at the individual level, and it was compared with hearing threshold level and with aircraft noise measured at the environmental level. individual hearing threshold levels did not differ between environmental high- and low-noise-exposure groups, as evidenced by the lack of difference between the two groups for noise exposure measured at the individual level. However, the proportion of students who were annoyed by aircraft noise was higher in the environmental high-noise-exposure group, although personal 24-h noise exposure was not a factor for annoyance. The results indicated that environmental noise measurement was not an appropriate criterion for assessment of auditory damage (or noise-induced hearing loss) in Taiwan. As well, aircraft-noise exposure in Taiwan did not appear to affect the hearing threshold but nonetheless annoyed schoolchildren near the airport., AS A CONSEQUENCE of the rapid increase in air traffic, aircraft-noise pollution in the vicinity of airports has become a major public health concern. Individuals who reside near an airport [...]

Published
1995

118. Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians

Author

Jirong Long, Anna H. Wu, Cheng Har Yip, Mikael Hartman, Mi Ryung Han, Chiu-Chen Tseng, Ji Yeob Choi, Artitaya Lophatananon, Douglas F. Easton, Xiao-Ou Shu, Joe Dennis, Soo Hwang Teo, Hui Miao, Chen-Yang Shen, Suleeporn Sangrajrang, Paul Brennan, Alison M. Dunning, Hidemi Ito, Qiuyin Cai, Kenneth Muir, Kyriaki Michailidou, Yu-Tang Gao, Qin Wang, Shou Tung Chen, Ying Zheng, Daehee Kang, Yong-Bing Xiang, Wei Zheng, Keitaro Matsuo, and Manjeet K. Bolla

Subjects
0301 basic medicine, Oncology, Risk, Asian Continental Ancestry Group, Cancer Research, medicine.medical_specialty, PALB2, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Original Manuscript, Breast Neoplasms, Penetrance, Polymorphism, Single Nucleotide, 03 medical and health sciences, Databases, Breast cancer, Asian People, Gene Frequency, Genetic, Internal medicine, Databases, Genetic, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, skin and connective tissue diseases, CHEK2, Alleles, Genetic Association Studies, Gynecology, business.industry, Chromosome Mapping, Genetic Variation, General Medicine, Single Nucleotide, medicine.disease, Minor allele frequency, 030104 developmental biology, Population Surveillance, RAD51C, Female, Breast Cancer Genetics, business
Abstract

Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS). We found three missense variants with minor allele frequency (MAF)

Published
2017
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119. Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Author

Javier Benitez, Sara Margolin, Diether Lambrechts, Alexandra J. van den Broek, Chen-Yang Shen, Veli-Matti Kosma, Matthias W. Beckmann, Siranoush Manoukian, Antoinette Hollestelle, Montserrat Garcia-Closas, Paul Brennan, Chiu-Chen Tseng, Marjanka K. Schmidt, Carolien H.M. van Deurzen, Peter A. Fasching, Melissa C. Southey, Manjeet K. Bolla, Robert Winqvist, Keitaro Matsuo, Douglas F. Easton, Carl Blomqvist, Adelheid Soubry, Paul D.P. Pharoah, Pascal Guénel, Jenna Lilyquist, Anna González-Neira, Hidemi Ito, Daehee Kang, Thérèse Truong, Fergus J. Couch, Renske Keeman, Kenneth Muir, Caroline Seynaeve, Katri Pylkäs, Simon S. Cross, Per Hall, Olivier Brouckaert, Roger L. Milne, Cheng Har Yip, Qin Wang, Sten Cornelissen, Anja Rudolph, Kamila Czene, Artitaya Lophatananon, Mikael Eriksson, Xiao-Ou Shu, Jonine D. Figueroa, Julia A. Knight, Arto Mannermaa, Jyh-Cherng Yu, Hans Wildiers, John L. Hopper, Wei Zheng, Jingmei Li, Rob A. E. M. Tollenaar, Anthony J. Swerdlow, Hermann Brenner, Henrik Flyger, Patrick Neven, Georgia Chenevix-Trench, Irene L. Andrulis, Paolo Peterlongo, Ji Yeob Choi, Annouschka Laenen, Annika Lindblom, Hiltrud Brauch, Anna H. Wu, Heli Nevanlinna, Michael Jones, Angela Cox, Volker Arndt, Soo-Hwang Teo, Jenny Chang-Claude, Stig E. Bojesen, Graham G. Giles, Suleeporn Saajrang, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Benitez, Javier [0000-0002-0923-7202], Blomqvist, Carl [0000-0003-3041-1938], Brauch, Hiltrud [0000-0001-7531-2736], Brenner, Hermann [0000-0002-6129-1572], Chenevix-Trench, Georgia [0000-0002-1878-2587], Cox, Angela [0000-0002-5138-1099], Eriksson, Mikael [0000-0001-8135-4270], González-Neira, Anna [0000-0002-5421-2020], Guénel, Pascal [0000-0002-8359-518X], Jones, Michael [0000-0001-7479-3451], Li, Jingmei [0000-0001-8587-7511], Matsuo, Keitaro [0000-0003-1761-6314], Peterlongo, Paolo [0000-0001-6951-6855], Pylkäs, Katri [0000-0002-2449-0521], Southey, Melissa C [0000-0002-6313-9005], Swerdlow, Anthony [0000-0001-5550-4159], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Lambrechts, Diether [0000-0002-3429-302X], Apollo - University of Cambridge Repository, Medical Oncology, Pathology, Department of Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, HUS Comprehensive Cancer Center, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), National Health and Medical Research Council (Australia), New South Wales Cancer Council (Reino Unido), Victorian Health Promotion Foundation, Dutch Cancer Society (Holanda), Agence Nationale de la Recherche (Francia), French Agency for Food, Environmental and Occupational Health & Safety (Francia), Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Centro de Investigación Biomedica en Red - CIBER, Federal Ministry of Education & Research (Alemania), Cancer Society of Finland, Ministry of Education, Culture, Sports, Science, and Technology (Japón), Japan Agency for Medical Research and Development, United States Army Medical Research and Development Command, California Breast Cancer Research Program, German Cancer Aid, Ministry of Higher Education (Malasia), Biomedical Research Council (Singapore), National Institutes of Health (Estados Unidos), and National Research Foundation of Korea

Subjects
0301 basic medicine, Oncology, Triple Negative Breast Neoplasms, Cohort Studies, 0302 clinical medicine, HORMONE-RECEPTOR STATUS, Medizinische Fakultät, Risk Factors, Odds Ratio, Young adult, Reproductive History, POPULATION, Age at menarche, education.field_of_study, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Parity, PREGNANCY, 030220 oncology & carcinogenesis, Age at breast cancer diagnosis, kConFab, Menarche, Female, Cohort study, Research Article, Adult, medicine.medical_specialty, 3122 Cancers, Population, Breast Neoplasms, DIAGNOSIS, lcsh:RC254-282, Risk Assessment, MENARCHE, 1ST BIRTH, 03 medical and health sciences, Young Adult, AGE, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Journal Article, medicine, Biomarkers, Tumor, Humans, ddc:610, education, Aged, Gynecology, Pregnancy, business.industry, Odds ratio, medicine.disease, 030104 developmental biology, Age at first full-time pregnancy, Breast cancer subtype, business
Abstract

Background Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. Methods We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. Results Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16–1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01–2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45–1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70–0.88, p, published version, peerReviewed

Published
2017
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120. T Oligo-Primed Polymerase Chain Reaction (TOP-PCR): A Robust Method for the Amplification of Minute DNA Fragments in Body Fluids

Author

Kuo Ping Chiu, Yu-Feng Huang, Alice L. Yu, Chen-Yang Shen, Tzu-Han Chen, Yu-Shin Nai, Hsin-Chieh Shiau, Mohit K. Midha, and Chien-Jen Chen

Subjects
0301 basic medicine, Poly T, Sensitivity and Specificity, Polymerase Chain Reaction, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, law, Multiplex polymerase chain reaction, Genetics, Humans, Ligase chain reaction, Polymerase chain reaction, DNA Primers, Multidisciplinary, Inverse polymerase chain reaction, Multiple displacement amplification, Reproducibility of Results, Molecular biology, Body Fluids, Good Health and Well Being, 030104 developmental biology, Real-time polymerase chain reaction, chemistry, Generic health relevance, Cell-Free Nucleic Acids, Hot start PCR, DNA
Abstract

Body fluid DNA sequencing is a powerful noninvasive approach for the diagnosis of genetic defects, infectious agents and diseases. The success relies on the quantity and quality of the DNA samples. However, numerous clinical samples are either at low quantity or of poor quality due to various reasons. To overcome these problems, we have developed T oligo-primed polymerase chain reaction (TOP-PCR) for full-length nonselective amplification of minute quantity of DNA fragments. TOP-PCR adopts homogeneous “half adaptor” (HA), generated by annealing P oligo (carrying a phosphate group at the 5′ end) and T oligo (carrying a T-tail at the 3′ end), for efficient ligation to target DNA and subsequent PCR amplification primed by the T oligo alone. Using DNA samples from body fluids, we demonstrate that TOP-PCR recovers minute DNA fragments and maintains the DNA size profile, while enhancing the major molecular populations. Our results also showed that TOP-PCR is a superior method for detecting apoptosis and outperforms the method adopted by Illumina for DNA amplification.

Published
2017
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121. Association analysis identifies 65 new breast cancer risk loci

Author

Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Published
2017
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122. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1

Author

Siew-Kee Low, Wei Lu, Min Ho Park, Yoshio Kasuga, Jiemin Liao, Sei Hyun Ahn, Ji Yeob Choi, Hyuna Sung, Michiaki Kubo, Bingshan Li, Kyota Ashikawa, Yanfeng Zhang, Hidemi Ito, Koichi Matsuda, Chen-Yang Shen, Ryan J. Delahanty, Bu Tian Ji, Yu-Tang Gao, Han Sung Kang, Yusuke Nakamura, Motoki Iwasaki, Hiroji Iwata, Chia-Ni Hsiung, Mi Kyung Kim, Ying Zheng, Ellen P S Man, Daehee Kang, Ui-Soon Khoo, Soo Hwang Teo, Xiao-Ou Shu, Yong-Bing Xiang, Wanqing Wen, Jiajun Shi, Wei Zheng, Chun Li, Shoichiro Tsugane, Keitaro Matsuo, Hui Miao, Peter B. Kang, Pei-Ei Wu, Qiuyin Cai, Sue K. Park, Kelvin Y.K. Chan, Dong-Young Noh, Jirong Long, Shivaani Mariapun, Ben Zhang, Sun-Seog Kweon, Atsushi Takahashi, Mikael Hartman, and Min-Ho Shin

Subjects
Adult, Risk, Breast Neoplasms, Genome-wide association study, Biology, White People, Article, Breast cancer, Asian People, Genetics, medicine, Genome-Wide Association Analysis, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Genetic association, Chromosomes, Human, Pair 15, Asia, Eastern, Case-control study, Middle Aged, medicine.disease, 3. Good health, Chromosomes, Human, Pair 1, Genetic Loci, Case-Control Studies, Susceptibility locus, Chromosomes, Human, Pair 5, Female, Genome-Wide Association Study
Abstract

In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

Published
2014
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123. Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry

Author

Hidemi Ito, Ji Yeob Choi, Douglas F. Easton, Keitaro Matsuo, Paul D.P. Pharoah, Joe Dennis, Daehee Kang, Xingyi Guo, Yong-Bing Xiang, Ying Zheng, Montserrat Garcia-Closas, Chen-Yang Shen, Paul Brennan, Chiu-Chen Tseng, Manjeet K. Bolla, Wanqing Wen, Qiuyin Cai, Soo Hwang Teo, Jacques Simard, Kyriaki Michailidou, Wei Zheng, Xiao-Ou Shu, Per Hall, Yu-Tang Gao, Hui Miao, Qin Wang, Anna H. Wu, Jirong Long, Cheng Har Yip, Artitaya Lophatananon, Suleeporn Sangrajrang, Alison M. Dunning, Kenneth Muir, Shou-Tung Chen, Mikael Hartman, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Genome-wide association study, Bioinformatics, 0302 clinical medicine, Risk Factors, Surgical oncology, Odds Ratio, skin and connective tissue diseases, Medicine(all), Research Support, Non-U.S. Gov't, Methodology for SNP data analysis, 3. Good health, Population Surveillance, 030220 oncology & carcinogenesis, Female, Risk assessment, Algorithms, Research Article, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, Breast Neoplasms, Single-nucleotide polymorphism, Risk Assessment, 03 medical and health sciences, Breast cancer, Asian People, Research Support, N.I.H., Extramural, Prediction model, Internal medicine, Journal Article, medicine, Humans, Genetic Predisposition to Disease, Statistical methods in genetics, Genetic Association Studies, Genetic association, Models, Statistical, business.industry, Case-control study, Genetic Variation, Odds ratio, medicine.disease, 030104 developmental biology, Case-Control Studies, business, Breast cancer risk, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract

Background Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. Methods We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. Results We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P

Published
2016
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124. Association of Diabetes With All-Cause and Cause-Specific Mortality in Asia

Author

Woon-Puay Koh, Keiko Wada, Keun-Young Yoo, Yoon Ok Ahn, Manami Inoue, Shoichiro Tsugane, Jian-Min Yuan, Jing Gao, Xiao-Ou Shu, John D. Potter, Eiko Saito, Yumi Sugawara, Norie Sawada, Jae Jeong Yang, Seiki Kanemura, Chen-Yang Shen, Eric J. Grant, Mangesh S. Pednekar, Chisato Nagata, Fujiko Irie, Wanqing Wen, Keitaro Matsuo, Shafiur Rahman, Wen-Harn Pan, Hidemi Ito, Hui Cai, Pei Ei Wu, Hong Lan Li, San Lin You, Yu Chen, Sue K. Park, Jiang He, Shu Zhang, Toshimi Sairenchi, Prakash C. Gupta, Kee Seng Chia, Habibul Ashan, Yasutake Tomata, Jin-Hu Fan, Chien-Jen Chen, Paolo Boffetta, Myung Hee Shin, Akiko Tamakoshi, Yu-Tang Gao, Wei Zheng, Danxia Yu, Yong-Bing Xiang, Daehee Kang, Ichiro Tsuji, Renwei Wang, Atsuko Sadakane, Dongfeng Gu, You-Lin Qiao, Yang J.J., Yu D., Wen W., Saito E., Rahman S., Shu X.-O., Chen Y., Gupta P.C., Gu D., Tsugane S., Xiang Y.-B., Gao Y.-T., Yuan J.-M., Tamakoshi A., Irie F., Sadakane A., Tomata Y., Kanemura S., Tsuji I., Matsuo K., Nagata C., Chen C.-J., Koh W.-P., Shin M.-H., Park S.K., Wu P.-E., Qiao Y.-L., Pednekar M.S., He J., Sawada N., Li H.-L., Gao J., Cai H., Wang R., Sairenchi T., Grant E., Sugawara Y., Zhang S., Ito H., Wada K., Shen C.-Y., Pan W.-H., Ahn Y.-O., You S.-L., Fan J.-H., Yoo K.-Y., Ashan H., Chia K.S., Boffetta P., Inoue M., Kang D., Potter J.D., and Zheng W.

Subjects
Adult, Male, Asia, Risk Factors, Diabetes management, Cause of Death, Diabetes mellitus, Diabetes Mellitus, Prevalence, medicine, Humans, Prospective Studies, Prospective cohort study, Proportional Hazards Models, Aged, business.industry, Proportional hazards model, Hazard ratio, Diabetes Mellitu, General Medicine, Middle Aged, medicine.disease, Prospective Studie, Relative risk, Cohort, Proportional Hazards Model, Female, business, Body mass index, Human, Demography
Abstract

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations. Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status. Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018. Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction

Published
2019
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125. Tobacco Smoking and Mortality in Asia

Author

Ichiro Tsuji, Hidemi Ito, Hong Lan Li, San Lin You, Kee Seng Chia, Fujiko Irie, Shoichiro Tsugane, Keiko Wada, Jian-Min Yuan, Eiko Saito, Woon-Puay Koh, Manami Inoue, Keun-Young Yoo, Myung Hee Shin, Jing Gao, Mangesh S. Pednekar, Chisato Nagata, Chen-Yang Shen, John D. Potter, Yoon Ok Ahn, You-Lin Qiao, Paolo Boffetta, Dongfeng Gu, Habibul Ashan, Daehee Kang, Renwei Wang, Chien-Jen Chen, Norie Sawada, Keitaro Matsuo, Atsuko Sadakane, Wen-Harn Pan, Wanqing Wen, Danxia Yu, Yong-Bing Xiang, Hui Cai, Sue K. Park, Xiao-Ou Shu, Akiko Tamakoshi, Yu-Tang Gao, Jiang He, Shafiur Rahman, Yumi Sugawara, Wei Zheng, Yasutake Tomata, Eric J. Grant, Jae Jeong Yang, Seiki Kanemura, Prakash C. Gupta, Yang J.J., Yu D., Wen W., Shu X.-O., Saito E., Rahman S., Gupta P.C., He J., Tsugane S., Xiang Y.-B., Gao Y.-T., Koh W.-P., Tamakoshi A., Irie F., Sadakane A., Tsuji I., Kanemura S., Matsuo K., Nagata C., Chen C.-J., Yuan J.-M., Shin M.-H., Park S.K., Pan W.-H., Qiao Y.-L., Pednekar M.S., Gu D., Sawada N., Li H.-L., Gao J., Cai H., Grant E., Tomata Y., Sugawara Y., Ito H., Wada K., Shen C.-Y., Wang R., Ahn Y.-O., You S.-L., Yoo K.-Y., Ashan H., Chia K.S., Boffetta P., Inoue M., Kang D., Potter J.D., and Zheng W.

Subjects
Asia, business.industry, Hazard ratio, Tobacco control, General Medicine, medicine.disease, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Relative risk, Cohort, Attributable risk, Tobacco Smoking, medicine, Humans, 030212 general & internal medicine, Cohort Studie, Prospective cohort study, Lung cancer, business, Human, Demography, Cohort study
Abstract

Importance Understanding birth cohort–specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations. Objectives To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations. Design, Setting, and Participants This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India. Exposures Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking. Main Outcomes and Measures Country or region and birth cohort–specific mortality and the population attributable risk for deaths from all causes and from lung cancer. Results Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions. Conclusions and Relevance In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

Published
2019
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126. Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

Author

Per Hall, Hui Cai, Roger L. Milne, Douglas F. Easton, Anja Rudolph, José Ignacio Arias, Vessela N. Kristensen, Julia A. Knight, Lisa B. Signorello, Petra Seibold, Jonathan Tyrer, Arto Mannermaa, Alan Ashworth, Andreas Schneeweiss, Sandra Deming-Halverson, Katarzyna Durda, Kimael Eriksson, Thilo Dörk, Isabel dos Santos Silva, Alfons Meindl, Laura Baglietto, Fredrick R. Schumacher, Peter Devilee, Qiuyin Cai, Janet E. Olson, Keith Humphreys, Annegien Broeks, Soo Hwang Teo, Michael P. Lux, Sze Yee Phuah, Federick Marme, Pascal Guénel, Hidemi Ito, Irene L. Andrulis, Natalia Bogdanova, Christoph Engel, Juliet D. French, Nina Ditsch, Xianshu Wang, Susan L. Slager, Bernardo Bonanni, Hermann Brenner, Nick Orr, Marie Rose Christiaens, Martine Dumont, Martin O'Reilly, Annika Lindblom, Catriona McLean, Ans M.W. van den Ouweland, Marjanka K. Schmidt, Sara Margolin, Kerstin B. Meyer, Martha J. Shrubsole, Malcolm W.R. Reed, Hans Ulrich Ulmer, Georgia Chenevix-Trench, Kyriaki Michailidou, Brian E. Henderson, Nicola Miller, Sandrine Tchatchou, Stig E. Bojesen, Pornthep Siriwanarangsan, Joe Dennis, Jaana M. Hartikainen, Matthias W. Beckmann, Fergus J. Couch, David Van Den Berg, Celine M. Vachon, Pierre Laurent-Puig, Montserrat Garcia-Closas, Ian Tomlinson, Thomas Brüning, Maya Ghoussaini, Mikael Hartman, Kristiina Aittomäki, Thérèse Truong, Katarzyna Jaworska, Yon Ko, Yu Tang Gao, Paolo Peterlongo, Stacey L. Edwards, Saskia Carlebur, Hartef Darabi, Pei Ei Wu, Ute Hamann, M. Pilar Zamora, Taru A. Muranen, Jirong Long, Stephen J. Chanock, William Blot, Sonja Helbig, Heiko Müller, Christina Clarke Dur, Ji Yeob Choi, Melissa C. Southey, Olivia Fletcher, Ming-Feng Hou, Hiroji Iwata, Nichola Johnson, Wei Zheng, Robert Winqvist, Diether Lambrechts, Javier Benitez, Chen-Yang Shen, Suleeporn Sangrajrang, Chia-Ni Hsiung, James McKay, Kristen S. Purrington, Cheng Har Yip, Ann Smeets, Valerie Gaborieau, Keitaro Matsuo, Anthony J. Swerdlow, Anne Lise Børresen-Dale, Anna Jakubowska, Dong Young Noh, Paul D.P. Pharoah, Ines de Santiago, Hiltrud Brauch, Vesa Kataja, Yasushi Yatabe, Anna H. Wu, Grethe I. Grenaker Alnæs, Jonine D. Figueroa, Christopher A. Haiman, Florence Menegaux, Hoda Anton-Culver, Paul Brennan, Veli-Matti Kosma, Bruce A.J. Ponder, Dieter Flesch-Janys, Thomas Rüdiger, Shaik Ahmad Buhari, Katri Pylkäs, Gord Glendon, Rita K. Schmutzler, Julian Peto, Chiu-Chen Tseng, Sune F. Nielsen, Mark S. Goldberg, Angela Cox, Carolien H.M. van Deurzen, Artitaya Lophatananon, Radhika Prathalingham, Børge G. Nordestgaard, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Florentia Fostira, Wei-Yen Lim, Barbara Burwinkel, Jenny Chang-Claude, Michael J. Kerin, Maartje J. Hooning, Kamila Czene, Asta Försti, Loic Le Marchand, Gianluca Severi, Volker Arndt, John L. Hopper, Jan Lubinski, Jacques Simard, Frans B. L. Hogervorst, Alison M. Dunning, Kenneth Muir, Saila Kauppila, Laura J. van't Veer, John W.M. Martens, Helen Tsimiklis, Loris Bernard, Heli Nevanlinna, Jolanta Lissowska, Robert Pilarski, Qin Wang, Paolo Radice, Robert A.E.M. Tollenaar, Jianjun Liu, Graham G. Giles, Henrik Flyger, Arif B. Ekici, Xiao-Ou Shu, Manjeet K. Bolla, Carl Blomqvist, Daehee Kang, Argyrios Ziogas, Bernard Thienpont, Patricia Harrington, Sue K. Park, Christa Stegmaier, Sarah Stewart-Brown, Elinor J. Sawyer, Miao Hui, Susan L. Neuhausen, Daniel O. Stram, Christof Sohn, Minouk J. Schoemaker, Jingmei Li, Carmel Apicella, Caroline M. Seynaeve, Clinical Genetics, Medical Oncology, Pathology, and Cardiothoracic Surgery

Subjects
Fibroblast Growth Factor, african-american, Genome-wide association study, Medical and Health Sciences, Chromosome conformation capture, 0302 clinical medicine, 2.1 Biological and endogenous factors, Genetics(clinical), Aetiology, Promoter Regions, Genetic, Genetics (clinical), Cancer, African Continental Ancestry Group, Genetics & Heredity, Genetics, 0303 health sciences, Tumor, Chromosome Mapping, Biological Sciences, 3. Good health, Chromatin, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, kConFab Investigators, Female, RNA Interference, women, GENICA Network, transcription, reveals, Type 2, Alleles, Asian Continental Ancestry Group, Binding Sites, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromatin Immunoprecipitation, E2F1 Transcription Factor, European Continental Ancestry Group, Genetic Association Studies, Haplotypes, Hepatocyte Nuclear Factor 3-alpha, Humans, Position-Specific Scoring Matrices, Protein Binding, Receptor, Fibroblast Growth Factor, Type 2, Genetic Loci, Receptor, Australian Ovarian Cancer Study Group, Black People, Single-nucleotide polymorphism, Locus (genetics), Biology, determinant, White People, Article, Cell Line, estrogen-receptor binding, Promoter Regions, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Asian People, Breast Cancer, expression, ddc:610, Allele, 030304 developmental biology, Neoplastic, Prevention, Human Genome, Molecular biology, susceptibility loci, Gene Expression Regulation, genome-wide association, chromatin, Hypersensitive site, Chromatin immunoprecipitation
Abstract

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. © 2013 The American Society of Human Genetics.

Published
2013
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127. New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women

Author

Yong-Bing Xiang, Yu-Tang Gao, Chen-Yang Shen, Jirong Long, Min Hyuk Lee, Qiuyin Cai, Sung Won Kim, Jiajun Shi, Wei Zheng, Jong Won Lee, Ying Zheng, Motoki Iwasaki, Sei Hyun Ahn, Bu Tian Ji, Keun-Young Yoo, Wei Lu, Dong Young Noh, Hyuna Sung, Jong-Young Lee, Keitaro Matsuo, Wenjing Wang, Mi Kyung Kim, Xiao-Ou Shu, Ben Zhang, Ji-Yeob Choi, Wonshik Han, Shoichiro Tsugane, Daehee Kang, and Sue K. Park

Subjects
Adult, Oncology, China, medicine.medical_specialty, Genotype, Epidemiology, Breast Neoplasms, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Breast cancer, Asian People, Japan, Risk Factors, Internal medicine, Republic of Korea, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Genetics, Chromosomes, Human, Pair 10, business.industry, Chromosome Mapping, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Genetic Loci, Female, business
Abstract

Background: Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study (GWAS) conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations. Methods: We evaluated nine of those nonreplication loci in East Asians to identify new risk variants for breast cancer in these regions. First, we analyzed single-nucleotide polymorphisms (SNP) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (stage 1). In each region, we selected an SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (stage 2). Logistic regression models were used to calculate adjusted ORs and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants. Results: Two SNPs were replicated in stage 2 at P < 0.05: rs1419026 at 6q14 [per allele OR, 1.07; 95% confidence interval (CI), 1.03–1.12; P = 3.0 × 10−4] and rs941827 at 10q25 (OR, 0.92, 95% CI, 0.89–0.96; P = 5.3 × 10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR, 0.88; 95% CI, 0.82–0.97; P = 5.3 × 10−5). Conclusion: We identified a new breast cancer risk variant at 10q25 in East Asian women. Impact: Results from this study improve the understanding of the genetic basis for breast cancer. Cancer Epidemiol Biomarkers Prev; 22(7); 1297–303. ©2013 AACR.

Published
2013
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128. Changing Blood Lead Levels and Oxidative Stress with Duration of Residence Among Taiwan Immigrants

Author

Chen-Yang Shen, Chin-Ching Wu, Saou-Hsing Liou, Wei-Te Wu, Tsung-Yun Liu, Yu-Jen Lin, Trong-Neng Wu, and Chun-Yuh Yang

Subjects
Adult, Gerontology, medicine.medical_specialty, Time Factors, Epidemiology, media_common.quotation_subject, Immigration, Taiwan, Emigrants and Immigrants, medicine.disease_cause, Demographic data, Selenium, chemistry.chemical_compound, Malondialdehyde, Environmental health, Health care, medicine, Humans, media_common, business.industry, Public health, Public Health, Environmental and Occupational Health, Oxidative Stress, Lead, chemistry, Lead exposure, Female, Residence, business, Oxidative stress
Abstract

Immigrants lack appropriate health care access and other resources needed to reduce their exposure to preventable environmental health risks. Little is known about the impact of lead exposure and oxidative stress among immigrants. Thus, this study was to examine the differences between the blood lead levels (BLLs) and oxidative stress levels of immigrants and non-immigrants, and to investigate the determinants of increased BLLs or oxidative stress levels among immigrants. We collected demographic data of 239 immigrant women and 189 non-immigrant women who resettled in the central area of Taiwan. Each study participant provided blood samples for genotyping and for measuring blood metal levels and oxidative stress. Recent immigrants were at risk for elevated BLLs. Decreased BLLs, malondialdehyde (MDA), and increased blood selenium levels were significantly associated with duration of residence in Taiwan. Elevated BLLs and MDA in recent immigrants may serve as a warning sign for the health care system. The nation's health will benefit from improved regulation of living environments, thereby improving the health of immigrants.

Published
2013
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129. Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls

Author

Joe Dennis, Sarah Stewart-Brown, Per Hall, Hui Cai, Pei Ei Wu, Soo Chin Lee, Alison M. Dunning, Kenneth Muir, Wenjin Wang, Min Hyuk Lee, Francois Bacot, Hyuna Sung, Chiu-Chen Tseng, Zefang Ren, Hidemi Ito, Artitaya Lophatananon, Ben Zhang, Wei Lu, Kexin Chen, Jong Won Lee, Daniel O. Stram, Mi Kyung Kim, Wonshik Han, Chiun-Sheng Huang, Soo Hwang Teo, Ji Yeob Choi, David Van Den Berg, Hui Miao, Xiao-Ou Shu, Jiajun Shi, Wei Zheng, Mikael Hartman, Hongbing Shen, Jirong Long, Douglas F. Easton, Qin Wang, Javier Benitez, Chun Li, Hideo Tanaka, Jyh Cherng Yu, Bu Tian Ji, Motoki Iwasaki, Daniel C. Tessier, Thomas C. Putti, Daniel Vincent, Tien Yin Wong, Ming-Feng Hou, Ui-Soon Khoo, Keitaro Matsuo, Cheng Har Yip, Hiroji Iwata, Keun-Young Yoo, Dong Young Noh, Paul D.P. Pharoah, Anna H. Wu, Sung-Won Kim, In Nee Kang, Yong-Bing Xiang, Ying Zheng, Wanqing Wen, Jong-Young Lee, Pornthep Siriwanarangsan, Chen-Yang Shen, Suleeporn Sangrajrang, Daehee Kang, Aiko Sueta, Yu Tang Gao, Qiuyin Cai, Kyriaki Michailidou, Manjeet K. Humphreys, Sue K. Park, and Christopher A. Haiman

Subjects
Adult, Oncology, China, medicine.medical_specialty, Population, Estrogen receptor, Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Asian People, Internal medicine, Republic of Korea, Genetics, medicine, Humans, Genetic Predisposition to Disease, education, Molecular Biology, Genetics (clinical), Aged, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Association Studies Articles, Case-control study, Cancer, General Medicine, Middle Aged, medicine.disease, 3. Good health, Receptors, Estrogen, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Genome-Wide Association Study
Abstract

In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of, published_or_final_version

Published
2013
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130. Effects of chemokine-like factor 1 on vascular smooth muscle cell migration and proliferation in vascular inflammation

Author

Chen-yang Shen, Qingle Li, Peiying He, Xiaoming Zhang, Weidong Yu, Jian Chen, Tao Zhang, and Yang Jiao

Subjects
Male, Vasculitis, Neointima, Chemokine, Vascular smooth muscle, Cell, Muscle, Smooth, Vascular, Rats, Sprague-Dawley, Restenosis, Cell Movement, medicine, Animals, Humans, Cells, Cultured, Cell Proliferation, Neointimal hyperplasia, Gene knockdown, MARVEL Domain-Containing Proteins, biology, Chemistry, Chemotaxis, Anatomy, medicine.disease, Rats, medicine.anatomical_structure, cardiovascular system, Cancer research, biology.protein, Chemokines, Cardiology and Cardiovascular Medicine
Abstract

Objective Vascular smooth muscle cell (VSMC) migration and proliferation are key components of vascular inflammation that may lead to atherosclerosis and restenosis, in which cytokines are considered as pivotal factors regarding recruitment of VSMC. A member of recently described family of chemokines, chemokine-like factor 1 (CKLF1), displays a wide spectrum of chemotaxis. This study investigated the role of CKLF1 in VSMC migration and proliferation during the process of vascular inflammation. Methods and results : The effects of CKLF1 on migration, proliferation and neointimal formation were investigated in cultured VSMCs, rat balloon injured arteries and human atherosclerotic plaques. CKLF1 overexpression greatly enhanced, whereas shRNA knockdown markedly retarded, VSMC migration and proliferation in vitro . In addition, CKLF1 protein accumulated preferentially in neointima of the injured rat arteries in vivo . CKLF1 overexpression resulted in a 2.5-fold increase in intimal thickness. In contrast, shRNA-mediated CKLF1 knockdown significantly suppressed neointima formation by 70% compared that in control group. Intriguingly, besides animal model, higher level of CKLF1 was observed in human atherosclerotic plaques than that in normal arteries. Conclusion CKLF1 plays an essential role in migration and proliferation of VSMCs, which in turn facilitated neointimal hyperplasia and atherosclerosis. Inhibition of CKLF1 activity provides a potential target for the prevention of atherosclerosis and restenosis.

Published
2013
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131. B-Myb Induces APOBEC3B Expression Leading to Somatic Mutation in Multiple Cancers

Author

Wen-Cheng Chou, Chen-Yang Shen, Wei-Ting Chen, Ling-Yueh Hu, Chia-Ni Hsiung, Jyh-Cherng Yu, and Huan-Ming Hsu

Subjects
0301 basic medicine, DNA damage, Somatic hypermutation, Breast Neoplasms, Cell Cycle Proteins, Biology, Gene Expression Regulation, Enzymologic, Article, Minor Histocompatibility Antigens, 03 medical and health sciences, chemistry.chemical_compound, Transactivation, Germline mutation, Cytidine Deaminase, Humans, Multidisciplinary, Cytosine deaminase, Cytidine deaminase, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, 030104 developmental biology, chemistry, Mutation, Cancer research, MCF-7 Cells, Trans-Activators, Female, Cytosine, DNA, Signal Transduction
Abstract

The key signature of cancer genomes is the accumulation of DNA mutations, the most abundant of which is the cytosine-to-thymine (C-to-T) transition that results from cytosine deamination. Analysis of The Cancer Genome Atlas (TCGA) database has demonstrated that this transition is caused mainly by upregulation of the cytosine deaminase APOBEC3B (A3B), but the mechanism has not been completely characterized. We found that B-Myb (encoded by MYBL2) binds the A3B promoter, causing transactivation, and this is responsible for the C-to-T transitions and DNA hypermutation in breast cancer cells. Analysis of TCGA database yielded similar results, supporting that MYBL2 and A3B are upregulated and putatively promote C-to-T transitions in multiple cancer types. Moreover, blockade of EGF receptor with afatinib attenuated B-Myb–A3B signaling, suggesting a clinically relevant means of suppressing mutagenesis. Our results suggest that B-Myb–A3B contributes to DNA damage and could be targeted by inhibiting EGF receptor.

Published
2016

132. 11q13 is a susceptibility locus for hormone receptor positive breast cancer

Author

Dong Young Noh, Pascal Guénel, Graeme Elliott, Vesa Kataja, Shamil Gancev, Xianshu Wang, Shan Wang-Gohrke, Annegien Broeks, Florence Menegaux, Hans Wildiers, Richard van Hien, Natalia Bogdanova, Jean Wang, Puttisak Puttawibul, Betül T. Yesilyurt, Peter Devilee, Gord Glendon, Katri Pylkäs, Mark E. Sherman, Jenny Chang-Claude, Federik Marme, Michael Bremer, Katarzyna Durda, Sarah Schott, Vessela N. Kristensen, Paolo Radice, Teresa Selander, Kamila Czene, Alfons Meindl, Gianluca Severi, Angela Cox, Maartje J. Hooning, Claus R. Bartram, John L. Hopper, Ursel Eilber, Michael Jones, M. Pilar Zamora, Stephen J. Chanock, Laura Baglietto, Caroline M. Seynaeve, Daehee Kang, Thilo Dörk, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Loris Bernard, Stig E. Bojesen, Barbara Burwinkel, Douglas F. Easton, Arif B. Ekici, kConFab Investigators, Mervi Grip, Robert A.E.M. Tollenaar, Argyrios Ziogas, Jonathan Beesley, Paolo Peterlongo, Volker Arndt, Xiaoqing Chen, Nichola Johnson, Jaana M. Hartikainen, Ming-Feng Hou, Diether Lambrechts, Ruediger Schulz-Wendtland, Jan Lubinski, Taru A. Muranen, Heli Nevanlinna, Esther M. John, Graham G. Giles, Chen-Yang Shen, Jolanta Lissowska, Ian W. Brock, Grethe I. Grenaker Alnæs, Gillian S. Dite, Charlotte Lanng, Hiltrud Brauch, Anthony J. Swerdlow, MC Southey, Christina Justenhoven, Manjeet K. Humphreys, Keun-Young Yoo, Elinor J. Sawyer, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Fergus J. Couch, Peter Schürmann, Stefan Nickels, Jianjun Liu, Marjanka K. Schmidt, Zachary S. Fredericksen, Yuri I. Rogov, Ute Hamann, Elza Khusnutdinova, Hermann Brenner, Sara Margolin, Natalia Antonenkova, Peter A. Fasching, Matthias W. Beckmann, Johann H. Karstens, Montserrat Garcia-Closas, Patrick Neven, Thomas Brüning, Carl Blomqvist, Heiko Müller, Jyh Cherng Yu, Katarzyna Jaworska, Yon Ko, Pei Ei Wu, Arto Mannermaa, Rebecca Hein, Darya Prokofieva, Melissa C. Southey, Andreas Schneeweiss, Irene L. Andrulis, Christa Stegmaier, Robert Winqvist, Annika Lindblom, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Alexander Miron, Roger L. Milne, Marina Bermisheva, Dieter Flesch-Janys, Christof Sohn, Nicola Miller, Georgia Chenevix-Trench, Kristiina Aittomäki, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Siranoush Manoukian, Robert Paridaens, Anne Lise Børresen-Dale, Suthee Rattanamongkongul, Olivia Fletcher, Simon S. Cross, Artitaya Lophatananon, Isabel dos Santos Silva, Janet E. Olson, Nick Orr, Per Hall, Alan Ashworth, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Alison M. Dunning, Kenneth Muir, Sten Cornelissen, Carmel Apicella, Arja Jukkola-Vuorinen, Michael J. Kerin, ~, and Medical Oncology

Subjects
Oncology, hormone receptor status, Estrogen receptor, Genome-wide association study, 0302 clinical medicine, Risk Factors, Genotype, Receptors, single-nucleotide polymorphisms, common variants, Pair 11, Progesterone, Genetics (clinical), Genetics, 0303 health sciences, repair genes, Single Nucleotide, identifies 5, 11q13, Breast cancer susceptibility, Genome-wide association, Hormone receptor status, Polymorphisms, Risk factors, Breast Neoplasms, Chromosomes, Human, Pair 11, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, 3. Good health, ovarian-cancer, 030220 oncology & carcinogenesis, Human, brca1 mutations, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, Article, White People, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Polymorphism, 030304 developmental biology, breast cancer susceptibility, Odds ratio, tumor characteristics, medicine.disease, confer susceptibility, Estrogen, genome-wide association, family registry, Ovarian cancer, polymorphisms
Abstract

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

Published
2016
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133. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author

Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed

Published
2016
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134. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author

Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, 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Human Genet, D-48149 Munster, Germany [ 137 ] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France [ 138 ] Inst Curie, Dept Tumour Biol, Paris, France [ 139 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 140 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France [ 141 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 142 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 143 ] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain [ 144 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 145 ] Univ Helsinki, Cent Hosp, Helsinki, Finland [ 146 ] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands [ 147 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands [ 148 ] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands [ 149 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 150 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 151 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 152 ] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain [ 153 ] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 154 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain [ 155 ] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital University of Iceland [ 156 ] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland [ 157 ] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada [ 158 ] Univ Laval, Quebec City, PQ, Canada [ 159 ] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada [ 160 ] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy [ 161 ] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal [ 162 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 163 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 164 ] McGill Univ, Program Canc Genet, Montreal, PQ, Canada [ 165 ] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic [ 166 ] Masaryk Univ, Fac Med, Brno, Czech Republic [ 167 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 168 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria [ 169 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 170 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA [ 171 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 172 ] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel [ 173 ] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 174 ] NN Petrov Oncol Res Inst, St Petersburg, Russia [ 175 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 176 ] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia [ 177 ] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA [ 178 ] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada [ 179 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada [ 180 ] Vejle Hosp, Dept Clin Genet, Vejle, Denmark [ 181 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark [ 182 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 183 ] Univ Hosp Pisa, Pisa, Italy [ 184 ] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia [ 185 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 186 ] Lund Univ, Dept Oncol, Lund, Sweden [ 187 ] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden [ 188 ] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden [ 189 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 190 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 191 ] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 192 ] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 193 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 194 ] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA [ 195 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 196 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 197 ] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia [ 198 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 199 ] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA [ 200 ] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada [ 201 ] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia [ 202 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 203 ] Harvard Univ, Sch Med, Boston, MA USA [ 204 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 205 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA [ 206 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England

Subjects
0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund

Published
2016
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135. Genome-wide association study in East Asians identifies two novel breast cancer susceptibility loci

Author

Siew-Kee Low, Qiuyin Cai, Mi Ryung Han, Dong Young Noh, Jirong Long, Ji Yeob Choi, Min-Ho Shin, Yu-Tang Gao, Yong-Bing Xiang, Hidemi Ito, Chen-Yang Shen, Min Ho Park, Koichi Matsuda, Motoki Iwasaki, Atsushi Takahashi, Bingshan Li, Ying Zheng, Wanqing Wen, Hiroji Iwata, Shoichiro Tsugane, Keitaro Matsuo, Xingyi Guo, Daehee Kang, Jiajun Shi, Wei Zheng, Michiaki Kubo, Sue K. Park, Mi Kyung Kim, Xiao-Ou Shu, Yoshio Kasuga, and Sun-Seog Kweon

Subjects
0301 basic medicine, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, Asian People, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Molecular Biology, Allele frequency, Genetics (clinical), Asia, Eastern, Association Studies Articles, General Medicine, Odds ratio, Middle Aged, medicine.disease, 030104 developmental biology, Genetic Loci, Female, Genome-Wide Association Study
Abstract

Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have been shown to play an important role in breast cancer aetiology. We conducted a two-stage genome-wide association study (GWAS) including 14 224 cases and 14 829 controls of East Asian women to search for novel genetic susceptibility loci for breast cancer. Single nucleotide polymorphisms (SNPs) in two loci were found to be associated with breast cancer risk at the genome-wide significance level. The first locus, represented by rs12118297 at 1p22.3 (near the LMO4 gene), was associated with breast cancer risk with odds ratio (OR) and (95% confidence interval (CI)) of 0.91 (0.88-0.94) and a P-value of 4.48 × 10- 8 This association was replicated in another study, DRIVE GAME-ON Consortium, including 16 003 cases and 41 335 controls of European ancestry (OR = 0.95, 95% CI = 0.91-0.99, P-value = 0.019). The second locus, rs16992204 at 21q22.12 (near the LINC00160 gene), was associated with breast cancer risk with OR (95% CI) of 1.13 (1.07-1.18) and a P-value of 4.63 × 10 - 8 The risk allele frequency for this SNP is zero in European-ancestry populations in 1000 Genomes Project and thus its association with breast cancer risk cannot be assessed in DRIVE GAME-ON Consortium. Functional annotation using the ENCODE data indicates that rs12118297 might be located in a repressed element and locus 21q22.12 may affect breast cancer risk through regulating LINC00160 expressions and interaction with oestrogen receptor signalling. Our findings provide additional insights into the genetics of breast cancer.

Published
2016

136. Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer

Author

I-Chun Chen, Ming-Yang Wang, Kuei-Pin Chung, Tsu-Hsin Hsueh, Kuan-Ting Kuo, Yuan-Ching Chang, Chiun-Sheng Huang, Pei-Fang Wu, Ching-Hung Lin, Ann-Lii Cheng, Chen-Yang Shen, Tzu-Pin Lu, Wen-Hung Kuo, and Yen-Shen Lu

Subjects
Adult, 0301 basic medicine, Oncology, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Receptor, ErbB-2, Population, Estrogen receptor, CA 15-3, Breast Neoplasms, Protein Serine-Threonine Kinases, medicine.disease_cause, Disease-Free Survival, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, AMP-Activated Protein Kinase Kinases, Internal medicine, Gene expression, medicine, Humans, skin and connective tissue diseases, education, Aged, Neoplasm Staging, Regulation of gene expression, education.field_of_study, Multidisciplinary, business.industry, Middle Aged, Prognosis, medicine.disease, Gene Expression Regulation, Neoplastic, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Neoplasm Recurrence, Local, Carcinogenesis, business
Abstract

Liver kinase B1 (LKB1) is a tumor suppressor, and its loss might lead to activation of the mammalian target of rapamycin (mTOR) and tumorigenesis. This study aimed to determine the clinical relevance of LKB1 gene and protein expression in breast cancer patients. LKB1 protein expression was evaluated using immunohistochemistry in tumors from early breast cancer patients in two Taiwanese medical centers. Data on LKB1 gene expression were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set. The correlations between LKB1 expression, clinicopathologic factors, and patient outcome were analyzed. LKB1 expression was significantly associated with estrogen receptor (ER) expression in 2 of the 4 cohorts, but not with other clinicopathologic factors. LKB1 expression was not a predictor for relapse-free survival, overall survival (OS), or breast cancer-specific survival. In a subgroup analysis of the two Taiwanese cohorts, high LKB1 protein expression was predictive of high OS in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients (P = 0.013). Our study results indicate that LKB1 expression is not prognostic in the whole population of breast cancer patients, but it is a potential predictor of OS in the subset of HER2-positive patients

Published
2016
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137. Fanconi anemia genes in lung adenocarcinoma- a pathway-wide study on cancer susceptibility

Author

Shi Yi Yang, Ying-Huang Tsai, Pan-Chyr Yang, Chao A. Hsiung, Chen-Yang Shen, Yuh Min Chen, Chia-Ni Hsiung, Jyh Cherng Yu, Huan Ming Hsu, Ming Shyan Huang, Wu Chou Su, Kuan-Yu Chen, Chien-Jen Chen, Yao Jen Li, Pei Ei Wu, and Gee-Chen Chang

Subjects
0301 basic medicine, Oncology, Lung adenocarcinoma, Male, medicine.medical_specialty, Lung Neoplasms, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA repair, Single-nucleotide polymorphism, Biology, Adenocarcinoma, 03 medical and health sciences, Gene interaction, Fanconi anemia, Internal medicine, Genotype, medicine, Genetic predisposition, Genetic susceptibility, Humans, Pharmacology (medical), Genetic Predisposition to Disease, Polymorphism, Lung cancer, Molecular Biology, Genetics, Biochemistry, medical, BRCA2 Protein, Polymorphism, Genetic, Research, Biochemistry (medical), Fanconi Anemia Complementation Group C Protein, Case-control study, General Medicine, Cell Biology, medicine.disease, 030104 developmental biology, Female
Abstract

Background Carcinogens in cigarette smoke can induce the formation of DNA-DNA cross-links, which are repaired by the Fanconi anemia (FA) pathway, and it is tempting to speculate that this pathway is involved in lung tumorigenesis. This study is to determine whether genetic polymorphism of the FA genes is associated with an elevated risk of lung adenocarcinoma, and whether the association between genotypes and risk is modified by exposure to cigarette smoke. Methods This case–control study genotyped 53 single-nucleotide polymorphisms (SNPs) in FA genes in 709 patients (354 males and 355 females) with lung adenocarcinoma and in 726 cancer-free individuals (339 males and 387 females). Genotypic frequencies of SNPs were compared between cases and controls to identify important FA genes associated with cancer susceptibility. Joint effects in determining cancer risk contributed by genes and smoking-related risk factors and by multiple genes involved in different FA subpathways were evaluated by multivariate regression analysis and stratified analysis. All analyses were performed on males and females separately, and the comparison of results was considered a way of examining the validity of study findings. Results Lung adenocarcinomas in both male and female patients were associated with (a) genotypic polymorphisms of FANCC and FANCD1; (b) a combined effect of harboring a higher number of high-risk genotypes and smoking/passive smoking; (c) specific interactions of multiple genes, proteins encoded by which have been known to work jointly within the FA pathway. Conclusions Genetic polymorphism of the FA genes is associated with inter-individual susceptibility to lung adenocarcinoma. Electronic supplementary material The online version of this article (doi:10.1186/s12929-016-0240-9) contains supplementary material, which is available to authorized users.

Published
2016

138. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Author

Stacey L. Edwards, Daniel Vincent, Antoinette Hollestelle, Melissa C. Southey, Thilo Dörk, Jonine Figueroa, Robert Winqvist, Wei Zheng, Keitaro Matsuo, Fergus J. Couch, Don M. Conroy, Anna Jakubowska, Paul D.P. Pharoah, Sara Margolin, Simon S. Cross, Joe Dennis, Rebecca Mayes, Annegien Broeks, Mitul Shah, Matthias W. Beckmann, Mahdi Moradi Marjaneh, Pei-Ei Wu, Javier Benitez, Hanna Fues Wahl, Ute Hamann, Rita K. Schmutzler, Guillermo Pita, Nichola Johnson, Suleeporn Sangrajrang, James McKay, Barbara Burwinkel, Hoda Anton-Culver, Pascal Guénel, Douglas F. Easton, Veli-Matti Kosma, Hidemi Ito, Angela Cox, Georgia Chenevix-Trench, M. Rosario Alonso, Mark S. Goldberg, Hatef Darabi, Volker Arndt, Qin Wang, Manjeet K. Bolla, Nick Orr, Soo Hwang Teo, Soo-Chin Lee, Penny Soucy, Jonathan Beesley, Paolo Peterlongo, Ji Yeob Choi, Anthony J. Swerdlow, Jacques Simard, Kamila Czene, Anna González-Neira, Jenny Chang-Claude, Heli Nevanlinna, Ian Tomlinson, Thérèse Truong, Chen-Yang Shen, Harald Surowy, Henrik Flyger, Marjanka K. Schmidt, Graham G. Giles, John L. Hopper, Celine M. Vachon, Olivia Fletcher, Stig E. Bojesen, Mikael Hartman, Arnaud Droit, Per Hall, Cheng Har Yip, Maya Ghoussaini, Artitaya Lophatananon, Mieke Kriege, Anna H. Wu, Siranoush Manoukian, Kyriaki Michailidou, Christopher A. Haiman, Roger L. Milne, Xiao-Ou Shu, Daniel O. Stram, Katri Pylkäs, Sofia Khan, Irene L. Andrulis, Annika Lindblom, Emily Hallberg, Diana Torres, Anja Rudolph, Arto Mannermaa, Hermann Brenner, Vessela N. Kristensen, Daehee Kang, Caroline Seynaeve, Elinor J. Sawyer, Silje Nord, Hiltrud Brauch, Jan Lubinski, Natalia Bogdanova, Juliet D. French, Susan L. Neuhausen, Montserrat Garcia-Closas, Thomas Brüning, Loic Le Marchand, Peter A. Fasching, Diether Lambrechts, Daniel C. Tessier, Peter Devilee, Eva Galle, Alfons Meindl, Alison M. Dunning, Siddhartha Kar, Kenneth Muir, Curtis Olswold, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Department of Obstetrics and Gynecology, Clinicum, School of Medicine / Clinical Medicine, Cancer Research UK (Reino Unido), European Research Council, NIH - National Cancer Institute (NCI) (Estados Unidos), Post-cancer GWAS Initiative, Dutch Cancer Society (Holanda), Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Instituto de Salud Carlos III, Finlands Akademi (Finlandia), Ministry of Education, Culture, Sports, Science, and Technology (Japón), Japan Agency for Medical Research and Development, United States Army Medical Research and Development Command, California Breast Cancer Research Program, Stichting tegen Kanker, Deutsche Krebshilfe, National Health and Medical Research Council (Australia), Ministry of Economic Development, Innovation and Export Trade, Ministry of Higher Education (Malasia), Agency for Science, Technology and Research (Singapur), National Medical Research Council (Singapur), The Research Council of Norway, Southern and Eastern Norway Regional Health Authority, Finnish Cancer (Center of Excellence grant), Genetic Associations and Mechanisms in Oncology (GAME-ON) Initiative, Yorkshire Cancer Research, BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology, NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos), Hellenic Cooperative Oncology Group research grant, Institute of Cancer Research (Reino Unido), United States of Department of Health & Human Services, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Vesicular Transport Proteins, Genome-wide association study, 0302 clinical medicine, Breast cancer, Genetics research, Medicine and Health Sciences, HUMAN GENOME, Genetics, Multidisciplinary, Chromosome Mapping, ASSOCIATION, Tag SNP, 3. Good health, 030220 oncology & carcinogenesis, Female, EXPRESSION, SUSCEPTIBILITY LOCI, Genotype, European Continental Ancestry Group, 3122 Cancers, Quantitative Trait Loci, Locus (genetics), Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, White People, REGION, RC0254, 03 medical and health sciences, SDG 3 - Good Health and Well-being, REVEALS, medicine, SNP, Humans, Genetic Predisposition to Disease, FUNCTIONAL VARIANTS, Genetic association, RISK LOCUS, CONSORTIUM, medicine.disease, ENHANCERS, 030104 developmental biology, Risk factors, Imputation (genetics), Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus., published version, peerReviewed

Published
2016
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139. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Author

Melissa C. Southey, Daniel Klevebring, Robert Winqvist, Irene L. Andrulis, Keitaro Matsuo, Anna Jakubowska, Susan L. Neuhausen, Paul D.P. Pharoah, Natalia Bogdanova, Lisa B. Signorello, Annika Lindblom, Kamila Czene, Drakoulis Yannoukakos, Caroline Seynaeve, Asaf Wyszynski, Michael D. Cole, John L. Hopper, kConFab Investigators, Elinor J. Sawyer, Qin Wang, Vessela N. Kristensen, Hidemi Ito, Paolo Radice, Daehee Kang, Sara Margolin, Hermann Brenner, Annegien Broeks, William J. Blot, Yu-Tang Gao, Mitul Shah, Matthias W. Beckmann, Wei Zheng, Brian E. Henderson, Peter Devilee, Javier Benitez, David Van Den Berg, Christopher A. Haiman, Thilo Dörk, Hatef Darabi, Ans M.W. van den Ouweland, Alfons Meindl, Frederik Marmé, Jacques Simard, Isabel dos-Santos-Silva, Jan Lubinski, Pei-Ei Wu, Veli-Matti Kosma, Katri Pylkäs, Mikael Hartman, Soo-Hwang Teo, Tien Yin Wong, Suleeporn Sangrajrang, Paolo Peterlongo, Douglas F. Easton, James McKay, Fergus J. Couch, Angela Cox, Maartje J. Hooning, Ji Yeob Choi, Anja Rudolph, Arto Mannermaa, Anna H. Wu, Ute Hamann, Montserrat Garcia-Closas, Christine B. Ambrosone, Janet E. Olson, Hiltrud Brauch, Rita K. Schmutzler, Julian Peto, Manjeet K. Bolla, Alison M. Dunning, Heli Nevanlinna, Børge G. Nordestgaard, Hui Miao, Yali Zhang, Kenneth Muir, Barbara Burwinkel, Nick Orr, Aida Karina Dieffenbach, Marjanka K. Schmidt, Jirong Long, Martine Dumont, Jenny Chang-Claude, Kristin Lam, Chen-Yang Shen, Anthony J. Swerdlow, Chi-Chen Hong, Peter A. Fasching, Stig E. Bojesen, Diether Lambrechts, Xiao-Ou Shu, Graham G. Giles, Christopher I. Amos, Joe Dennis, Hans Wildiers, Christian Lytle, Sofia Khan, Pascal Guénel, Elisa V. Bandera, Artitaya Lophatananon, Georgia Chenevix-Trench, Kyriaki Michailidou, Song Yao, Roger L. Milne, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Per Hall, Jonine D. Figueroa, Julia A. Knight, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Adult, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Breast cancer, SDG 3 - Good Health and Well-being, Genotype, Genetics, medicine, Medicine and Health Sciences, Humans, Genetic Predisposition to Disease, Copy-number variation, Enhancer, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), Genetic association, Aged, Sequence Deletion, Association Studies Articles, Case-control study, General Medicine, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Enhancer Elements, Genetic, Case-Control Studies, Chromosomes, Human, Pair 2, MCF-7 Cells, Female, Carrier Proteins, Insulin-Like Growth Factor Binding Protein 5
Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

Published
2016
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140. Pathway Analyses Identify TGFBR2 as Potential Breast Cancer Susceptibility Gene: Results from a Consortium Study among Asians

Author

Hongbing Shen, Motoki Iwasaki, Ya Lan Shieh, Shenming Wang, Bu Tian Ji, Kelvin Y.K. Chan, Xiaoming Xie, Shoichiro Tsugane, Keitaro Matsuo, Yao Liu, Yu-Tang Gao, Zefang Ren, Hiroji Iwata, Alicia Beeghly-Fadiel, Chen-Yang Shen, Zhibin Hu, Xiangyu Ma, Xiao-Ou Shu, Ying Zheng, Yoshio Kasuga, Pei Ei Wu, Wei Lu, Yong-Bing Xiang, Ui-Soon Khoo, Qiuyin Cai, Ben Zhang, Wenjing Wang, Jiajun Shi, Wei Zheng, Harold L. Moses, Hidemi Ito, and Jirong Long

Subjects
Adult, China, Epidemiology, Breast Neoplasms, Single-nucleotide polymorphism, Protein Serine-Threonine Kinases, Biology, Bioinformatics, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, Breast cancer, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Breast, Allele, Genotyping, Receptor, Transforming Growth Factor-beta Type II, Case-control study, Cancer, Middle Aged, Prognosis, medicine.disease, Minor allele frequency, Oncology, Case-Control Studies, Female, Breast Cancer Genetics, Receptors, Transforming Growth Factor beta, Polymorphism, Restriction Fragment Length, Signal Transduction
Abstract

Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer. Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case–control study among Asian women. Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65–0.89; P = 8.42 × 10−4). Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility. Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Cancer Epidemiol Biomarkers Prev; 21(7); 1176–84. ©2012 AACR.

Published
2012
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141. EGFRexon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients

Author

Yuh Min Chen, Gee-Chen Chang, Chen-Yang Shen, Chi Ren Tsai, Pan-Chyr Yang, Jiun Yi Hsia, Cheng Yen Chuang, Ying-Huang Tsai, Ming Shyan Huang, Chao A. Hsiung, Kun-Chieh Chen, Tsung-Ying Yang, Kuan-Yu Chen, Chien-Jen Chen, Wu Chou Su, Shi Yi Yang, Yao Jen Li, Chih Yi Chen, Kuo-Hsuan Hsu, Chung Ping Hsu, and Kuo Meng Liao

Subjects
Adult, Male, Cancer Research, Lung Neoplasms, DNA Repair, DNA repair, DNA Mutational Analysis, Adenocarcinoma of Lung, Single-nucleotide polymorphism, Adenocarcinoma, Biology, Polymorphism, Single Nucleotide, Exon, Sex Factors, Genotype, NAD(P)H Dehydrogenase (Quinone), medicine, Humans, SNP, Alleles, Genetic Association Studies, Aged, Sequence Deletion, Aged, 80 and over, Polymorphism, Genetic, Smoking, Exons, Odds ratio, Middle Aged, medicine.disease, DNA-Binding Proteins, ErbB Receptors, DNA Repair Enzymes, Exodeoxyribonucleases, Logistic Models, MutS Homolog 2 Protein, Oncology, Cancer research, Female, ERCC4
Abstract

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females.

Published
2012
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142. 19p13.1 Is a Triple-Negative-Specific Breast Cancer Susceptibility Locus

Author

Linde M. Braaf, Andreas Schneeweiss, Alexandra V. Stavropoulou, Elinor J. Sawyer, Christoph Engel, Pascal Guénel, Hans Ulrich Ulmer, Efraim H. Rosenberg, Mervi Grip, Hans-Peter Sinn, Chen-Yang Shen, Daniel J. Park, Monica Barile, Annie Perkins, Xianshu Wang, Susan L. Slager, Leslie Bernstein, José Ignacio Arias Peŕez, Puttisak Puttawibul, Gianluca Severi, Helen Gogas, Diana Eccles, Sara Margolin, Michael J. Kerin, Carl Blomqvist, Irene L. Andrulis, Minouk J. Schoemaker, Dario Greco, Javier Benitez, Matthias W. Beckmann, Maria Pilar Zamora, Qin Wang, Diether Lambrechts, Hoda Anton-Culver, Foluso O. Ademuyiwa, Veli-Matti Kosma, Mark E. Sherman, Anne Sophie Dieudonne, F Marmé, Helena Hwang, Peter Devilee, Shan Wang-Gohrke, Alina Vrieling, Melissa C. Southey, Annika Lindblom, Paolo Radice, Penelope Miron, Theŕeśe Truong, Per Hall, Douglas F. Easton, Siranoush Manoukian, Drakoulis Yannoukakos, Rita K. Schmutzler, Vessela N. Kristensen, Julian Peto, Jonathan Beesley, Arndt Hartmann, Priyanka Sharma, Alison M. Dunning, Paolo Peterlongo, Christine B. Ambrosone, Henrik Flyger, Nichola Johnson, Jonine D. Figueroa, Barbara Burwinkel, Kenneth Muir, Roger L. Milne, Sigrid Hatse, Julia A. Knight, Ylermi Soini, Alan Ashworth, Artitaya Lophatananon, Robert Winqvist, Alfons Meindl, Thomas Rüdiger, George Fountzilas, Annegien Broeks, Simon S. Cross, Rob A. E. M. Tollenaar, Paul D.P. Pharoah, Alexander Miron, Montserrat Garcia-Closas, Laura Baglietto, Matthew L. Kosel, Arif B. Ekici, Heiko Müller, Jyh Cherng Yu, Grethe Grenaker Alnsæ, Argyrios Ziogas, Thomas Dünnebier, Ian Tomlinson, Anna Marie Mulligan, Ruth Swann, Chia-Ni Hsiung, Sarah Schott, Christina Clarke Dur, Catriona McLean, Georgia Chenevix-Trench, Caroline Seynaeve, Hiltrud Brauch, Orr Nicholas, Carmel Apicella, Vernon S. Pankratz, Olivia Fletcher, Surapon Wiangnon, Arja Jukkola-Vuorinen, Anne Lise Brøresen-Dale, Dieter Flesch-Janys, Fergus J. Couch, Peter A. Fasching, Brøge G. Nordestgaard, Kristiina Aittomäki, Marie Rose Christiaens, Jaana M. Hartikainen, Manjeet K. Humphreys, Ute Hamann, Marjanka K. Schmidt, Isabel dos Santos Silva, Harsh B. Pathak, Janet E. Olson, Jenny Chang-Claude, Graham G. Giles, Miriam Dwek, Stig E. Bojesen, Florence Menegaux, Christa Stegmaier, Katri Pylkäs, Huan Ming Hsu, Sune F. Nielsen, Christof Sohn, Kamila Czene, Claus R. Bartram, Jo Ellen Weaver, John L. Hopper, Xiaoqing Chen, Emilie Cordina-Duverger, Stefan Nickels, Esther M. John, Heli Nevanlinna, Jolanta Lissowska, Zachary S. Fredericksen, Angela Cox, Maartje J. Hooning, Volker Arndt, MW Reed, Celine M. Vachon, Yon Ko, Anthony J. Swerdlow, Gord Glendon, Hans Fischer, Arto Mannermaa, Kristen N. Stevens, Hermann Brenner, Andrew K. Godwin, Clinical Genetics, and Medical Oncology

Subjects
Oncology, Cancer Research, Receptor, ErbB-2, population, Estrogen receptor, consortium, Genome-wide association study, brca1, ErbB-2, 0302 clinical medicine, common variants, Receptors, risk-factors, skin and connective tissue diseases, Progesterone, Triple-negative breast cancer, 0303 health sciences, education.field_of_study, Chromosome Mapping, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Receptors, Progesterone, complex, Receptor, Human, Risk, medicine.medical_specialty, Population, Breast Neoplasms, Genetic Loci, Humans, Chromosomes, Human, Pair 19, Genetic Predisposition to Disease, Biology, Article, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Genetic predisposition, education, 030304 developmental biology, Gynecology, Pair 19, tumor subtypes, confer susceptibility, medicine.disease, Estrogen, 14q24.1 rad51l1, genome-wide association, Ovarian cancer
Abstract

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Published
2012
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143. 7q21-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium

Author

Argyrios Ziogas, Alfons Meindl, Jonathan Beesley, Jianjun Liu, Georgia Chenevix-Trench, Caroline Seynaeve, Laura Baglietto, Malcolm W.R. Reed, Angela Cox, Kamila Czene, Douglas F. Easton, Arif B. Ekici, Kristiina Aittomäki, Chen-Yang Shen, John L. Hopper, Peter A. Fasching, Lorna Gibson, Núria Malats, Stig E. Bojesen, Astrid K. Irwanto, Tuomas Heikkinen, Peter Devilee, Heli Nevanlinna, Ian W. Brock, Xiaoqing Chen, Jolanta Lissowska, Ruediger Schulz-Wendtland, Henrik Flyger, Montserrat Garcia-Closas, Xianshu Wang, Justo Lorenzo-Bermejo, Jenny Chang-Claude, Zachary S. Fredericksen, Jyh Cherng Yu, Julian Peto, Børge G. Nordestgaard, Sara Margolin, Annika Lindblom, Arto Mannermaa, Letitia D. Smith, Barbara Burwinkel, Matthias W. Beckmann, Beate Pesch, Joerg Heil, José Ignacio Arias, Fergus J. Couch, Rebecca Hein, Dong Young Noh, Olivia Fletcher, Stephen J. Chanock, Ute Hamann, Graeme Elliott, Per Hall, Vesa Kataja, Pei Ei Wu, Keun-Young Yoo, Daehee Kang, Karen A. Pooley, Yon Ko, Carl Blomqvist, Dallas R. English, Mark E. Sherman, Graham G. Giles, Alina Vrieling, Roger L. Milne, Rob A. E. M. Tollenaar, Shan Wang-Gohrke, Gianluca Severi, Alison M. Dunning, Carmel Apicella, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Christie J. van Asperen, Isabel dos Santos Silva, Janet E. Olson, Dieter Flesch-Janys, Bernd Frank, Melissa C. Southey, Paul D.P. Pharoah, Huan Ming Hsu, M. Pilar Zamora, Manjeet K. Humphreys, Medical Oncology, and Hematology

Subjects
Oncology, A Kinase Anchor Proteins, Logistic regression, Medical and Health Sciences, 0302 clinical medicine, Medizinische Fakultät, Risk Factors, Epidemiology, Odds Ratio, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, Single Nucleotide, AOCS Group, Biological Sciences, Control subjects, 3. Good health, 030220 oncology & carcinogenesis, Pair 7, Female, GENICA Network, Chromosomes, Human, Pair 7, Human, Asian Continental Ancestry Group, medicine.medical_specialty, Alleles, Breast Neoplasms, Case-Control Studies, Cytoskeletal Proteins, European Continental Ancestry Group, Genes, Recessive, Genetic Predisposition to Disease, Humans, Logistic Models, Polymorphism, Single Nucleotide, Single-nucleotide polymorphism, Biology, Chromosomes, Article, White People, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Recessive, ddc:610, Polymorphism, Allele, 030304 developmental biology, Case-control study, Odds ratio, medicine.disease, Genes
Abstract

Background: Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies. Methods: The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression. Results: For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p=0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p=0.001). The OR was greater at younger ages (p trend=0.01). Conclusion: This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.

Published
2011
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144. Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in Taiwan

Author

Yung-Chu Hsu, Hsiang-Yu Yu, Hung-Ting Liao, Hui-Ping Chuang, Chien-Hsiun Chen, Yu-Hsiang Su, Jer-Yuarn Wu, Shu-Yi Lin, Jing-Jane Tsai, Sheng-Feng Sung, Long-Sun Ro, Cheng-Hsien Lu, Chung-Ta Lu, Chih-Ta Tai, Yu-Hsuan Lin, Shey-Lin Wu, Yuan-Tsong Chen, Li-Chen Huang, Chen-Yang Shen, Peiyuan F. Hsieh, Ying Ju Chen, Luke I Chen, Sheng-Hsing Lan, Wen-Hung Chung, Juei-Jueng Lin, Pei-Joung Tsai, Chin-Song Lu, Cheung-Ter Ong, Chun-Che Chu, Shuen-Iu Hung, Pei Chen, Chi-Feng Chang, and Chih-Chao Yang

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Incidence (epidemiology), medicine.medical_treatment, General Medicine, Carbamazepine, Southeast asian, medicine.disease, Toxic epidermal necrolysis, Anticonvulsant, Internal medicine, Immunology, medicine, Young adult, business, Pharmacogenetics, medicine.drug, Genetic testing
Abstract

Background Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens–Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS–TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS–TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. Methods From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them ...

Published
2011
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145. 'Hide-then-hit' to explain the importance of genotypic polymorphism of DNA repair genes in determining susceptibility to cancer

Author

Chen-Yang Shen and Pei-Ei Wu

Subjects
Genetics, Polymorphism, Genetic, Cell cycle checkpoint, DNA Repair, Genotype, DNA repair, Single-nucleotide polymorphism, Cell Biology, General Medicine, Biology, Bioinformatics, chemistry.chemical_compound, Gene interaction, chemistry, Neoplasms, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Gene, DNA
Abstract

Interindividual variations in DNA repair capacity/efficiency linked to the presence of polymorphisms in DNA repair-related genes have been suggested to account for different risk of developing cancers. In this review article, on the basis of breast cancer formation as a model, we propose a 'hide-then-hit' hypothesis indicating the importance of escaping checkpoint surveillance for sub-optimal DNA repair variants to cause cancer. Therefore, only cells with subtle defects in repair capacity arising from low-penetrance variants of DNA repair genes would have the opportunity to grow and accumulate the genetic changes needed for cancer formation, without triggering cell-cycle checkpoint surveillance. Furthermore, distinct from high-penetrance alleles, these polymorphic alleles of DNA repair genes would predispose carriers to a higher risk of developing cancer but would not necessarily cause cancer. To examine this, we simultaneously genotyped multiple SNPs of cell-cycle checkpoint genes and the DNA repair genes. Support for the hypothesis came from observations that breast cancer risk associated with variant genotypes of DNA repair genes became more significant in the subgroups of women with specific genotypic statuses of checkpoint genes. This 'hide-then-hit' hypothesis is certainly needed to be confirmed by biological evidence in which a cause-effect relationship has to be established. However, based on this, possible gene-gene interaction is considered to play an important role in modifying the cancer risk associated with genotypic polymorphism of DNA repair gene in different study populations.

Published
2011
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146. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium

Author

Peter Hillemanns, Mark E. Robson, Roger L. Milne, Amanda B. Spurdle, Rob A. E. M. Tollenaar, Federik Marme, Michael Bremer, Jan Lubinski, Linda Titus-Ernstoff, Kamila Czene, Stephen J. Chanock, Mervi Grip, Graham G. Giles, Penny Webb, G. Chenevix-Trench, Natalia Bogdanova, John L. Hopper, Frances P. O'Malley, Arto Mannermaa, Mark E. Sherman, Chen-Yang Shen, Suleeporn Sangrajrang, Julian Peto, Irene L. Andrulis, Yuri I. Rogov, Annika Lindblom, Børge G. Nordestgaard, James McKay, Barbara Burwinkel, M. Pilar Zamora, José Ignacio Arias, Beate Pesch, Vijai Joseph, Shamil Hanafievich Gantcev, Fergus J. Couch, Dong Young Noh, Betül T. Yesilyurt, Jenny Chang-Claude, Ute Hamann, Vesa Kataja, Sara Margolin, Thilo Dörk, Katarzyna Jaworska, Yon Ko, Nichola Johnson, Hiltrud Brauch, Matthias W. Beckmann, Heli Nevanlinna, Malcolm W.R. Reed, Melissa C. Southey, Arif B. Ekici, Jolanta Lissowska, Isabel dos Santos Silva, Johann H. Karstens, Robert Winqvist, Shian Ling Ding, Stig E. Bojesen, Ian Tomlinson, Anna Marie Mulligan, Montserrat Garcia-Closas, Volker Harth, Katarzyna Durda, Valerie Gaborieau, Tuomas Heikkinen, Thomas Brüning, Mia M. Gaudet, Monica Barile, Sylvia Rabstein, Christina Justenhoven, Anna Jakubowska, Paul D.P. Pharoah, Jonathan Beesley, Hermann Brenner, Elza Khusnutdinova, Heiko Müller, Jyh Cherng Yu, Adam M. Lee, Paolo Peterlongo, Clare Turnbull, Doug Easton, Radka Platte, Keun-Young Yoo, J. Margriet Collée, Paolo Radice, Laura Baglietto, Sei Hyun Ahn, Paul Brennan, Olivia Fletcher, Fleur Hammet, Ans M.W. van den Ouweland, Catriona Maclean, Carl Blomqvist, Sheila Seal, Peter Schürmann, Natalia Antonenkova, Katri Pylkäs, Angela Cox, Kenneth Offit, Huan Ming Hsu, Arja Jukkola-Vuorinen, Maartje J. Hooning, Peter A. Fasching, Alison M. Dunning, Nick Orr, Volker Arndt, Javier Benitez, Diether Lambrechts, Robert B. Diasio, Manjeet K. Humphreys, Ian W. Brock, Marjanka K. Schmidt, Per Hall, Hoda Anton-Culver, Anthony J. Swerdlow, Jonine D. Figueroa, Julia A. Knight, Ylermi Soini, Alan Ashworth, Veli-Matti Kosma, Anna deFazio, Reiner Strick, Darya Prokofieva, Shan Wang-Gohrke, Polly A. Newcomb, Dorota M. Gertig, Henrik Flyger, David D.L. Bowtell, Laura J. van't Veer, John W.M. Martens, Carmel Apicella, Anthony Renwick, Andreas Schneeweiss, Michael J. Kerin, Christian Baisch, Xianshu Wang, Kathleen Egan, Argyrios Ziogas, A. Green, Marina Bermisheva, Christof Sohn, Stéphanie Peeters, Daehee Kang, Rebecca Hein, Nazneen Rahman, Annegien Broeks, Georgia Chenevix-Trench, Elinor J. Sawyer, Louise A. Brinton, Michael Jones, Xiaoqing Chen, Kristiina Aittomäki, Esther M. John, Siranoush Manoukian, Hand Peter Fischer, Amy Trentham-Dietz, Simon S. Cross, Marie Rose Chrisiaens, Gianluca Severi, Medical Oncology, and Clinical Genetics

Subjects
Oncology, Receptor, ErbB-2, 6q25.1, Estrogen receptor, Genome-wide association study, Alleles, Breast Neoplasms, Case-Control Studies, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 14, Confidence Intervals, DNA-Binding Proteins, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Humans, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, Risk Factors, Genome-Wide Association Study, Molecular Biology, Genetics, Genetics (clinical), brca1, 0302 clinical medicine, ErbB-2, Receptors, glucose, mutation carriers, Progesterone, 0303 health sciences, Association Studies Articles, General Medicine, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, Pair 1, metaanalysis, Human, Receptor, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, SNP, Polymorphism, 030304 developmental biology, Genetic heterogeneity, Pair 14, Case-control study, Odds ratio, confer susceptibility, medicine.disease, Estrogen, susceptibility loci, Immunology, genome-wide association, polymorphisms
Abstract

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2) = 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 x 10 25]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P = 6.7 x 10 23) and lobular histology (case-only P = 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

Published
2011
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147. Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies

Author

Gillian S. Dite, Brian E. Henderson, U Hamann, Rulla M. Tamimi, Agnes Jager, Laurence N. Kolonel, J Heinz, Hans Wildiers, Celine M. Vachon, Päivi Heikkilä, Chen-Yang Shen, Laura J. Van 'T Veer, Pasi Hirvikoski, Suleeporn Sangrajrang, James McKay, Päivi Auvinen, Michael Bremer, Ann Smeets, Kamila Czene, William J. Tapper, Peter Hillemanns, Fergus J. Couch, John L. Hopper, Douglas F. Easton, Jose Ignacio Arias Perez, Roger L. Milne, Helen Tsimiklis, Carmel Apicella, Antoinette Hollestelle, Zachary S. Fredericksen, Argyrios Ziogas, Helen Cramp, Melissa C. Southey, Malcolm W.R. Reed, Tjoung Won Park-Simon, Janet E. Olson, Primitiva Menéndez Rodríguez, Robert Winqvist, Fabrice Odefrey, Bohdan Górski, Caroline Seynaeve, Matthew L. Kosel, Valerie Gaborieau, Mia M. Gaudet, Diether Lambrechts, Anna Jakubowska, Paul D.P. Pharoah, Fleur Hammet, Amanda B. Spurdle, Stig E. Bojesen, Thilo Dörk, Victoria Cafourek, Julia A. Knight, Frances P O'Malley, Daniel Connley, Letitia D. Smith, David L. Wachter, Flora E. van Leeuwen, David Dynnes Ørsted, Helene Holland, Sabapathy P. Balasubramanian, Aysun Ay, Tuomas Heikkinen, Jaana M. Kauppinen, Diljit Kaur-Knudsen, Børge G. Nordestgaard, Gord Glendon, Paul Brennan, Jacek Gronwald, Mervi Grip, Elinor J. Sawyer, Kristy Driver, Jan Lubinski, Hoda Anton-Culver, Louise A. Brinton, Veli-Matti Kosma, Mieke Kriege, P. E.A. Huijts, Irene L. Andrulis, P. Zamora, S. Chanock, Pei Ei Wu, Tomasz Byrski, Arja Jukkola-Vuorinen, Peter A. Fasching, Tomasz Huzarski, Hatef Darabi, Andreas Meyer, Raem Tollenaar, Fiona M. Blows, Ian Tomlinson, Xiaohong R. Yang, Dallas R. English, Diana Eccles, Ans M.W. van den Ouweland, Johann H. Karstens, Montserrat Garcia-Closas, Alina Vrieling, Graham G. Giles, Michael J. Kerin, Show Lin Yang, Nicola Miller, Sue Gerty, Thomas Brüning, Christopher A. Haiman, Kari Mononen, Loic Le Marchand, Jyh Cherng Yu, Anna Marie Mulligan, Jenny Chang-Claude, Christian R. Loehberg, Matthias W. Beckmann, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Susan E. Hankinson, Gianluca Severi, Angela M. Jones, Heli Nevanlinna, Caroline Weltens, Jolanta Lissowska, Hiltrud Brauch, Giu Cheng Hsu, Sebastian M. Jud, Per Hall, Hans Fischer, Arto Mannermaa, Christina Justenhoven, Laura Baglietto, Katri Pylkäs, Kristiina Aittomäki, Sara Margolin, T. Vandorpe, M. Barile, Ylermi Soini, Beate Pesch, Ellen L. Goode, Nayana Weerasooriya, Peter Devilee, Carl Blomqvist, Margriet Collée, Vesa Kataja, Arndt Hartmann, Manjeet K. Humphreys, Siranoush Manoukian, Annika Lindblom, Marjanka K. Schmidt, Yon Ko, Patrick Neven, Chia-Ni Hsiung, Xianshu Wang, Keith Humphreys, Dieter Flesch-Janys, Niall M. McInerney, Javier Benítez, Esther M. John, Jianjun Liu, Peter Sinn, Reijo Sironen, Annegien Broeks, Rebecca Hein, Shou Tung Chen, Paolo Radice, Simon S. Cross, Mark E. Sherman, Robert Paridaens, Shan Wang-Gohrke, Sebastian B. Weihbrecht, Jonine D. Figueroa, Catriona McLean, Georgia Chenevix-Trench, David J. Hunter, Henrik Flyger, Beata Peplonska, VU University medical center, EMGO - Quality of care, Virology, Medical Oncology, Clinical Genetics, Surgery, and University of Groningen

Subjects
Oncology, Cancer Research, Receptor, ErbB-2, Estrogen receptor, Body Mass Index, ErbB-2, 0302 clinical medicine, Risk Factors, Receptors, Odds Ratio, EPITHELIAL OVARIAN-CANCER, Progesterone, REPAIR GENES, 2. Zero hunger, 0303 health sciences, education.field_of_study, Tumor, Medicine (all), Age Factors, SINGLE-NUCLEOTIDE POLYMORPHISMS, Articles, 3. Good health, ErbB Receptors, Parity, ESTROGEN, Receptors, Estrogen, POSTMENOPAUSAL WOMEN, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Receptor, Receptor, erbB-2, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Oncology and Carcinogenesis, Population, Breast Neoplasms, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Biomarkers, Tumor, medicine, Humans, Oncology & Carcinogenesis, Obesity, Risk factor, education, 030304 developmental biology, Menarche, HORMONE-RECEPTOR, DIFFERENT HISTOPATHOLOGIC TYPES, Epidermal Growth Factor, business.industry, Parturition, Case-control study, Case-Control Studies, Keratin-5, Logistic Models, Receptor, Epidermal Growth Factor, Cancer, Odds ratio, BASAL-LIKE SUBTYPE, medicine.disease, Endocrinology, PROGESTERONE-RECEPTOR STATUS, business, Biomarkers
Abstract

BACKGROUND: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. METHODS: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. RESULTS: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. CONCLUSIONS: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

Published
2010
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148. The clinical implications of MMP-11 and CK-20 expression in human breast cancer

Author

Chen-Yang Shen, Chiun-Sheng Huang, Jia-Ching Shieh, Chia-Wei Chang, Jyh-Cherng Yu, Chun-Wen Cheng, Hsiao-Wei Wang, Yi-Ping Fu, and Pei-Ei Wu

Subjects
Adult, Oncology, medicine.medical_specialty, Clinical Biochemistry, Cell, Breast Neoplasms, Keratin-20, Biology, Biochemistry, Antibodies, Metastasis, Breast cancer, Matrix Metalloproteinase 11, Internal medicine, Progesterone receptor, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Aged, Neoplasm Staging, Regulation of gene expression, Biochemistry (medical), Cancer, General Medicine, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Real-time polymerase chain reaction, medicine.anatomical_structure, Receptors, Estrogen, Lymphatic Metastasis, Female, Receptors, Progesterone
Abstract

Background Tumor invasiveness and metastasis in cancer progression is manifested by epigenetic abnormality. However, it remains unknown whether transcription regulation of matrix metalloproteinase-11( MMP-11 ) and cytoskeleton-20 ( CK-20 ) genes for the homoeostasis of epithelial/connective interface that can enhance cell dissemination and invasion may act as alternative mutators to tumor clinicopathology. Methods Paired cancerous and tumor-adjacent normal tissues from 72 breast cancer patients were assayed for the expression of MMP-11 and CK-20 by using real-time RT-PCR. The expression profiles were evaluated for the association with clinicopathological factors. Results Breast tumor tissues displayed higher expression levels of MMP-11 and CK-20 than those of the adjacent non-cancerous tissues. Overexpression of either MMP-11 or CK-20 correlated with patients having poorly differentiated tumors ( P MMP-11 = 0.01 and P CK-20 = 0.05) and lymph node metastasis (LNM) ( P MMP-11 = 0.004 and P CK-20 = 0.001). A synergistic effect between MMP-11 and CK-20 on risk elevation was significant in patients with advanced tumor stage (OR = 2.03, 95%CI = 1.10–3.77) and LNM (OR = 2.83, 95%CI = 1.20–4.71). Additionally, patients lacking progesterone receptor exhibited high expression of MMP-11 and CK-20 . Conclusion We demonstrate that MMP-11 and CK-20 are probable prognostic markers whose expression reflects the stages of tumor differentiation and LNM of breast cancer.

Published
2010
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149. Genetic susceptibility to the development and progression of breast cancer associated with polymorphism of cell cycle and ubiquitin ligase genes

Author

Ming-Feng Hou, Shian-ling Ding, Huan-Ming Hsu, Chen-Yang Shen, Giu-Cheng Hsu, Pei-Ei Wu, Shu-Hsin Kuo, Lin Yi Jung, Chih-Hao Chang, Chun-Wen Cheng, Shou-Tung Chen, and Jyh-Cherng Yu

Subjects
Adult, Cancer Research, F-Box-WD Repeat-Containing Protein 7, Cyclin E, Ubiquitin-Protein Ligases, Estrogen receptor, Breast Neoplasms, Cell Cycle Proteins, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Breast cancer, Pregnancy, Genotype, medicine, Humans, Genetic Predisposition to Disease, S-Phase Kinase-Associated Proteins, Aged, biology, F-Box Proteins, Cell Cycle, Cancer, General Medicine, Middle Aged, medicine.disease, Ubiquitin ligase, Case-Control Studies, Disease Progression, biology.protein, Cancer research, Female, Breast disease
Abstract

Tumor levels of the cell cycle regulators cyclin E and p27 correlate strongly with survival in breast cancer patients and are specifically regulated by the ubiquitin ligases hCDC4 and SKP2. This study was to explore whether genetic susceptibility to breast cancer is associated with polymorphism of these genes and whether gene-gene and gene-risk factor [i.e. full-term pregnancy (FTP)] interactions are important in determining cancer risk. A two-stage case-control study based on single-nucleotide polymorphisms was performed. The first study (560 cases and 1122 controls) was to define the contribution of cell cycle and ubiquitin ligase genes to cancer susceptibility. The second study (926 cases and 923 controls) was to confirm the association identified in the first stage and to map the variant alleles. Increased breast cancer risk was associated with both polymorphism of hCDC4 and a joint effect of cyclin E and hCDC4. These associations were more significant in nulliparous women, and cancer risk associated with a lower number of FTPs was only seen in women with a higher number of high-risk genotypes, providing support for an effect of gene-risk factor interaction in determining susceptibility. Sequence variants of intron 2 in hCDC4 were found to be the most significant polymorphism and high-stage estrogen receptor (ER)-negative patients carrying the homozygous variant genotype manifested significantly poorer survival. This study concludes that polymorphism of hCDC4 is a risk factor for breast cancer development by interacting with either cyclin E or FTP and may also prove useful in predicting progression of patients with high-stage and ER-negative breast cancers.

Published
2009
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150. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Author

Eugenia E. Calle, Alice J. Sigurdson, Susan E. Hankinson, Alfons Meindl, Hoda Anton-Culver, Letitia D. Smith, Richard van Hien, R.A.E.M. Tollenaar, Louise A. Brinton, Veli-Matti Kosma, Stephen J. Chanock, Laura Baglietto, Anna González-Neira, Jonathan J. Morrison, Olivia Fletcher, Radka Platte, Michele M. Doody, Sei Hyun Ahn, Douglas F. Easton, Henrik Flyger, Merethe Kumle, Georgia Chenevix-Trench, Chen-Yang Shen, Beata Peplonska, Kamila Czene, J. David Curb, Christi J. van Asperen, Per Hall, Natalia Antonenkova, Irene L. Andrulis, Mieke Schutte, Claus R. Bartram, John L. Hopper, Daehee Kang, Amanda B. Spurdle, Peter Kraft, David J. Hunter, Kristiina Aittomäki, Bruce H. Alexander, Bruce A.J. Ponder, Malcolm W.R. Reed, Julia A. Knight, Christine D. Berg, Melissa C. Southey, S. A. Fedorova, Giu Cheng Hsu, Catherine A. McCarty, Arto Mannermaa, Rebecca Hein, Gianluca Severi, Peter Schürmann, Diana Eccles, Argyrios Ziogas, Shou Tung Chen, Ian W. Brock, Fergus J. Couch, Garnet L. Anderson, Ellen L. Goode, Nichola Johnson, Sara Margolin, Paul D.P. Pharoah, Annika Lindblom, W. Ryan Diver, Ute Hamann, Robert N. Hoover, Michael R. Stratton, Iosif V. Zalutsky, Yuqing Li, Sten Cornelissen, Natalia Bogdanova, Caroline Seynaeve, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Robert Luben, Aleksandar Rajkovic, Stig E. Bojesen, Heather Spencer Feigelson, Saundra S. Buys, Marina Bermisheva, Barbara Burwinkel, Peter Devilee, Isabel dos Santos Silva, Jonathan Beesley, Thilo Dörk, Gilles Thomas, Lars J. Vatten, Tuomas Heikkinen, Ross L. Prentice, David G. Cox, D. Gareth Evans, Manjeet K. Humphreys, Marjanka K. Schmidt, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Janet E. Olson, Dallas R. English, Maya Ghoussaini, Heli Nevanlinna, Dong Young Noh, Jolanta Lissowska, Graeme Elliott, Vesa Kataja, Nazneen Rahman, Peter Hillemanns, Annegien Broeks, Roger L. Milne, Johann H. Karstens, Christina Justenhoven, Montserrat Garcia-Closas, Karen A. Pooley, Zachary S. Fredericksen, Jyh Cherng Yu, Angela Cox, Maartje J. Hooning, Alison M. Dunning, Ans M.W. van den Ouweland, Hiltrud Brauch, Regina G. Ziegler, Jianjun Liu, Parveen Bhatti, Kristian Hveem, Kevin B. Jacobs, Catherine S. Healey, Jenny Chang-Claude, Michael J. Thun, Rogier A. Oldenburg, Elza Khusnutdinova, Xianshu Wang, Keun-Young Yoo, Carl Blomqvist, Gloria Ribas, Graham G. Giles, and Javier Benitez

Subjects
Genotype, Breast Neoplasms, Genome-wide association study, Biology, Article, Chromosomes, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Chromosome Mapping, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 3, Disease Susceptibility, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Genetics, Genetic predisposition, medicine, 030304 developmental biology, Genetic association, 0303 health sciences, Genome, Pair 17, Cancer, medicine.disease, 3. Good health, TOX3, Pair 3, 030220 oncology & carcinogenesis, Breast disease, Human
Abstract

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

Published
2009
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