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11 results on '"Pooley, Karen [0000-0002-1274-9460]"'

1. Telomere length and common disease: study design and analytical challenges

Author

Barrett, Jennifer H., Iles, Mark M., Dunning, Alison M., Pooley, Karen A., Dunning, Alison [0000-0001-6651-7166], Pooley, Karen [0000-0002-1274-9460], and Apollo - University of Cambridge Repository

Subjects
Review Paper, Cardiovascular Diseases, Risk Factors, Neoplasms, Smoking, Genetics, Humans, Telomere Homeostasis, Genetics(clinical), Obesity, Telomere
Abstract

Telomeres, the repetitive sequences that protect the ends of chromosomes, help to maintain genomic integrity and are of key importance to human health. The aim here is to give an overview of the evidence for the importance of telomere length (TL) to the risk of common disease, considering the strengths and weaknesses of different epidemiological study designs. Methods for measuring TL are described, all of which are subject to considerable measurement error. TL declines with age and varies in relation to factors such as smoking and obesity. It is also highly heritable (estimated heritability of ~40 to 50 %), and genome-wide studies have identified a number of associated genetic variants. Epidemiological studies have shown shorter TL to be associated with risk of a number of common diseases, including cardiovascular disease and some cancers. The relationship with cancer appears complex, in that longer telomeres are associated with higher risk of some cancers. Prospective studies of the relationship between TL and disease, where TL is measured before diagnosis, have numerous advantages over retrospective studies, since they avoid the problems of reverse causality and differences in sample handling, but they are still subject to potential confounding. Studies of the genetic predictors of TL in relation to disease risk avoid these drawbacks, although they are not without limitations. Telomere biology is of major importance to the risk of common disease, but the complexities of the relationship are only now beginning to be understood.

Published
2015

2. Rare, protein-truncating variants in $\textit{ATM}$, $\textit{CHEK2}$ and $\textit{PALB2}$, but not $\textit{XRCC2}$, are associated with increased breast cancer risks

Author

Decker, B, Allen, J, Luccarini, C, Pooley, KA, Shah, M, Bolla, MK, Wang, Q, Ahmed, S, Baynes, C, Conroy, DM, Brown, J, Luben, R, Ostrander, EA, Pharoah, PD, Dunning, AM, Easton, DF, Allen, Jamie [0000-0002-8677-2225], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], 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
Cancer: breast, Genetic Variation, Breast Neoplasms, Ataxia Telangiectasia Mutated Proteins, DNA-Binding Proteins, Checkpoint Kinase 2, Evidence Based Practice, Sequence Analysis, Protein, Genetic Epidemiology, Humans, Female, Genetic Predisposition to Disease, Fanconi Anemia Complementation Group N Protein, Geneticscreening/counselling
Abstract

BACKGROUND: Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. METHODS: Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms. RESULTS: Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. CONCLUSIONS: Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.

Published
2017
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3. Reproducibility of telomere length assessment: an international collaborative study

Author

Alison M. Dunning, Veryan Codd, Laureline Roger, Carmen Martin-Ruiz, Duncan M. Baird, Tim De Meyer, Göran Roos, Sofie Bekaert, Martin M Dokter, Petra Boukamp, Ulrika Svenson, Damir Krunic, Andrew Kingston, Thomas von Zglinicki, Pim van der Harst, Rachel Cooper, Andrew Wong, Nilesh J. Samani, Karen A. Pooley, Paul G. Shiels, Richard M. Cawthon, Liane M. McGlynn, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Cardiovascular Centre (CVC), Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
BIOMARKER, Gerontology, Aging, medicine.medical_specialty, FIBROBLASTS, International Cooperation, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Real-Time Polymerase Chain Reaction, SOUTHERN BLOTS, Epidemiology, medicine, Humans, EPIDEMIOLOGY, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, human, ComputingMilieux_MISCELLANEOUS, Reproducibility, business.industry, HUMAN-CELLS, MORTALITY, DEMENTIA, FLOW-CYTOMETRY, Methodology, Reproducibility of Results, Biology and Life Sciences, Public Health, Global Health, Social Medicine and Epidemiology, DNA, General Medicine, ASSOCIATION, Telomere, telomeres, R1, 3. Good health, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Blotting, Southern, Ageing, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, CARDIOVASCULAR-DISEASE, biomarker, variation, Corrigendum, business, Biomarkers
Abstract

Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories.\ud \ud Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques.\ud \ud Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63–0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy.\ud \ud Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.

Published
2014

4. POT1 loss-of-function variants predispose to familial melanoma

Author

Andrew J. Ramsay, Zhihao Ding, Carlos López-Otín, Jimmy Z. Liu, Judith Symmons, Carla Daniela Robles-Espinoza, Víctor Quesada, D. Timothy Bishop, Nicholas G. Martin, Jiyeon Choi, Jane M. Palmer, Mia Petljak, Michael Gartside, Nelleke A. Gruis, David J. Adams, Alison M. Dunning, Karen A. Pooley, Grant W. Montgomery, Nicholas K. Hayward, Matthew M. Makowski, Peter Johansson, Antonia L. Pritchard, Julia Newton-Bishop, Jessamy Tiffen, Kevin M. Brown, Mark Harland, Helen Snowden, Lauren G. Aoude, Thomas M. Keane, Mitchell S. Stark, Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Models, Molecular, Skin Neoplasms, Molecular Sequence Data, Telomere-Binding Proteins, Mutation, Missense, Biology, Shelterin Complex, Article, Telomere binding, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Base sequence, Amino Acid Sequence, Melanoma, Loss function, Netherlands, 030304 developmental biology, Early onset, Telomere-binding protein, Neoplasms, Connective Tissue, 0303 health sciences, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Australia, Telomere Homeostasis, Sequence Analysis, DNA, Telomere, Familial Melanoma, medicine.disease, United Kingdom, Pedigree, 3. Good health, 030220 oncology & carcinogenesis, Sequence Alignment, Protein Binding
Abstract

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Published
2014

5. 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, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany [ 58 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 59 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Basis Genet Risk & Genet Testing, Milan, Italy [ 60 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 61 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 62 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 63 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 64 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia [ 65 ] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia [ 66 ] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 67 ] Univ Oslo, Inst Clin Med, Oslo, Norway [ 68 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 69 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA [ 70 ] Univ Oulu, NordLab Oulu Univ Hosp, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 71 ] Univ Oulu, NordLab Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland [ 72 ] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 73 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 74 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 75 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 76 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 77 ] Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands [ 78 ] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands [ 79 ] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands [ 80 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 81 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 82 ] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands [ 83 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 84 ] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England [ 85 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 86 ] Int Epidemiol Inst, Rockville, MD USA [ 87 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 88 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 89 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 90 ] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore [ 91 ] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore [ 92 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 93 ] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore [ 94 ] Pontificia Univ Javerianar, Inst Human Genet, Bogota, Colombia [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France [ 97 ] Natl Canc Inst, Bangkok, Thailand [ 98 ] Roswell Pk Canc Inst, Buffalo, NY 14263 USA [ 99 ] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 100 ] China Med Univ, Sch Publ Hlth, Taichung, Taiwan [ 101 ] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan [ 102 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England [ 103 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 104 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 105 ] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 106 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 107 ] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA [ 108 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 109 ] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA [ 110 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 111 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 112 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 113 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 114 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 115 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 116 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 117 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 118 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain [ 119 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 120 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain [ 121 ] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA [ 122 ] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA [ 123 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 124 ] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy [ 125 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 126 ] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy [ 127 ] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece [ 128 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 129 ] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan [ 130 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England [ 131 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 132 ] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany [ 133 ] Univ Dusseldorf, Dusseldorf, Germany [ 134 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 135 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany [ 136 ] Univ Munster, Inst 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

6. Germline TERT promoter mutations are rare in familial melanoma

Author

Harland, M., Petljak, M., Robles-Espinoza, C.D., Ding, Z.H., Gruis, N.A., Doorn, R. van, Pooley, K.A., Dunning, A.M., Aoude, L.G., Wadt, K.A.W., Gerdes, A.M., Brown, K.M., Hayward, N.K., Newton-Bishop, J.A., Adams, D.J., Bishop, D.T., Petljak, M, Robles-Espinoza, CD, Ding, Z, Gruis, NA, van Doorn, R, Pooley, KA, Dunning, AM, Aoude, LG, Wadt, KAW, Gerdes, A-M, Brown, KM, Hayward, N, Newton-Bishop, JA, Adams, DJ, Bishop, DT, Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Cancer Research, Skin Neoplasms, TERT, Polymerase Chain Reaction, Pedigree, Young Adult, Familial, Oncology, Genetic, Mutation, Genetics, Humans, Female, Genetic Predisposition to Disease, Genetics(clinical), Promoter Regions, Genetic, Telomerase, Melanoma, Germ-Line Mutation
Abstract

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains

Published
2016

7. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, M, Bishop, DT, Lee, JE, Brossard, M, Martin, NG, Moses, EK, Song, F, Barrett, JH, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Taylor, JC, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, MF, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Duffy, DL, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NE, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, GenoMEL Consortium, Essen-Heidelberg Investigators, The SDH Study Group, Q-MEGA and QTWIN Investigators, AMFS Investigators, ATHENS Melanoma Study Group, Landi, MT, Lang, J, Lathrop, M, Lubinski, J, Mackie, RM, Mann, GJ, Molvern, A, Montgomery, GW, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Qureshi, AA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Hayward, NK, Han, J, Schulze, HJ, Dunning, AM, Newton-Bishop, JA, Demenais, F, Amos, CI, MacGregor, S, Iles, MM, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Candidate gene, Skin Neoplasms, Medizin, Single-nucleotide polymorphism, Genome-wide association study, Biology, Genome, Polymorphism, Single Nucleotide, Article, Polymorphism (computer science), ATHENS Melanoma Study Group, Genetics, Chromosomes, Human, Humans, Genetic Predisposition to Disease, AMFS Investigators, Melanoma, Genetic association, 11 Medical And Health Sciences, 06 Biological Sciences, GenoMEL Consortium, Human genetics, 3. Good health, Genetic Loci, Case-Control Studies, SDH Study Group, Expression quantitative trait loci, Q-MEGA and QTWIN Investigators, Essen-Heidelberg Investigators, Developmental Biology, Genome-Wide Association Study
Abstract

© 2015 Nature America, Inc. All rights reserved.Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10-8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Published
2015

8. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author

Carvajal-Carmona, L.G., O'Mara, T.A., Painter, J.N.., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Pooley, K., Beesley, J., Cheng, T., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Wentzensen, N., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Scott, R.J., Ashton, K., Proietto, T., Otton, G., Wersaell, O., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A.-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Spurdle, A.B., Thompson, D.J., NSECG, ANECS, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], 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
National Study of Endometrial Cancer Genetics Group, Australian Ovarian Cancer Study, Polymorphism, Single Nucleotide, Chromosomes, Promoter Regions, Paediatrics and Reproductive Medicine, Databases, Uterine Cancer, Genetic, Complementary and Alternative Medicine, Risk Factors, Models, Australian National Endometrial Cancer Study Group, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Testing, Aetiology, Polymorphism, Promoter Regions, Genetic, Telomerase, Cancer, Genetics & Heredity, Neoplastic, Models, Genetic, Nucleic Acid, RENDOCAS, Prevention, Human Genome, Membrane Proteins, Single Nucleotide, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Haplotypes, Genetic Loci, Chromosomes, Human, Pair 5, Female, GENICA Network, Pair 5, Databases, Nucleic Acid, Human
Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility. ispartof: Human Genetics vol:134 issue:2 pages:231-45 ispartof: location:Germany status: published

Published
2015

9. Genetic variation and gastric cancer risk: a field synopsis and meta-analysis

Author

Karen A. Pooley, Donato Nitti, Daunia Verdi, Simone Mocellin, Pooley, Karen [0000-0002-1274-9460], and Apollo - University of Cambridge Repository

Subjects
Oncology, medicine.medical_specialty, Genome-wide association study, Biology, Bioinformatics, GASTRIC CARCINOMA, GSTP1, Gene Frequency, Risk Factors, Stomach Neoplasms, Internal medicine, Genetic variation, medicine, Genetic predisposition, Carcinoma, SNP, Humans, Genetic Predisposition to Disease, GENETIC POLYMORPHISMS, Stomach cancer, Polymorphism, Genetic, Gastroenterology, Genetic Variation, medicine.disease, META-ANALYSIS, CANCER GENETICS, Neoplasm Proteins, Meta-analysis, Genome-Wide Association Study
Abstract

Background Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available. Methods We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative). Results Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110). Conclusions We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes.

Published
2015

10. Telomerase and the search for the end of cancer

Author

Simone Mocellin, Karen A. Pooley, Donato Nitti, Pooley, Karen [0000-0002-1274-9460], and Apollo - University of Cambridge Repository

Subjects
Telomerase, Small molecule inhibitors, TERT, medicine.medical_treatment, Biology, Bioinformatics, Critical discussion, Targeted therapy, Gene therapy, Neoplasms, medicine, Animals, Humans, Molecular Biology, Cancer, Tumor biology, Neoplasms therapy, Telomere, medicine.disease, Immunology, Molecular Medicine, Immunotherapy, Cancer, Gene therapy, Immunotherapy, Small molecule inhibitors, Targeted therapy, Telomerase, Telomere, TERT
Abstract

Many of the fundamental molecular mechanisms underlying tumor biology remain elusive and, thus, developing specific anticancer therapies remains a challenge. The recently discovered relationships identified among telomeres, telomerase, aging, and cancer have opened a new avenue in tumor biology research that may revolutionize anticancer therapy. This review summarizes the critical aspects of telomerase biology that underpin the development of novel telomerase-targeting therapies for malignant diseases, and special regard is given to the aspects of telomerase that make it such an appealing target, such as the widespread expression of telomerase in cancers. Despite significant progress, issues remain to be addressed before telomerase-based therapies are truly effective and we include critical discussion of the results obtained thus far.

Published
2013

11. The effect on melanoma risk of genes previously associated with telomere length

Author

Iles, M. M., Bishop, D. T., Taylor, J. C., Hayward, N. K., Brossard, M., Cust, A. E., Dunning, A. M., Lee, J. E., Moses, E. K., Akslen, L. A., Amfs, Investigators, Andresen, P. A., Avril, M. F., Azizi, E., Scarrà, G. B., Brown, K. M., Debniak, T., Elder, D. E., Friedman, E., Ghiorzo, P., Gillanders, E. M., Goldstein, A. M., Gruis, N. A., Hansson, J., Harland, M., Helsing, P., Hočevar, M., Höiom, V., Ibd, Investigators, Ingvar, C., Kanetsky, P. A., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Nicholas Martin, Molven, A., Montgomery, G. W., Novaković, S., Olsson, H., Puig, S., Puig-Butille, J. A., Qmega Qtwin, And Investigators, Radford-Smith, G. L., Randerson-Moor, J., Sdh, Study Group, Stoep, N., Doorn, R., Whiteman, D. C., Macgregor, S., Pooley, K. A., Ward, S. V., Mann, G. J., Amos, C. I., Pharoah, P. D., Demenais, F., Law, M. H., Newton Bishop, J. A., Barrett, J. H., GenoMEL Consortium, Dunning, Alison [0000-0001-6651-7166], Pooley, Karen [0000-0002-1274-9460], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Skin Neoplasms, Telomere-Binding Proteins, Australia, DNA Helicases, Confounding Factors, Epidemiologic, Zinc Fingers, Telomere, Polymorphism, Single Nucleotide, United States, Europe, Ribonucleoproteins, Predictive Value of Tests, Research Design, Humans, RNA, Israel, Melanoma, Telomerase, Germ-Line Mutation
Abstract

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

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