Mitchell J Machiela1, Jonathan N Hofmann1, Robert Carreras-Torres2, Kevin M Brown1, Mattias Johansson2, Zhaoming Wang3, Matthieu Foll2, Peng Li2, Nathaniel Rothman1, Sharon A Savage1, Valerie Gaborieau2, James D McKay2, Yuanqing Ye4, Marc Henrion5, Fiona Bruinsma6, Susan Jordan7, Gianluca Severi8, Kristian Hveem9, Lars J Vatten10, Tony Fletcher11, Kvetoslava Koppova12, Susanna C Larsson13, Alicja Wolk13, Rosamonde E Banks14, Peter J Selby14, Douglas F Easton15, Paul Pharoah15, Gabriella Andreotti1, Laura E Beane Freeman1, Stella Koutros1, Demetrius Albanes1, Satu Mannisto16, Stephanie Weinstein1, Peter E Clark17, Todd E Edwards17, Loren Lipworth17, Susan M Gapstur18, Victoria L Stevens18, Hallie Carol19, Matthew L Freedman19, Mark M Pomerantz19, Eunyoung Cho20, Peter Kraft21, Mark A Preston22, Kathryn M Wilson21, J Michael Gaziano23, Howard S Sesso21, Amanda Black1, Neal D Freedman1, Wen-Yi Huang1, John G Anema24, Richard J Kahnoski24, Brian R Lane25, Sabrina L Noyes26, David Petillo26, Leandro M Colli1, Joshua N Sampson1, Celine Besse27, Helene Blanche28, Anne Boland27, Laurie Burdette1, Egor Prokhortchouk29, Konstantin G Skryabin29, Meredith Yeager1, Mirjana Mijuskovic30, Miodrag Ognjanovic31, Lenka Foretova31, Ivana Holcatova32, Vladimir Janout33, Dana Mates34, Anush Mukeriya35, Stefan Rascu36, David Zaridze35, Vladimir Bencko37, Cezary Cybulski38, Eleonora Fabianova12, Viorel Jinga37, Jolanta Lissowska39, Jan Lubinski40, Marie Navratilova32, Peter Rudnai41, Neonila Szeszenia-Dabrowska42, Simone Benhamou43, Geraldine Cancel-Tassin44, Olivier Cussenot45, H Bas Bueno-de-Mesquita46, Federico Canzian47, Eric J Duell48, Börje Ljungberg49, Raviprakash T Sitaram49, Ulrike Peters50, Emily White50, Garnet L Anderson50, Lisa Johnson50, Juhua Luo51, Julie Buring21, I-Min Lee52, Wong-Ho Chow4, Lee E Moore1, Christopher Wood53, Timothy Eisen54, James Larkin55, Toni K Choueiri19, G Mark Lathrop56, Bin Tean Teh26, Jean-Francois Deleuze57, Xifeng Wu4, Richard S Houlston58, Paul Brennan2, Stephen J Chanock1, Ghislaine Scelo2, Mark P Purdue59. 1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA. 2. International Agency for Research on Cancer (IARC), Lyon, France. 3. St. Jude Children's Research Hospital, Memphis, TN, USA. 4. Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Icahn School of Medicine, New York, NY, USA. 6. Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia. 7. QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Public Health, The University of Queensland, Brisbane, Australia. 8. Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia; Human Genetics Foundation (HuGeF), Torino, Italy; Centre de Recherche en Épidémiologie et Santé des Populations, Université Paris-Saclay, UPS, USQ, Gustave Roussy, Villejuif, France. 9. HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Sweden. 10. Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. 11. London School of Hygiene and Tropical Medicine, University of London, London, UK. 12. Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia. 13. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 14. Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds, UK. 15. Department of Oncology, and Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 16. National Institute for Health and Welfare, Helsinki, Finland. 17. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. 18. American Cancer Society, Atlanta, GA, USA. 19. Dana-Farber Cancer Institute, Boston, MA, USA. 20. Brown University, Providence, RI, USA. 21. Harvard T.H. Chan School of Public Health, Boston, MA, USA. 22. Brigham and Women's Hospital, Boston, MA, USA. 23. Brigham and Women's Hospital, Boston, MA, USA; Veterans Administration, Boston, MA, USA. 24. Division of Urology, Spectrum Health, Grand Rapids, MI, USA. 25. Division of Urology, Spectrum Health, Grand Rapids, MI, USA; College of Human Medicine, Michigan State University, Grand Rapids, MI, USA. 26. Van Andel Research Institute, Center for Cancer Genomics and Quantitative Biology, Grand Rapids, MI, USA. 27. Centre National de Recherche en Genomique Humaine (CNRGH), Institut de biologie François Jacob, Commissariat à l'Energie Atomique et aux Energies Alternatives, Evry, France. 28. Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France. 29. Center 'Bioengineering' of the Russian Academy of Sciences, Moscow, Russian Federation; Kurchatov Scientific Center, Moscow, Russian Federation. 30. Clinic for Nephrology, Military Medical Academy, Belgrade, Serbia. 31. International Organization for Cancer Prevention and Research (IOCPR), Belgrade, Serbia. 32. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. 33. Second Faculty of Medicine, Institute of Public Health and Preventive Medicine, Charles University, Prague, Czech Republic. 34. Department of Preventive Medicine, Faculty of Medicine, Palacky University, Czech Republic. 35. National Institute of Public Health, Bucharest, Romania. 36. Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation. 37. Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital, Bucharest, Romania. 38. First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University, Prague, Czech Republic. 39. The M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland. 40. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 41. National Public Health Center, National Directorate of Environmental Health, Budapest, Hungary. 42. Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland. 43. INSERM U946, Paris, France; CNRS UMR8200, Institute Gustave Roussy, Villejuif, France. 44. CeRePP, Paris, France; UPMC Univ Paris 06, Institut Universitaire de Cancérologie, Paris, France. 45. CeRePP, Paris, France; UPMC Univ Paris 06, Institut Universitaire de Cancérologie, Paris, France; AP-HP, Department of Urology, Hopitaux Universitaires Est Parisien Tenon, Paris, France. 46. Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, UK; Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia. 47. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 48. Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain. 49. Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden. 50. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 51. Department of Epidemiology and Biostatistics, School of Public Health Indiana University Bloomington, Bloomington, IN, USA. 52. Harvard T.H. Chan School of Public Health, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. 53. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 54. University of Cambridge, Cambridge, UK. 55. Royal Marsden NHS Foundation Trust, London, UK. 56. McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada. 57. Centre National de Recherche en Genomique Humaine (CNRGH), Institut de biologie François Jacob, Commissariat à l'Energie Atomique et aux Energies Alternatives, Evry, France; Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain, Paris, France. 58. The Institute of Cancer Research, London, UK. 59. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA. Electronic address: purduem@mail.nih.gov.
Abstract
BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma. Published by Elsevier B.V.
BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma. Published by Elsevier B.V.
Authors: Xifeng Wu; Christopher I Amos; Yong Zhu; Hua Zhao; Barton H Grossman; Jerry W Shay; Sherry Luo; Waun Ki Hong; Margaret R Spitz Journal: J Natl Cancer Inst Date: 2003-08-20 Impact factor: 13.506
Authors: Maren Weischer; Børge G Nordestgaard; Richard M Cawthon; Jacob J Freiberg; Anne Tybjærg-Hansen; Stig E Bojesen Journal: J Natl Cancer Inst Date: 2013-03-06 Impact factor: 13.506
Authors: Jonathan N Hofmann; Qing Lan; Richard Cawthon; H Dean Hosgood; Brian Shuch; Lee E Moore; Nathaniel Rothman; Wong-Ho Chow; Mark P Purdue Journal: Cancer Epidemiol Biomarkers Prev Date: 2013-03-19 Impact factor: 4.254
Authors: Philip C Haycock; Stephen Burgess; Aayah Nounu; Jie Zheng; George N Okoli; Jack Bowden; Kaitlin Hazel Wade; Nicholas J Timpson; David M Evans; Peter Willeit; Abraham Aviv; Tom R Gaunt; Gibran Hemani; Massimo Mangino; Hayley Patricia Ellis; Kathreena M Kurian; Karen A Pooley; Rosalind A Eeles; Jeffrey E Lee; Shenying Fang; Wei V Chen; Matthew H Law; Lisa M Bowdler; Mark M Iles; Qiong Yang; Bradford B Worrall; Hugh Stephen Markus; Rayjean J Hung; Chris I Amos; Amanda B Spurdle; Deborah J Thompson; Tracy A O'Mara; Brian Wolpin; Laufey Amundadottir; Rachael Stolzenberg-Solomon; Antonia Trichopoulou; N Charlotte Onland-Moret; Eiliv Lund; Eric J Duell; Federico Canzian; Gianluca Severi; Kim Overvad; Marc J Gunter; Rosario Tumino; Ulrika Svenson; Andre van Rij; Annette F Baas; Matthew J Bown; Nilesh J Samani; Femke N G van t'Hof; Gerard Tromp; Gregory T Jones; Helena Kuivaniemi; James R Elmore; Mattias Johansson; James Mckay; Ghislaine Scelo; Robert Carreras-Torres; Valerie Gaborieau; Paul Brennan; Paige M Bracci; Rachel E Neale; Sara H Olson; Steven Gallinger; Donghui Li; Gloria M Petersen; Harvey A Risch; Alison P Klein; Jiali Han; Christian C Abnet; Neal D Freedman; Philip R Taylor; John M Maris; Katja K Aben; Lambertus A Kiemeney; Sita H Vermeulen; John K Wiencke; Kyle M Walsh; Margaret Wrensch; Terri Rice; Clare Turnbull; Kevin Litchfield; Lavinia Paternoster; Marie Standl; Gonçalo R Abecasis; John Paul SanGiovanni; Yong Li; Vladan Mijatovic; Yadav Sapkota; Siew-Kee Low; Krina T Zondervan; Grant W Montgomery; Dale R Nyholt; David A van Heel; Karen Hunt; Dan E Arking; Foram N Ashar; Nona Sotoodehnia; Daniel Woo; Jonathan Rosand; Mary E Comeau; W Mark Brown; Edwin K Silverman; John E Hokanson; Michael H Cho; Jennie Hui; Manuel A Ferreira; Philip J Thompson; Alanna C Morrison; Janine F Felix; Nicholas L Smith; Angela M Christiano; Lynn Petukhova; Regina C Betz; Xing Fan; Xuejun Zhang; Caihong Zhu; Carl D Langefeld; Susan D Thompson; Feijie Wang; Xu Lin; David A Schwartz; Tasha Fingerlin; Jerome I Rotter; Mary Frances Cotch; Richard A Jensen; Matthias Munz; Henrik Dommisch; Arne S Schaefer; Fang Han; Hanna M Ollila; Ryan P Hillary; Omar Albagha; Stuart H Ralston; Chenjie Zeng; Wei Zheng; Xiao-Ou Shu; Andre Reis; Steffen Uebe; Ulrike Hüffmeier; Yoshiya Kawamura; Takeshi Otowa; Tsukasa Sasaki; Martin Lloyd Hibberd; Sonia Davila; Gang Xie; Katherine Siminovitch; Jin-Xin Bei; Yi-Xin Zeng; Asta Försti; Bowang Chen; Stefano Landi; Andre Franke; Annegret Fischer; David Ellinghaus; Carlos Flores; Imre Noth; Shwu-Fan Ma; Jia Nee Foo; Jianjun Liu; Jong-Won Kim; David G Cox; Olivier Delattre; Olivier Mirabeau; Christine F Skibola; Clara S Tang; Merce Garcia-Barcelo; Kai-Ping Chang; Wen-Hui Su; Yu-Sun Chang; Nicholas G Martin; Scott Gordon; Tracey D Wade; Chaeyoung Lee; Michiaki Kubo; Pei-Chieng Cha; Yusuke Nakamura; Daniel Levy; Masayuki Kimura; Shih-Jen Hwang; Steven Hunt; Tim Spector; Nicole Soranzo; Ani W Manichaikul; R Graham Barr; Bratati Kahali; Elizabeth Speliotes; Laura M Yerges-Armstrong; Ching-Yu Cheng; Jost B Jonas; Tien Yin Wong; Isabella Fogh; Kuang Lin; John F Powell; Kenneth Rice; Caroline L Relton; Richard M Martin; George Davey Smith Journal: JAMA Oncol Date: 2017-05-01 Impact factor: 31.777
Authors: Karen A Pooley; Stig E Bojesen; Maren Weischer; Sune F Nielsen; Deborah Thompson; Ali Amin Al Olama; Kyriaki Michailidou; Jonathan P Tyrer; Sara Benlloch; Judith Brown; Tina Audley; Robert Luben; K-T Khaw; David E Neal; Freddie C Hamdy; Jenny L Donovan; Zsofia Kote-Jarai; Caroline Baynes; Mitul Shah; Manjeet K Bolla; Qin Wang; Joe Dennis; Ed Dicks; Rongxi Yang; Anja Rudolph; Joellen Schildkraut; Jenny Chang-Claude; Barbara Burwinkel; Georgia Chenevix-Trench; Paul D P Pharoah; Andrew Berchuck; Rosalind A Eeles; Douglas F Easton; Alison M Dunning; Børge G Nordestgaard Journal: Hum Mol Genet Date: 2013-07-29 Impact factor: 6.150
Authors: Derek W Brown; Qing Lan; Nathaniel Rothman; John Pluta; Kristian Almstrup; Marlene D Dalgaard; Mark H Greene; Tom Grotmol; Chey Loveday; Stephen M Schwartz; Clare Turnbull; Fredrik Wiklund; Peter A Kanetsky; Katherine L Nathanson; Katherine A McGlynn; Mitchell J Machiela Journal: Cancer Epidemiol Biomarkers Prev Date: 2021-03-18 Impact factor: 4.090