Melissa A Richard1, Austin L Brown1, John W Belmont2, Michael E Scheurer1, Vidal M Arroyo1, Kayla L Foster1, Kathleen D Kern1, Melissa M Hudson3,4, Wendy M Leisenring5, M Fatih Okcu1, Yadav Sapkota4, Yutaka Yasui4, Lindsay M Morton6, Stephen J Chanock6, Leslie L Robison4, Gregory T Armstrong4, Smita Bhatia7,8, Kevin C Oeffinger9, Philip J Lupo1, Kala Y Kamdar1. 1. Section of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center and Baylor College of Medicine, Houston, Texas. 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. 3. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. 4. Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee. 5. Clinical Research and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington. 6. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 7. Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, Alabama. 8. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama. 9. Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Abstract
BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.
BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.
Authors: Lillian R Meacham; Charles A Sklar; Suwen Li; Qi Liu; Nora Gimpel; Yutaka Yasui; John A Whitton; Marilyn Stovall; Leslie L Robison; Kevin C Oeffinger Journal: Arch Intern Med Date: 2009-08-10
Authors: Melissa M Hudson; Matthew J Ehrhardt; Nickhill Bhakta; Malek Baassiri; Hesham Eissa; Wassim Chemaitilly; Daniel M Green; Daniel A Mulrooney; Gregory T Armstrong; Tara M Brinkman; James L Klosky; Kevin R Krull; Noah D Sabin; Carmen L Wilson; I-Chan Huang; Johnnie K Bass; Karen Hale; Sue Kaste; Raja B Khan; Deo Kumar Srivastava; Yutaka Yasui; Vijaya M Joshi; Saumini Srinivasan; Dennis Stokes; Mary Ellen Hoehn; Matthew Wilson; Kirsten K Ness; Leslie L Robison Journal: Cancer Epidemiol Biomarkers Prev Date: 2016-12-29 Impact factor: 4.254
Authors: Nicole M Warrington; Robin N Beaumont; Momoko Horikoshi; Felix R Day; Øyvind Helgeland; Charles Laurin; Jonas Bacelis; Shouneng Peng; Ke Hao; Bjarke Feenstra; Andrew R Wood; Anubha Mahajan; Jessica Tyrrell; Neil R Robertson; N William Rayner; Zhen Qiao; Gunn-Helen Moen; Marc Vaudel; Carmen J Marsit; Jia Chen; Michael Nodzenski; Theresia M Schnurr; Mohammad H Zafarmand; Jonathan P Bradfield; Niels Grarup; Marjolein N Kooijman; Ruifang Li-Gao; Frank Geller; Tarunveer S Ahluwalia; Lavinia Paternoster; Rico Rueedi; Ville Huikari; Jouke-Jan Hottenga; Leo-Pekka Lyytikäinen; Alana Cavadino; Sarah Metrustry; Diana L Cousminer; Ying Wu; Elisabeth Thiering; Carol A Wang; Christian T Have; Natalia Vilor-Tejedor; Peter K Joshi; Jodie N Painter; Ioanna Ntalla; Ronny Myhre; Niina Pitkänen; Elisabeth M van Leeuwen; Raimo Joro; Vasiliki Lagou; Rebecca C Richmond; Ana Espinosa; Sheila J Barton; Hazel M Inskip; John W Holloway; Loreto Santa-Marina; Xavier Estivill; Wei Ang; Julie A Marsh; Christoph Reichetzeder; Letizia Marullo; Berthold Hocher; Kathryn L Lunetta; Joanne M Murabito; Caroline L Relton; Manolis Kogevinas; Leda Chatzi; Catherine Allard; Luigi Bouchard; Marie-France Hivert; Ge Zhang; Louis J Muglia; Jani Heikkinen; Camilla S Morgen; Antoine H C van Kampen; Barbera D C van Schaik; Frank D Mentch; Claudia Langenberg; Jian'an Luan; Robert A Scott; Jing Hua Zhao; Gibran Hemani; Susan M Ring; Amanda J Bennett; Kyle J Gaulton; Juan Fernandez-Tajes; Natalie R van Zuydam; Carolina Medina-Gomez; Hugoline G de Haan; Frits R Rosendaal; Zoltán Kutalik; Pedro Marques-Vidal; Shikta Das; Gonneke Willemsen; Hamdi Mbarek; Martina Müller-Nurasyid; Marie Standl; Emil V R Appel; Cilius E Fonvig; Caecilie Trier; Catharina E M van Beijsterveldt; Mario Murcia; Mariona Bustamante; Sílvia Bonas-Guarch; David M Hougaard; Josep M Mercader; Allan Linneberg; Katharina E Schraut; Penelope A Lind; Sarah E Medland; Beverley M Shields; Bridget A Knight; Jin-Fang Chai; Kalliope Panoutsopoulou; Meike Bartels; Friman Sánchez; Jakob Stokholm; David Torrents; Rebecca K Vinding; Sara M Willems; Mustafa Atalay; Bo L Chawes; Peter Kovacs; Inga Prokopenko; Marcus A Tuke; Hanieh Yaghootkar; Katherine S Ruth; Samuel E Jones; Po-Ru Loh; Anna Murray; Michael N Weedon; Anke Tönjes; Michael Stumvoll; Kim F Michaelsen; Aino-Maija Eloranta; Timo A Lakka; Cornelia M van Duijn; Wieland Kiess; Antje Körner; Harri Niinikoski; Katja Pahkala; Olli T Raitakari; Bo Jacobsson; Eleftheria Zeggini; George V Dedoussis; Yik-Ying Teo; Seang-Mei Saw; Grant W Montgomery; Harry Campbell; James F Wilson; Tanja G M Vrijkotte; Martine Vrijheid; Eco J C N de Geus; M Geoffrey Hayes; Haja N Kadarmideen; Jens-Christian Holm; Lawrence J Beilin; Craig E Pennell; Joachim Heinrich; Linda S Adair; Judith B Borja; Karen L Mohlke; Johan G Eriksson; Elisabeth E Widén; Andrew T Hattersley; Tim D Spector; Mika Kähönen; Jorma S Viikari; Terho Lehtimäki; Dorret I Boomsma; Sylvain Sebert; Peter Vollenweider; Thorkild I A Sørensen; Hans Bisgaard; Klaus Bønnelykke; Jeffrey C Murray; Mads Melbye; Ellen A Nohr; Dennis O Mook-Kanamori; Fernando Rivadeneira; Albert Hofman; Janine F Felix; Vincent W V Jaddoe; Torben Hansen; Charlotta Pisinger; Allan A Vaag; Oluf Pedersen; André G Uitterlinden; Marjo-Riitta Järvelin; Christine Power; Elina Hyppönen; Denise M Scholtens; William L Lowe; George Davey Smith; Nicholas J Timpson; Andrew P Morris; Nicholas J Wareham; Hakon Hakonarson; Struan F A Grant; Timothy M Frayling; Debbie A Lawlor; Pål R Njølstad; Stefan Johansson; Ken K Ong; Mark I McCarthy; John R B Perry; David M Evans; Rachel M Freathy Journal: Nat Genet Date: 2019-05-01 Impact factor: 38.330
Authors: Lillian R Meacham; James G Gurney; Ann C Mertens; Kirsten K Ness; Charles A Sklar; Leslie L Robison; Kevin C Oeffinger Journal: Cancer Date: 2005-04-15 Impact factor: 6.921
Authors: Ayush Giri; Jacklyn N Hellwege; Jacob M Keaton; Jihwan Park; Chengxiang Qiu; Helen R Warren; Eric S Torstenson; Csaba P Kovesdy; Yan V Sun; Otis D Wilson; Cassianne Robinson-Cohen; Christianne L Roumie; Cecilia P Chung; Kelly A Birdwell; Scott M Damrauer; Scott L DuVall; Derek Klarin; Kelly Cho; Yu Wang; Evangelos Evangelou; Claudia P Cabrera; Louise V Wain; Rojesh Shrestha; Brian S Mautz; Elvis A Akwo; Muralidharan Sargurupremraj; Stéphanie Debette; Michael Boehnke; Laura J Scott; Jian'an Luan; Jing-Hua Zhao; Sara M Willems; Sébastien Thériault; Nabi Shah; Christopher Oldmeadow; Peter Almgren; Ruifang Li-Gao; Niek Verweij; Thibaud S Boutin; Massimo Mangino; Ioanna Ntalla; Elena Feofanova; Praveen Surendran; James P Cook; Savita Karthikeyan; Najim Lahrouchi; Chunyu Liu; Nuno Sepúlveda; Tom G Richardson; Aldi Kraja; Philippe Amouyel; Martin Farrall; Neil R Poulter; Markku Laakso; Eleftheria Zeggini; Peter Sever; Robert A Scott; Claudia Langenberg; Nicholas J Wareham; David Conen; Colin Neil Alexander Palmer; John Attia; Daniel I Chasman; Paul M Ridker; Olle Melander; Dennis Owen Mook-Kanamori; Pim van der Harst; Francesco Cucca; David Schlessinger; Caroline Hayward; Tim D Spector; Marjo-Riitta Jarvelin; Branwen J Hennig; Nicholas J Timpson; Wei-Qi Wei; Joshua C Smith; Yaomin Xu; Michael E Matheny; Edward E Siew; Cecilia Lindgren; Karl-Heinz Herzig; George Dedoussis; Joshua C Denny; Bruce M Psaty; Joanna M M Howson; Patricia B Munroe; Christopher Newton-Cheh; Mark J Caulfield; Paul Elliott; J Michael Gaziano; John Concato; Peter W F Wilson; Philip S Tsao; Digna R Velez Edwards; Katalin Susztak; Christopher J O'Donnell; Adriana M Hung; Todd L Edwards Journal: Nat Genet Date: 2018-12-21 Impact factor: 38.330
Authors: Josée Dupuis; Claudia Langenberg; Inga Prokopenko; Richa Saxena; Nicole Soranzo; Anne U Jackson; Eleanor Wheeler; Nicole L Glazer; Nabila Bouatia-Naji; Anna L Gloyn; Cecilia M Lindgren; Reedik Mägi; Andrew P Morris; Joshua Randall; Toby Johnson; Paul Elliott; Denis Rybin; Gudmar Thorleifsson; Valgerdur Steinthorsdottir; Peter Henneman; Harald Grallert; Abbas Dehghan; Jouke Jan Hottenga; Christopher S Franklin; Pau Navarro; Kijoung Song; Anuj Goel; John R B Perry; Josephine M Egan; Taina Lajunen; Niels Grarup; Thomas Sparsø; Alex Doney; Benjamin F Voight; Heather M Stringham; Man Li; Stavroula Kanoni; Peter Shrader; Christine Cavalcanti-Proença; Meena Kumari; Lu Qi; Nicholas J Timpson; Christian Gieger; Carina Zabena; Ghislain Rocheleau; Erik Ingelsson; Ping An; Jeffrey O'Connell; Jian'an Luan; Amanda Elliott; Steven A McCarroll; Felicity Payne; Rosa Maria Roccasecca; François Pattou; Praveen Sethupathy; Kristin Ardlie; Yavuz Ariyurek; Beverley Balkau; Philip Barter; John P Beilby; Yoav Ben-Shlomo; Rafn Benediktsson; Amanda J Bennett; Sven Bergmann; Murielle Bochud; Eric Boerwinkle; Amélie Bonnefond; Lori L Bonnycastle; Knut Borch-Johnsen; Yvonne Böttcher; Eric Brunner; Suzannah J Bumpstead; Guillaume Charpentier; Yii-Der Ida Chen; Peter Chines; Robert Clarke; Lachlan J M Coin; Matthew N Cooper; Marilyn Cornelis; Gabe Crawford; Laura Crisponi; Ian N M Day; Eco J C de Geus; Jerome Delplanque; Christian Dina; Michael R Erdos; Annette C Fedson; Antje Fischer-Rosinsky; Nita G Forouhi; Caroline S Fox; Rune Frants; Maria Grazia Franzosi; Pilar Galan; Mark O Goodarzi; Jürgen Graessler; Christopher J Groves; Scott Grundy; Rhian Gwilliam; Ulf Gyllensten; Samy Hadjadj; Göran Hallmans; Naomi Hammond; Xijing Han; Anna-Liisa Hartikainen; Neelam Hassanali; Caroline Hayward; Simon C Heath; Serge Hercberg; Christian Herder; Andrew A Hicks; David R Hillman; Aroon D Hingorani; Albert Hofman; Jennie Hui; Joe Hung; Bo Isomaa; Paul R V Johnson; Torben Jørgensen; Antti Jula; Marika Kaakinen; Jaakko Kaprio; Y Antero Kesaniemi; Mika Kivimaki; Beatrice Knight; Seppo Koskinen; Peter Kovacs; Kirsten Ohm Kyvik; G Mark Lathrop; Debbie A Lawlor; Olivier Le Bacquer; Cécile Lecoeur; Yun Li; Valeriya Lyssenko; Robert Mahley; Massimo Mangino; Alisa K Manning; María Teresa Martínez-Larrad; Jarred B McAteer; Laura J McCulloch; Ruth McPherson; Christa Meisinger; David Melzer; David Meyre; Braxton D Mitchell; Mario A Morken; Sutapa Mukherjee; Silvia Naitza; Narisu Narisu; Matthew J Neville; Ben A Oostra; Marco Orrù; Ruth Pakyz; Colin N A Palmer; Giuseppe Paolisso; Cristian Pattaro; Daniel Pearson; John F Peden; Nancy L Pedersen; Markus Perola; Andreas F H Pfeiffer; Irene Pichler; Ozren Polasek; Danielle Posthuma; Simon C Potter; Anneli Pouta; Michael A Province; Bruce M Psaty; Wolfgang Rathmann; Nigel W Rayner; Kenneth Rice; Samuli Ripatti; Fernando Rivadeneira; Michael Roden; Olov Rolandsson; Annelli Sandbaek; Manjinder Sandhu; Serena Sanna; Avan Aihie Sayer; Paul Scheet; Laura J Scott; Udo Seedorf; Stephen J Sharp; Beverley Shields; Gunnar Sigurethsson; Eric J G Sijbrands; Angela Silveira; Laila Simpson; Andrew Singleton; Nicholas L Smith; Ulla Sovio; Amy Swift; Holly Syddall; Ann-Christine Syvänen; Toshiko Tanaka; Barbara Thorand; Jean Tichet; Anke Tönjes; Tiinamaija Tuomi; André G Uitterlinden; Ko Willems van Dijk; Mandy van Hoek; Dhiraj Varma; Sophie Visvikis-Siest; Veronique Vitart; Nicole Vogelzangs; Gérard Waeber; Peter J Wagner; Andrew Walley; G Bragi Walters; Kim L Ward; Hugh Watkins; Michael N Weedon; Sarah H Wild; Gonneke Willemsen; Jaqueline C M Witteman; John W G Yarnell; Eleftheria Zeggini; Diana Zelenika; Björn Zethelius; Guangju Zhai; Jing Hua Zhao; M Carola Zillikens; Ingrid B Borecki; Ruth J F Loos; Pierre Meneton; Patrik K E Magnusson; David M Nathan; Gordon H Williams; Andrew T Hattersley; Kaisa Silander; Veikko Salomaa; George Davey Smith; Stefan R Bornstein; Peter Schwarz; Joachim Spranger; Fredrik Karpe; Alan R Shuldiner; Cyrus Cooper; George V Dedoussis; Manuel Serrano-Ríos; Andrew D Morris; Lars Lind; Lyle J Palmer; Frank B Hu; Paul W Franks; Shah Ebrahim; Michael Marmot; W H Linda Kao; James S Pankow; Michael J Sampson; Johanna Kuusisto; Markku Laakso; Torben Hansen; Oluf Pedersen; Peter Paul Pramstaller; H Erich Wichmann; Thomas Illig; Igor Rudan; Alan F Wright; Michael Stumvoll; Harry Campbell; James F Wilson; Richard N Bergman; Thomas A Buchanan; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Timo T Valle; David Altshuler; Jerome I Rotter; David S Siscovick; Brenda W J H Penninx; Dorret I Boomsma; Panos Deloukas; Timothy D Spector; Timothy M Frayling; Luigi Ferrucci; Augustine Kong; Unnur Thorsteinsdottir; Kari Stefansson; Cornelia M van Duijn; Yurii S Aulchenko; Antonio Cao; Angelo Scuteri; David Schlessinger; Manuela Uda; Aimo Ruokonen; Marjo-Riitta Jarvelin; Dawn M Waterworth; Peter Vollenweider; Leena Peltonen; Vincent Mooser; Goncalo R Abecasis; Nicholas J Wareham; Robert Sladek; Philippe Froguel; Richard M Watanabe; James B Meigs; Leif Groop; Michael Boehnke; Mark I McCarthy; Jose C Florez; Inês Barroso Journal: Nat Genet Date: 2010-01-17 Impact factor: 38.330
Authors: Denise Anderson; Heather J Cordell; Michaela Fakiola; Richard W Francis; Genevieve Syn; Elizabeth S H Scaman; Elizabeth Davis; Simon J Miles; Toby McLeay; Sarra E Jamieson; Jenefer M Blackwell Journal: PLoS One Date: 2015-03-11 Impact factor: 3.240
Authors: Mayuko Iijima; Wei Liu; John C Panetta; Melissa M Hudson; Ching-Hon Pui; Deo Kumar Srivastava; Kevin R Krull; Hiroto Inaba Journal: Cancer Date: 2021-04-29 Impact factor: 6.921