Yanfeng Zhang1, Jirong Long, Wei Lu, Xiao-Ou Shu, Qiuyin Cai, Ying Zheng, Chun Li, Bingshan Li, Yu-Tang Gao, Wei Zheng. 1. Authors' Affiliations: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center; Department of Biostatistics; Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee; Shanghai Center for Disease Control and Prevention; and Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
Abstract
BACKGROUND: To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk. METHODS: We investigated rare missense/nonsense variants with minor allele frequency (MAF) ≤5% located in flanking 500 kb of each of the index single-nucleotide polymorphism (SNP) in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations. RESULTS: Single marker analyses identified 38 missense variants being associated with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an OR of 6.2 [95% confidence interval (CI), 1.4-27.6; P = 6.2 × 10(-3)]. SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI, 2.2-124.5; P = 2.2 × 10(-4)). Gene-based analyses suggested eight genes associated with breast cancer risk at P < 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008). CONCLUSION: Our results identified associations of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biologic mechanisms underlying the associations. IMPACT: Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk.
BACKGROUND: To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk. METHODS: We investigated rare missense/nonsense variants with minor allele frequency (MAF) ≤5% located in flanking 500 kb of each of the index single-nucleotide polymorphism (SNP) in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations. RESULTS: Single marker analyses identified 38 missense variants being associated with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an OR of 6.2 [95% confidence interval (CI), 1.4-27.6; P = 6.2 × 10(-3)]. SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI, 2.2-124.5; P = 2.2 × 10(-4)). Gene-based analyses suggested eight genes associated with breast cancer risk at P < 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008). CONCLUSION: Our results identified associations of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biologic mechanisms underlying the associations. IMPACT: Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk.
Authors: Eva Colas; Cristina Perez; Silvia Cabrera; Nuria Pedrola; Marta Monge; Josep Castellvi; Fernando Eyzaguirre; Jesus Gregorio; Anna Ruiz; Marta Llaurado; Marina Rigau; Marta Garcia; Tugçe Ertekin; Melania Montes; Rafael Lopez-Lopez; Ramon Carreras; Jordi Xercavins; Alicia Ortega; Tamara Maes; Elisabet Rosell; Andreas Doll; Miguel Abal; Jaume Reventos; Antonio Gil-Moreno Journal: Int J Cancer Date: 2011-04-08 Impact factor: 7.396
Authors: Sean V Tavtigian; Peter J Oefner; Davit Babikyan; Anne Hartmann; Sue Healey; Florence Le Calvez-Kelm; Fabienne Lesueur; Graham B Byrnes; Shu-Chun Chuang; Nathalie Forey; Corinna Feuchtinger; Lydie Gioia; Janet Hall; Mia Hashibe; Barbara Herte; Sandrine McKay-Chopin; Alun Thomas; Maxime P Vallée; Catherine Voegele; Penelope M Webb; David C Whiteman; Suleeporn Sangrajrang; John L Hopper; Melissa C Southey; Irene L Andrulis; Esther M John; Georgia Chenevix-Trench Journal: Am J Hum Genet Date: 2009-09-24 Impact factor: 11.025
Authors: Florence Le Calvez-Kelm; Fabienne Lesueur; Francesca Damiola; Maxime Vallée; Catherine Voegele; Davit Babikyan; Geoffroy Durand; Nathalie Forey; Sandrine McKay-Chopin; Nivonirina Robinot; Tù Nguyen-Dumont; Alun Thomas; Graham B Byrnes; John L Hopper; Melissa C Southey; Irene L Andrulis; Esther M John; Sean V Tavtigian Journal: Breast Cancer Res Date: 2011-01-18 Impact factor: 6.466
Authors: Kyriaki Michailidou; Per Hall; Anna Gonzalez-Neira; Maya Ghoussaini; Joe Dennis; Roger L Milne; Marjanka K Schmidt; Jenny Chang-Claude; Stig E Bojesen; Manjeet K Bolla; Qin Wang; Ed Dicks; Andrew Lee; Clare Turnbull; Nazneen Rahman; Olivia Fletcher; Julian Peto; Lorna Gibson; Isabel Dos Santos Silva; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Kamila Czene; Astrid Irwanto; Jianjun Liu; Quinten Waisfisz; Hanne Meijers-Heijboer; Muriel Adank; Rob B van der Luijt; Rebecca Hein; Norbert Dahmen; Lars Beckman; Alfons Meindl; Rita K Schmutzler; Bertram Müller-Myhsok; Peter Lichtner; John L Hopper; Melissa C Southey; Enes Makalic; Daniel F Schmidt; Andre G Uitterlinden; Albert Hofman; David J Hunter; Stephen J Chanock; Daniel Vincent; François Bacot; Daniel C Tessier; Sander Canisius; Lodewyk F A Wessels; Christopher A Haiman; Mitul Shah; Robert Luben; Judith Brown; Craig Luccarini; Nils Schoof; Keith Humphreys; Jingmei Li; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Fergus J Couch; Xianshu Wang; Celine Vachon; Kristen N Stevens; Diether Lambrechts; Matthieu Moisse; Robert Paridaens; Marie-Rose Christiaens; Anja Rudolph; Stefan Nickels; Dieter Flesch-Janys; Nichola Johnson; Zoe Aitken; Kirsimari Aaltonen; Tuomas Heikkinen; Annegien Broeks; Laura J Van't Veer; C Ellen van der Schoot; Pascal Guénel; Thérèse Truong; Pierre Laurent-Puig; Florence Menegaux; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Barbara Burwinkel; M Pilar Zamora; Jose Ignacio Arias Perez; Guillermo Pita; M Rosario Alonso; Angela Cox; Ian W Brock; Simon S Cross; Malcolm W R Reed; Elinor J Sawyer; Ian Tomlinson; Michael J Kerin; Nicola Miller; Brian E Henderson; Fredrick Schumacher; Loic Le Marchand; Irene L Andrulis; Julia A Knight; Gord Glendon; Anna Marie Mulligan; Annika Lindblom; Sara Margolin; Maartje J Hooning; Antoinette Hollestelle; Ans M W van den Ouweland; Agnes Jager; Quang M Bui; Jennifer Stone; Gillian S Dite; Carmel Apicella; Helen Tsimiklis; Graham G Giles; Gianluca Severi; Laura Baglietto; Peter A Fasching; Lothar Haeberle; Arif B Ekici; Matthias W Beckmann; Hermann Brenner; Heiko Müller; Volker Arndt; Christa Stegmaier; Anthony Swerdlow; Alan Ashworth; Nick Orr; Michael Jones; Jonine Figueroa; Jolanta Lissowska; Louise Brinton; Mark S Goldberg; France Labrèche; Martine Dumont; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Hiltrud Brauch; Ute Hamann; Thomas Brüning; Paolo Radice; Paolo Peterlongo; Siranoush Manoukian; Bernardo Bonanni; Peter Devilee; Rob A E M Tollenaar; Caroline Seynaeve; Christi J van Asperen; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska; Katarzyna Durda; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Jaana M Hartikainen; Natalia V Bogdanova; Natalia N Antonenkova; Thilo Dörk; Vessela N Kristensen; Hoda Anton-Culver; Susan Slager; Amanda E Toland; Stephen Edge; Florentia Fostira; Daehee Kang; Keun-Young Yoo; Dong-Young Noh; Keitaro Matsuo; Hidemi Ito; Hiroji Iwata; Aiko Sueta; Anna H Wu; Chiu-Chen Tseng; David Van Den Berg; Daniel O Stram; Xiao-Ou Shu; Wei Lu; Yu-Tang Gao; Hui Cai; Soo Hwang Teo; Cheng Har Yip; Sze Yee Phuah; Belinda K Cornes; Mikael Hartman; Hui Miao; Wei Yen Lim; Jen-Hwei Sng; Kenneth Muir; Artitaya Lophatananon; Sarah Stewart-Brown; Pornthep Siriwanarangsan; Chen-Yang Shen; Chia-Ni Hsiung; Pei-Ei Wu; Shian-Ling Ding; Suleeporn Sangrajrang; Valerie Gaborieau; Paul Brennan; James McKay; William J Blot; Lisa B Signorello; Qiuyin Cai; Wei Zheng; Sandra Deming-Halverson; Martha Shrubsole; Jirong Long; Jacques Simard; Montse Garcia-Closas; Paul D P Pharoah; Georgia Chenevix-Trench; Alison M Dunning; Javier Benitez; Douglas F Easton Journal: Nat Genet Date: 2013-04 Impact factor: 38.330
Authors: Elise Ruark; Katie Snape; Peter Humburg; Chey Loveday; Ilirjana Bajrami; Rachel Brough; Daniel Nava Rodrigues; Anthony Renwick; Sheila Seal; Emma Ramsay; Silvana Del Vecchio Duarte; Manuel A Rivas; Margaret Warren-Perry; Anna Zachariou; Adriana Campion-Flora; Sandra Hanks; Anne Murray; Naser Ansari Pour; Jenny Douglas; Lorna Gregory; Andrew Rimmer; Neil M Walker; Tsun-Po Yang; Julian W Adlard; Julian Barwell; Jonathan Berg; Angela F Brady; Carole Brewer; Glen Brice; Cyril Chapman; Jackie Cook; Rosemarie Davidson; Alan Donaldson; Fiona Douglas; Diana Eccles; D Gareth Evans; Lynn Greenhalgh; Alex Henderson; Louise Izatt; Ajith Kumar; Fiona Lalloo; Zosia Miedzybrodzka; Patrick J Morrison; Joan Paterson; Mary Porteous; Mark T Rogers; Susan Shanley; Lisa Walker; Martin Gore; Richard Houlston; Matthew A Brown; Mark J Caufield; Panagiotis Deloukas; Mark I McCarthy; John A Todd; Clare Turnbull; Jorge S Reis-Filho; Alan Ashworth; Antonis C Antoniou; Christopher J Lord; Peter Donnelly; Nazneen Rahman Journal: Nature Date: 2012-12-16 Impact factor: 49.962
Authors: Yeon-Tae Jeong; Mario Rossi; Lukas Cermak; Anita Saraf; Laurence Florens; Michael P Washburn; Patrick Sung; Carl L Schildkraut; Carl Schildkraut; Michele Pagano Journal: J Cell Biol Date: 2013-01-14 Impact factor: 10.539
Authors: Chloe Y Y Cheung; Clara S Tang; Aimin Xu; Chi-Ho Lee; Ka-Wing Au; Lin Xu; Carol H Y Fong; Kelvin H M Kwok; Wing-Sun Chow; Yu-Cho Woo; Michele M A Yuen; JoJo S H Hai; Ya-Li Jin; Bernard M Y Cheung; Kathryn C B Tan; Stacey S Cherny; Feng Zhu; Tong Zhu; G Neil Thomas; Kar-Keung Cheng; Chao-Qiang Jiang; Tai-Hing Lam; Hung-Fat Tse; Pak-Chung Sham; Karen S L Lam Journal: Diabetologia Date: 2016-10-15 Impact factor: 10.122
Authors: Clara S Tang; He Zhang; Chloe Y Y Cheung; Ming Xu; Jenny C Y Ho; Wei Zhou; Stacey S Cherny; Yan Zhang; Oddgeir Holmen; Ka-Wing Au; Haiyi Yu; Lin Xu; Jia Jia; Robert M Porsch; Lijie Sun; Weixian Xu; Huiping Zheng; Lai-Yung Wong; Yiming Mu; Jingtao Dou; Carol H Y Fong; Shuyu Wang; Xueyu Hong; Liguang Dong; Yanhua Liao; Jiansong Wang; Levina S M Lam; Xi Su; Hua Yan; Min-Lee Yang; Jin Chen; Chung-Wah Siu; Gaoqiang Xie; Yu-Cho Woo; Yangfeng Wu; Kathryn C B Tan; Kristian Hveem; Bernard M Y Cheung; Sebastian Zöllner; Aimin Xu; Y Eugene Chen; Chao Qiang Jiang; Youyi Zhang; Tai-Hing Lam; Santhi K Ganesh; Yong Huo; Pak C Sham; Karen S L Lam; Cristen J Willer; Hung-Fat Tse; Wei Gao Journal: Nat Commun Date: 2015-12-22 Impact factor: 14.919
Authors: Sarah K Deasy; Ryo Uehara; Suman K Vodnala; Howard H Yang; Randall A Dass; Ying Hu; Maxwell P Lee; Robert J Crouch; Kent W Hunter Journal: PLoS Genet Date: 2019-05-24 Impact factor: 5.917