Xiang Shu1, Qin Zhou2, Xiaohui Sun2,3, Michelle Flesaker2,4, Xingyi Guo5, Jirong Long5, Mark E Robson6, Xiao-Ou Shu5, Wei Zheng5, Jonine L Bernstein2. 1. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ShuX@mskcc.org. 2. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Epidemiology, Zhejiang Chinese Medical University, Zhejiang, China. 4. Program in Statistical & Data Sciences, Smith College, Northampton, MA, USA. 5. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. 6. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract
BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (ntotal = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 × 10-4) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, Pheterogeneity < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy.
BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (ntotal = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 × 10-4) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, Pheterogeneity < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy.
Authors: Daniel F Gudbjartsson; Patrick Sulem; Simon N Stacey; Alisa M Goldstein; Thorunn Rafnar; Bardur Sigurgeirsson; Kristrun R Benediktsdottir; Kristin Thorisdottir; Rafn Ragnarsson; Steinunn G Sveinsdottir; Veronica Magnusson; Annika Lindblom; Konstantinos Kostulas; Rafael Botella-Estrada; Virtudes Soriano; Pablo Juberías; Matilde Grasa; Berta Saez; Raquel Andres; Dominique Scherer; Peter Rudnai; Eugene Gurzau; Kvetoslava Koppova; Lambertus A Kiemeney; Margret Jakobsdottir; Stacy Steinberg; Agnar Helgason; Solveig Gretarsdottir; Margaret A Tucker; José I Mayordomo; Eduardo Nagore; Rajiv Kumar; Johan Hansson; Jon H Olafsson; Jeffrey Gulcher; Augustine Kong; Unnur Thorsteinsdottir; Kari Stefansson Journal: Nat Genet Date: 2008-05-18 Impact factor: 38.330
Authors: Juliette Coignard; Michael Lush; Jonathan Beesley; Tracy A O'Mara; Joe Dennis; Jonathan P Tyrer; Daniel R Barnes; Lesley McGuffog; Goska Leslie; Manjeet K Bolla; Muriel A Adank; Simona Agata; Thomas Ahearn; Kristiina Aittomäki; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Norbert Arnold; Kristan J Aronson; Banu K Arun; Annelie Augustinsson; Jacopo Azzollini; Daniel Barrowdale; Caroline Baynes; Heiko Becher; Marina Bermisheva; Leslie Bernstein; Katarzyna Białkowska; Carl Blomqvist; Stig E Bojesen; Bernardo Bonanni; Ake Borg; Hiltrud Brauch; Hermann Brenner; Barbara Burwinkel; Saundra S Buys; Trinidad Caldés; Maria A Caligo; Daniele Campa; Brian D Carter; Jose E Castelao; Jenny Chang-Claude; Stephen J Chanock; Wendy K Chung; Kathleen B M Claes; Christine L Clarke; J Margriet Collée; Don M Conroy; Kamila Czene; Mary B Daly; Peter Devilee; Orland Diez; Yuan Chun Ding; Susan M Domchek; Thilo Dörk; Isabel Dos-Santos-Silva; Alison M Dunning; Miriam Dwek; Diana M Eccles; A Heather Eliassen; Christoph Engel; Mikael Eriksson; D Gareth Evans; Peter A Fasching; Henrik Flyger; Florentia Fostira; Eitan Friedman; Lin Fritschi; Debra Frost; Manuela Gago-Dominguez; Susan M Gapstur; Judy Garber; Vanesa Garcia-Barberan; Montserrat García-Closas; José A García-Sáenz; Mia M Gaudet; Simon A Gayther; Andrea Gehrig; Vassilios Georgoulias; Graham G Giles; Andrew K Godwin; Mark S Goldberg; David E Goldgar; Anna González-Neira; Mark H Greene; Pascal Guénel; Lothar Haeberle; Eric Hahnen; Christopher A Haiman; Niclas Håkansson; Per Hall; Ute Hamann; Patricia A Harrington; Steven N Hart; Wei He; Frans B L Hogervorst; Antoinette Hollestelle; John L Hopper; Darling J Horcasitas; Peter J Hulick; David J Hunter; Evgeny N Imyanitov; Agnes Jager; Anna Jakubowska; Paul A James; Uffe Birk Jensen; Esther M John; Michael E Jones; Rudolf Kaaks; Pooja Middha Kapoor; Beth Y Karlan; Renske Keeman; Elza Khusnutdinova; Johanna I Kiiski; Yon-Dschun Ko; Veli-Matti Kosma; Peter Kraft; Allison W Kurian; Yael Laitman; Diether Lambrechts; Loic Le Marchand; Jenny Lester; Fabienne Lesueur; Tricia Lindstrom; Adria Lopez-Fernández; Jennifer T Loud; Craig Luccarini; Arto Mannermaa; Siranoush Manoukian; Sara Margolin; John W M Martens; Noura Mebirouk; Alfons Meindl; Austin Miller; Roger L Milne; Marco Montagna; Katherine L Nathanson; Susan L Neuhausen; Heli Nevanlinna; Finn C Nielsen; Katie M O'Brien; Olufunmilayo I Olopade; Janet E Olson; Håkan Olsson; Ana Osorio; Laura Ottini; Tjoung-Won Park-Simon; Michael T Parsons; Inge Sokilde Pedersen; Beth Peshkin; Paolo Peterlongo; Julian Peto; Paul D P Pharoah; Kelly-Anne Phillips; Eric C Polley; Bruce Poppe; Nadege Presneau; Miquel Angel Pujana; Kevin Punie; Paolo Radice; Johanna Rantala; Muhammad U Rashid; Gad Rennert; Hedy S Rennert; Mark Robson; Atocha Romero; Maria Rossing; Emmanouil Saloustros; Dale P Sandler; Regina Santella; Maren T Scheuner; Marjanka K Schmidt; Gunnar Schmidt; Christopher Scott; Priyanka Sharma; Penny Soucy; Melissa C Southey; John J Spinelli; Zoe Steinsnyder; Jennifer Stone; Dominique Stoppa-Lyonnet; Anthony Swerdlow; Rulla M Tamimi; William J Tapper; Jack A Taylor; Mary Beth Terry; Alex Teulé; Darcy L Thull; Marc Tischkowitz; Amanda E Toland; Diana Torres; Alison H Trainer; Thérèse Truong; Nadine Tung; Celine M Vachon; Ana Vega; Joseph Vijai; Qin Wang; Barbara Wappenschmidt; Clarice R Weinberg; Jeffrey N Weitzel; Camilla Wendt; Alicja Wolk; Siddhartha Yadav; Xiaohong R Yang; Drakoulis Yannoukakos; Wei Zheng; Argyrios Ziogas; Kristin K Zorn; Sue K Park; Mads Thomassen; Kenneth Offit; Rita K Schmutzler; Fergus J Couch; Jacques Simard; Georgia Chenevix-Trench; Douglas F Easton; Nadine Andrieu; Antonis C Antoniou Journal: Nat Commun Date: 2021-02-17 Impact factor: 17.694
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Authors: Robert Carreras-Torres; Mattias Johansson; Philip C Haycock; Caroline L Relton; George Davey Smith; Paul Brennan; Richard M Martin Journal: BMJ Date: 2018-05-16