Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author:

Kapoor Pooja Middha12ORCID,Mavaddat Nasim3,Choudhury Parichoy Pal4,Wilcox Amber N45ORCID,Lindström Sara67,Behrens Sabine1ORCID,Michailidou Kyriaki38,Dennis Joe3ORCID,Bolla Manjeet K3,Wang Qin3ORCID,Jung Audrey1,Abu-Ful Zomoroda9,Ahearn Thomas4ORCID,Andrulis Irene L1011,Anton-Culver Hoda12ORCID,Arndt Volker13ORCID,Aronson Kristan J14,Auer Paul L1516,Freeman Laura E Beane4,Becher Heiko1718,Beckmann Matthias W19,Beeghly-Fadiel Alicia20,Benitez Javier2122,Bernstein Leslie23ORCID,Bojesen Stig E242526,Brauch Hiltrud2425262728,Brenner Hermann132930,Brüning Thomas31,Cai Qiuyin20,Campa Daniele132,Canzian Federico33,Carracedo Angel3435,Carter Brian D36,Castelao Jose E37,Chanock Stephen J4ORCID,Chatterjee Nilanjan43839ORCID,Chenevix-Trench Georgia40ORCID,Clarke Christine L41,Couch Fergus J42,Cox Angela43ORCID,Cross Simon S44,Czene Kamila45,Dai James Y15,Earp H Shelton46,Ekici Arif B47,Eliassen A Heather4849,Eriksson Mikael45,Evans D Gareth5051,Fasching Peter A1952,Figueroa Jonine45354,Fritschi Lin55ORCID,Gabrielson Marike45ORCID,Gago-Dominguez Manuela3456ORCID,Gao Chi4957,Gapstur Susan M36,Gaudet Mia M36,Giles Graham G2425262728ORCID,González-Neira Anna22,Guénel Pascal58,Haeberle Lothar59,Haiman Christopher A60,Håkansson Niclas61,Hall Per4562ORCID,Hamann Ute63,Hatse Sigrid64,Heyworth Jane65,Holleczek Bernd66,Hoover Robert N4,Hopper John L67,Howell Anthony68,Hunter David J495769,John Esther M70,Jones Michael E71,Kaaks Rudolf1,Keeman Renske72,Kitahara Cari M73,Ko Yon-Dschun74,Koutros Stella4ORCID,Kurian Allison W70,Lambrechts Diether7576,Le Marchand Loic77,Lee Eunjung60,Lejbkowicz Flavio9,Linet Martha73,Lissowska Jolanta78,Llaneza Ana79,MacInnis Robert J8067,Martinez Maria Elena5681,Maurer Tabea82,McLean Catriona83,Neuhausen Susan L23ORCID,Newman William G5051,Norman Aaron84,O’Brien Katie M85,Olshan Andrew F86,Olson Janet E84,Olsson Håkan87,Orr Nick88ORCID,Perou Charles M89,Pita Guillermo90,Polley Eric C84,Prentice Ross L15,Rennert Gad9ORCID,Rennert Hedy S9,Ruddy Kathryn J91ORCID,Sandler Dale P85ORCID,Saunders Christobel92,Schoemaker Minouk J71,Schöttker Ben1393,Schumacher Fredrick94,Scott Christopher84ORCID,Scott Rodney J2425262728,Shu Xiao-Ou20,Smeets Ann95,Southey Melissa C969798,Spinelli John J99100,Stone Jennifer67101,Swerdlow Anthony J71102ORCID,Tamimi Rulla M484957,Taylor Jack A85103,Troester Melissa A86,Vachon Celine M104,van Veen Elke M5051,Wang Xiaoliang67,Weinberg Clarice R105,Weltens Caroline106,Willett Walter49107108,Winham Stacey J109,Wolk Alicja61110,Yang Xiaohong R4ORCID,Zheng Wei20,Ziogas Argyrios12ORCID,Dunning Alison M111,Pharoah Paul D P3111ORCID,Schmidt Marjanka K72112,Kraft Peter4957ORCID,Easton Douglas F3111ORCID,Milne Roger L2425262728,García-Closas Montserrat4,Chang-Claude Jenny182, ,

Affiliation:

1. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

2. Faculty of Medicine, University of Heidelberg, Heidelberg, Germany

3. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

4. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

5. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

6. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA

7. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

8. Biostatistics Unit and the Cyprus, School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus

9. Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel

10. Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada

11. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

12. Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA

13. Division of Clinical Epidemiology and Aging Research, C070, German Cancer Research Center (DKFZ), Heidelberg, Germany

14. Department of Public Health Sciences and Cancer Research Institute, Queen’s University, Kingston, ON, Canada

15. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

16. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA

17. Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

18. Institute of Biometry and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

19. Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

20. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

21. Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain

22. Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

23. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

24. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

25. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

26. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

27. Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany

28. iFIT-Cluster of Excellence, University of Tuebingen, Tuebingen, Germany

29. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

30. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany

31. Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany

32. Department of Biology, University of Pisa, Pisa, Italy

33. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

34. Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain

35. Centro de Investigación en Red de Enfermedades Raras (CIBERER) y Centro Nacional de Genotipado (CEGEN-PRB2), Universidad de Santiago de Compostela, Santiago De Compostela, Spain

36. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA

37. Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain

38. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

39. Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

40. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

41. Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia

42. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

43. Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

44. Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK

45. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

46. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

47. Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

48. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

49. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

50. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

51. North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

52. David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA

53. Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK

54. Cancer Research UK Edinburgh Centre, Edinburgh, UK

55. School of Public Health, Curtin University, Perth, Western Australia, Australia

56. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

57. Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

58. Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France

59. Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

60. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

61. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

62. Department of Oncology, Södersjukhuset, Stockholm, Sweden

63. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

64. Laboratory of Experimental Oncology (LEO), Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium

65. School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia

66. Saarland Cancer Registry, Saarbrücken, Germany

67. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia

68. Division of Cancer Sciences, University of Manchester, Manchester, UK

69. Nuffield Department of Population Health, University of Oxford, Oxford, UK

70. Division of Oncology, Departments of Epidemiology & Population Health and of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

71. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK

72. Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

73. Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

74. Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany

75. VIB Center for Cancer Biology, VIB, Leuven, Belgium

76. Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium

77. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA

78. Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland

79. General and Gastroenterology Surgery Service, Hospital Universitario Central de Asturias, Oviedo, Spain

80. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia

81. Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA

82. Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

83. Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia

84. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

85. Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA

86. Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

87. Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden

88. Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Ireland, UK

89. Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

90. Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain

91. Department of Oncology, Mayo Clinic, Rochester, MN, USA

92. School of Medicine, University of Western Australia, Perth, Western Australia, Australia

93. Network Aging Research, University of Heidelberg, Heidelberg, Germany

94. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

95. Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium

96. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia

97. Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia

98. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia

99. Population Oncology, BC Cancer, Vancouver, BC, Canada

100. School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada

101. The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia

102. Division of Breast Cancer Research, The Institute of Cancer Research, London, UK

103. Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA

104. Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

105. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA

106. Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium

107. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

108. Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

109. Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA

110. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

111. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK

112. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

Abstract

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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