Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer-Reference-Cited by-同舟云学术

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer

Published:2024-06-04 Issue:15 Volume:84 Page:2533-2548
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Sun Xiaohui¹²^ORCID,Verma Shiv P.¹^ORCID,Jia Guochong³^ORCID,Wang Xinjun¹^ORCID,Ping Jie³^ORCID,Guo Xingyi³^ORCID,Shu Xiao-Ou³^ORCID,Chen Jianhong⁴^ORCID,Derkach Andriy¹^ORCID,Cai Qiuyin³^ORCID,Liang Xiaolin¹^ORCID,Long Jirong³^ORCID,Offit Kenneth⁵⁶^ORCID,Oh Jung H.⁷^ORCID,Reiner Anne S.¹^ORCID,Watt Gordon P.¹^ORCID,Woods Meghan¹^ORCID,Yang Yaohua³⁸⁹^ORCID,Ambrosone Christine B.⁴^ORCID,Ambs Stefan¹⁰^ORCID,Chen Yu¹¹^ORCID,Concannon Patrick¹²^ORCID,Garcia-Closas Montserrat¹³^ORCID,Gu Jian¹⁴^ORCID,Haiman Christopher A.¹⁵^ORCID,Hu Jennifer J.¹⁶^ORCID,Huo Dezheng¹⁷^ORCID,John Esther M.¹⁸¹⁹²⁰^ORCID,Knight Julia A.²¹²²^ORCID,Li Christopher I.²³^ORCID,Lynch Charles F.²⁴^ORCID,Mellemkjær Lene²⁵^ORCID,Nathanson Katherine L.²⁶²⁷^ORCID,Nemesure Barbara²⁸^ORCID,Olopade Olufunmilayo I.²⁹^ORCID,Olshan Andrew F.³⁰^ORCID,Pal Tuya³¹^ORCID,Palmer Julie R.³²^ORCID,Press Michael F.³³^ORCID,Sanderson Maureen³⁴^ORCID,Sandler Dale P.³⁵^ORCID,Troester Melissa A.³⁰^ORCID,Zheng Wei³^ORCID,Bernstein Jonine L.¹^ORCID,Buas Matthew F.¹^ORCID,Shu Xiang¹^ORCID

Affiliation:

1. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 1

2. Department of Epidemiology, Zhejiang Chinese Medical University, Hangzhou, China. 2

3. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. 3

4. Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York. 4

5. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 5

6. Department of Medicine, Weill Cornell Medical College, New York, New York. 6

7. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York. 7

8. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 8

9. UVA Comprehensive Cancer Center, University of Virginia, Charlottesville, Virginia. 9

10. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 10

11. Department of Population Health, New York University Grossman School of Medicine, New York, New York. 11

12. Department of Pathology, Immunology and Laboratory Medicine, Genetics Institute, University of Florida, Gainesville, Florida. 12

13. Trans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 13

14. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 14

15. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. 15

16. The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. 16

17. Department of Public Health Sciences, University of Chicago, Chicago, Illinois. 17

18. Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California. 18

19. Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California. 19

20. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California. 20

21. Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada. 21

22. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. 22

23. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 23

24. Department of Epidemiology, University of Iowa College of Public Health, Iowa City, Iowa. 24

25. Diet, Cancer and Health, Danish Cancer Institute, Copenhagen, Denmark. 25

26. Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 26

27. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 27

28. Department of Family, Population, and Preventive Medicine, Stony Brook Medicine, Stony Brook, New York. 28

29. Department of Medicine, University of Chicago, Chicago, Illinois. 29

30. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 30

31. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 31

32. Slone Epidemiology Center, Boston University, Boston, Massachusetts. 32

33. Department of Pathology, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, California. 33

34. Department of Family and Community Medicine, Meharry Medical College, Nashville, Tennessee. 34

35. Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. 35

Abstract

Abstract Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case–case comparisons among five breast cancer subtypes by applying a case–case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case–control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.

Funder

National Cancer Institute

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/cancerres/article-pdf/doi/10.1158/0008-5472.CAN-23-3854/3459897/can-23-3854.pdf

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