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Breast Cancer Res Treat. 2018 Apr;168(3):703-712. doi: 10.1007/s10549-017-4638-1. Epub 2018 Jan 4.

Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry.

Author information

1
Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
2
Center for Clinical Cancer Genetics & Global Health, Department of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 2020, Chicago, IL, 60637, USA.
3
Department of Medicine, University of Chicago, Chicago, USA.
4
Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria.
5
Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
6
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, USA.
7
Department of Medicine, University of Pennsylvania, Philadelphia, USA.
8
Chronic Disease Research Centre, Tropical Medicine Research Institute, University of the West Indies, Bridgetown, Barbados.
9
Department of Preventive Medicine, State University of New York, Stony Brook, USA.
10
Laboratory of Human Carcinogenesis, National Cancer Institute, Rockville, USA.
11
Center for Clinical Cancer Genetics & Global Health, Department of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 2020, Chicago, IL, 60637, USA. folopade@bsd.uchicago.edu.
12
Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave, MC 2007, Chicago, IL, 60637, USA. dhuo@uchicago.edu.

Abstract

BACKGROUND:

Few studies have evaluated the performance of existing breast cancer risk prediction models among women of African ancestry. In replication studies of genetic variants, a change in direction of the risk association is a common phenomenon. Termed flip-flop, it means that a variant is risk factor in one population but protective in another, affecting the performance of risk prediction models.

METHODS:

We used data from the genome-wide association study (GWAS) of breast cancer in the African diaspora (The Root consortium), which included 3686 participants of African ancestry from Nigeria, USA, and Barbados. Polygenic risk scores (PRSs) were constructed from the published odds ratios (ORs) of four sets of susceptibility loci for breast cancer. Discrimination capacity was measured using the area under the receiver operating characteristic curve (AUC).

RESULTS:

Flip-flop phenomenon was observed among 30~40% of variants across studies. Using the 34 variants with consistent directionality among previous studies, we constructed a PRS with AUC of 0.531 (95% confidence interval [CI]: 0.512-0.550), which is similar to the PRS using 93 variants and ORs from European ancestry populations (AUC = 0.525, 95% CI: 0.506-0.544). Additionally, we found the 34-variant PRS has good discriminative accuracy in women with family history of breast cancer (AUC = 0.586, 95% CI: 0.532-0.640).

CONCLUSIONS:

We found that PRS based on variants identified from prior GWASs conducted in women of European and Asian ancestries did not provide a comparable degree of risk stratification for women of African ancestry. Further large-scale fine-mapping studies in African ancestry populations are desirable to discover population-specific genetic risk variants.

KEYWORDS:

Breast neoplasms; Flip-flop; Polygenic risk score; Women of African ancestry

PMID:
29302764
PMCID:
PMC5916755
[Available on 2019-04-01]
DOI:
10.1007/s10549-017-4638-1

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