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

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Fig. 1

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Abbreviations

MAF:

Minor allele frequency

WHI:

The Women Health Initiative

AABC:

The African-American Breast Cancer GWAS study

BCAC:

The Breast Cancer Association Consortium

ROOT:

GWAS of Breast Cancer in the African Diaspora

OR:

Odds ratio

AUC:

Area under the receiver operating characteristic curve

PRS:

Polygenic risk score

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Acknowledgements

This work was in part supported by the American Cancer Society (MRSG-13-063-01-TBG and CRP-10-119-01-CCE), National Cancer Institute (CA142996, CA161032), Susan G. Komen for the Cure, and Breast Cancer Research Foundation. SW was supported by a University of Chicago Global Health Fellowship.

Funding

This work was in part supported by the American Cancer Society MRSG-13-063-01-TBG (DH) and CRP-10-119-01-CCE (OIO), National Cancer Institute CA142996 (OIO) and CA161032 (OIO), Susan G. Komen for the Cure (OIO), and Breast Cancer Research Foundation (OIO, DH). The funding agencies have no involvement in the study design, data collection, analysis, interpretation of data, writing of the manuscript, or decision to submit the manuscript for publication. SW was supported by a University of Chicago Center for Global Health Postdoctoral Research Fellowship.

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Author notes

  1. Shengfeng Wang and Frank Qian have contributed equally to this paper.

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China

    Shengfeng Wang

  2. Center for Clinical Cancer Genetics & Global Health, Department of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 2020, Chicago, IL, 60637, USA

    Shengfeng Wang, Yonglan Zheng & Olufunmilayo I. Olopade

  3. Department of Medicine, University of Chicago, Chicago, USA

    Frank Qian

  4. Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Temidayo Ogundiran

  5. Center for Population and Reproductive Health, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Oladosu Ojengbede

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

    Wei Zheng & William Blot

  7. Department of Medicine, University of Pennsylvania, Philadelphia, USA

    Katherine L. Nathanson

  8. Chronic Disease Research Centre, Tropical Medicine Research Institute, University of the West Indies, Bridgetown, Barbados

    Anselm Hennis

  9. Department of Preventive Medicine, State University of New York, Stony Brook, USA

    Barbara Nemesure

  10. Laboratory of Human Carcinogenesis, National Cancer Institute, Rockville, USA

    Stefan Ambs

  11. Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave, MC 2007, Chicago, IL, 60637, USA

    Dezheng Huo

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  1. Shengfeng Wang
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  2. Frank Qian
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Corresponding authors

Correspondence to Olufunmilayo I. Olopade or Dezheng Huo.

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Wang, S., Qian, F., Zheng, Y. et al. Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry. Breast Cancer Res Treat 168, 703–712 (2018). https://doi.org/10.1007/s10549-017-4638-1

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  • DOI: https://doi.org/10.1007/s10549-017-4638-1

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