Familial Cancer

, Volume 17, Issue 2, pp 187–195 | Cite as

Discovery of mutations in homologous recombination genes in African-American women with breast cancer

  • Yuan Chun Ding
  • Aaron W. Adamson
  • Linda Steele
  • Adam M. Bailis
  • Esther M. John
  • Gail Tomlinson
  • Susan L. Neuhausen
Original Article


African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African-Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein–protein interactions in yeast two-hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment.


Homologous recombination Germline mutations Breast cancer African-Americans Loss of protein function 



We thank David Schild for the yeast two-hybrid plasmids containing human XRCC3, XRCC2, RAD51D, RAD51C, and RAD51B; Jeremy Stark for the plasmid containing human RAD51, Carl VanNess for performing sample preparation and sequencing reactions, and Leila Su for help with the structural modeling of RAD51. This work was funded by the Morris and Horowitz Families Endowed Professorship (SLN), R50CA211280 (AWA); and African-American breast cancer cases were collected under funding from the National Institutes of Health R01CA74415 (SLN). Research reported in this publication included work performed in the Bioinformatics Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10689_2017_36_MOESM1_ESM.xls (36 kb)
Table 1S. PCR Primers and Conditions (XLS 36 KB)
10689_2017_36_MOESM2_ESM.xlsx (28 kb)
Table 2S. 125 Variants (XLSX 28 KB)
10689_2017_36_MOESM3_ESM.xlsx (18 kb)
Table 3S. Low Frequency Missense and Nonsense Variants (XLSX 18 KB)
10689_2017_36_MOESM4_ESM.xlsx (13 kb)
Table 4S. List of Y2H Variants and Activity (XLSX 12 KB)
10689_2017_36_MOESM5_ESM.pdf (333 kb)
Figure S1. Modeling Mutation Effect on RAD51 Protein Stability (PDF 333 KB)


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Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Department of Population SciencesBeckman Research Institute of City of HopeDuarteUSA
  2. 2.Department of Molecular and Cellular BiologyBeckman Research Institute of City of HopeDuarteUSA
  3. 3.Cancer Prevention Institute of CaliforniaFremontUSA
  4. 4.Department of Health Research & Policy (Epidemiology), and Stanford Cancer InstituteStanford University School of MedicineStanfordUSA
  5. 5.Department of PediatricsUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  6. 6.Hamon Center for Therapeutic Oncology ResearchUniversity of Texas Southwestern Medical CenterDallasUSA

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