Human Genetics

, Volume 132, Issue 5, pp 523–536

Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation

  • Erica S. Rinella
  • Yongzhao Shao
  • Lauren Yackowski
  • Sreemanta Pramanik
  • Ruth Oratz
  • Freya Schnabel
  • Saurav Guha
  • Charles LeDuc
  • Christopher L. Campbell
  • Susan D. Klugman
  • Mary Beth Terry
  • Ruby T. Senie
  • Irene L. Andrulis
  • Mary Daly
  • Esther M. John
  • Daniel Roses
  • Wendy K. Chung
  • Harry Ostrer
Original Investigation

DOI: 10.1007/s00439-013-1269-4

Cite this article as:
Rinella, E.S., Shao, Y., Yackowski, L. et al. Hum Genet (2013) 132: 523. doi:10.1007/s00439-013-1269-4

Abstract

The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Erica S. Rinella
    • 1
  • Yongzhao Shao
    • 2
  • Lauren Yackowski
    • 3
  • Sreemanta Pramanik
    • 4
  • Ruth Oratz
    • 12
  • Freya Schnabel
    • 1
  • Saurav Guha
    • 5
  • Charles LeDuc
    • 5
  • Christopher L. Campbell
    • 3
  • Susan D. Klugman
    • 6
  • Mary Beth Terry
    • 7
  • Ruby T. Senie
    • 7
  • Irene L. Andrulis
    • 8
  • Mary Daly
    • 9
  • Esther M. John
    • 10
    • 11
  • Daniel Roses
    • 1
  • Wendy K. Chung
    • 5
  • Harry Ostrer
    • 3
  1. 1.Department of SurgeryNew York University Langone Medical CenterNew YorkUSA
  2. 2.Division of BiostatisticsNew York University School of MedicineNew YorkUSA
  3. 3.Department of PathologyAlbert Einstein College of MedicineBronxUSA
  4. 4.Kolkata Zonal LaboratoryNational Environmental Engineering Research InstituteKolkataIndia
  5. 5.Department of PediatricsColumbia University Medical CenterNew YorkUSA
  6. 6.Department of Obstetrics and Gynecology and Women’s HealthMontefiore Medical Center, Albert Einstein College of MedicineBronxUSA
  7. 7.Department of EpidemiologyMailman School of Public Health of Columbia UniversityNew YorkUSA
  8. 8.Department of Molecular GeneticsUniversity of Toronto, Samuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada
  9. 9.Clinical GeneticsFox Chase Cancer CenterPhiladelphiaUSA
  10. 10.Cancer Prevention Institute of CaliforniaFremontUSA
  11. 11.Stanford University School of Medicine and Stanford Cancer InstituteStanfordUSA
  12. 12.Department of MedicineNew York University Langone Medical CenterNew YorkUSA