Generalizability of PGS313 for breast cancer risk in a Los Angeles biobank

Helen Shang; Yi Ding; Vidhya Venkateswaran; Kristin Boulier; Nikhita Kathuria-Prakash; Parisa Boodaghi Malidarreh; Jacob M Luber; Bogdan Pasaniuc

doi:10.1016/j.xhgg.2024.100302

Generalizability of PGS₃₁₃ for breast cancer risk in a Los Angeles biobank

HGG Adv. 2024 Jul 18;5(3):100302. doi: 10.1016/j.xhgg.2024.100302. Epub 2024 May 3.

Authors

Helen Shang¹, Yi Ding², Vidhya Venkateswaran³, Kristin Boulier⁴, Nikhita Kathuria-Prakash⁵, Parisa Boodaghi Malidarreh⁶, Jacob M Luber⁷, Bogdan Pasaniuc⁸

Affiliations

¹ Division of Internal Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA; Department of Computer Science and Engineering, University of Texas at Arlington, Arlington, TX, USA. Electronic address: hshang@mednet.ucla.edu.
² Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Oral Biology, UCLA School of Dentistry, Los Angeles, CA, USA.
⁴ Division of Cardiology, Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.
⁵ Division of Hematology-Oncology, Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.
⁶ Department of Computer Science and Engineering, University of Texas at Arlington, Arlington, TX, USA; Multi-Interprofessional Center for Health Informatics, University of Texas at Arlington, Arlington, TX, USA.
⁷ Department of Computer Science and Engineering, University of Texas at Arlington, Arlington, TX, USA; Multi-Interprofessional Center for Health Informatics, University of Texas at Arlington, Arlington, TX, USA; Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA.
⁸ Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

Abstract

Polygenic scores (PGSs) summarize the combined effect of common risk variants and are associated with breast cancer risk in patients without identifiable monogenic risk factors. One of the most well-validated PGSs in breast cancer to date is PGS₃₁₃, which was developed from a Northern European biobank but has shown attenuated performance in non-European ancestries. We further investigate the generalizability of the PGS₃₁₃ for American women of European (EA), African (AFR), Asian (EAA), and Latinx (HL) ancestry within one institution with a singular electronic health record (EHR) system, genotyping platform, and quality control process. We found that the PGS₃₁₃ achieved overlapping areas under the receiver operator characteristic (ROC) curve (AUCs) in females of HL (AUC = 0.68, 95% confidence interval [CI] = 0.65-0.71) and EA ancestry (AUC = 0.70, 95% CI = 0.69-0.71) but lower AUCs for the AFR and EAA populations (AFR: AUC = 0.61, 95% CI = 0.56-0.65; EAA: AUC = 0.64, 95% CI = 0.60-0.680). While PGS₃₁₃ is associated with hormone-receptor-positive (HR+) disease in EA Americans (odds ratio [OR] = 1.42, 95% CI = 1.16-1.64), this association is lost in African, Latinx, and Asian Americans. In summary, we found that PGS₃₁₃ was significantly associated with breast cancer but with attenuated accuracy in women of AFR and EAA descent within a singular health system in Los Angeles. Our work further highlights the need for additional validation in diverse cohorts prior to the clinical implementation of PGSs.

Keywords: PRS313; Polygenic scores; big data; biobank; bioinformatics; breast cancer; cancer risk prediction; genetic admixture.

Published by Elsevier Inc.

MeSH terms

Adult
Aged
Biological Specimen Banks*
Breast Neoplasms* / epidemiology
Breast Neoplasms* / ethnology
Breast Neoplasms* / genetics
Female
Genetic Predisposition to Disease*
Humans
Los Angeles / epidemiology
Middle Aged
Multifactorial Inheritance
Polymorphism, Single Nucleotide
ROC Curve
Risk Factors