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. 2020 Jun 8:4:PO.19.00360.
doi: 10.1200/PO.19.00360. eCollection 2020.

Development and Validation of a Clinical Polygenic Risk Score to Predict Breast Cancer Risk

Elisha Hughes  1 , Placede Tshiaba  1 , Shannon Gallagher  1 , Susanne Wagner  1 , Thaddeus Judkins  1 , Benjamin Roa  1 , Eric Rosenthal  1 , Susan Domchek  2 , Judy Garber  3 , Johnathan Lancaster  1 , Jeffrey Weitzel  4 , Allison W Kurian  5 , Jerry S Lanchbury  1 , Alexander Gutin  1 , Mark Robson  6
Affiliations

Development and Validation of a Clinical Polygenic Risk Score to Predict Breast Cancer Risk

Elisha Hughes et al. JCO Precis Oncol. .

Abstract

Purpose: Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet < 10% are found to have pathogenic variants in known breast cancer susceptibility genes. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms [SNPs]) with individually modest breast cancer risk that, in aggregate, account for considerable breast cancer susceptibility. Here, we describe the development and empirical validation of an SNP-based polygenic breast cancer risk score.

Methods: A panel of 94 SNPs was examined for association with breast cancer in women of European ancestry undergoing hereditary cancer genetic testing and negative for pathogenic variants in breast cancer susceptibility genes. Candidate polygenic risk scores (PRSs) as predictors of personal breast cancer history were developed through multivariable logistic regression models adjusted for age, cancer history, and ancestry. An optimized PRS was validated in 2 independent cohorts (n = 13,174; n = 141,160).

Results: Within the training cohort (n = 24,259), 4,291 women (18%) had a personal history of breast cancer and 8,725 women (36%) reported breast cancer in a first-degree relative. The optimized PRS included 86 variants and was highly predictive of breast cancer status in both validation cohorts (P = 6.4 × 10-66; P < 10-325). The odds ratio (OR) per unit standard deviation was consistent between validations (OR, 1.45 [95% CI, 1.39 to 1.52]; OR 1.47 [95% CI, 1.45 to 1.49]). In a direct comparison, the 86-SNP PRS outperformed a previously described PRS of 77 SNPs.

Conclusion: The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments. Elisha HughesEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsPlacede TshiabaEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsShannon GallagherEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsSusanne WagnerEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Patents, Royalties, Other Intellectual Property: Co-author of patents held by Myriad Genetics, no royaltiesThaddeus JudkinsEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsBenjamin RoaEmployment: Myriad Genetics Leadership: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Research Funding: Myriad Genetics Patents, Royalties, Other Intellectual Property: Intellectual property held by employer Myriad Genetics (Inst) Travel, Accommodations, Expenses: Myriad GeneticsEric RosenthalEmployment: Myriad Genetic Laboratories Stock and Other Ownership Interests: Myriad Genetic LaboratoriesSusan DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers Squibb Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/917904Judy GarberConsulting or Advisory Role: Novartis (I), GTx (I), Helix BioPharma, Konica Minolta, Aleta BioTherapeutics (I), H3 Biomedicine (I), Kronos Bio (I) Research Funding: Novartis (I), Ambry Genetics, Invitae Genetics, Myriad Genetics Other Relationship: Susan G. Komen for the Cure (I), American Association for Cancer Research, Diane Helis Henry Medical Foundation, James P. Wilmot Foundation (I), Adrienne Helis Malvin Medical Research Foundation (I), Breast Cancer Research Foundation, Facing our Risk of Cancer EmpoweredJohnathan LancasterEmployment: Myriad Genetics, Regeneron Stock and Other Ownership Interests: Myriad Genetics, RegeneronJeffrey WeitzelSpeakers' Bureau: AstraZenecaAllison W. KurianResearch Funding: Myriad Genetics (Inst) Other Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, GenentechJerry S. LanchburyEmployment: Myriad Genetics Leadership: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Patents, Royalties, Other Intellectual Property: I am an inventor on multiple patents filed by Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsAlexander GutinEmployment: Myriad Genetics, Myriad Genetics (I) Stock and Other Ownership Interests: Myriad Genetics, Myriad Genetics (I), Gilead SciencesMark RobsonHonoraria: AstraZeneca Consulting or Advisory Role: Change Health Care Research Funding: AstraZeneca (Inst), Myriad Genetics (Inst), InVitae (Inst), AbbVie (Inst), Tesaro (Inst), Medivation (Inst), Pfizer (Inst) Travel, Accommodations, Expenses: AstraZeneca, Pfizer Other Relationship: Research to Practice, Clinical Care Options, Physician Education Resource Uncompensated Relationships: Merck, Pfizer, Daiichi Sankyo Open Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summary No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Cumulative likelihood ratio of individual single-nucleotide polymorphism (SNP) contributions to breast cancer risk discrimination. (*) For linked SNPs in CCND1, TERT, and ESR1, only one data point is shown per linkage disequilibrium block. df, degrees of freedom.
FIG 2.
FIG 2.
Observed versus theoretical estimates of breast cancer relative risk under the multiplicative polygenic model in (A) validation 1 and (B) validation 2.
See this image and copyright information in PMC

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