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  • Review Article
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Polygenic scores in cancer

Nature Reviews Cancer volume 23, pages 619–630 (2023)Cite this article

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Abstract

Since the publication of the first genome-wide association study for cancer in 2007, thousands of common alleles that are associated with the risk of cancer have been identified. The relative risk associated with individual variants is small and of limited clinical significance. However, the combined effect of multiple risk variants as captured by polygenic scores (PGSs) may be much greater and therefore provide risk discrimination that is clinically useful. We review the considerable research efforts over the past 15 years for developing statistical methods for PGSs and their application in large-scale genome-wide association studies to develop PGSs for various cancers. We review the predictive performance of these PGSs and the multiple challenges currently limiting the clinical application of PGSs. Despite this, PGSs are beginning to be incorporated into clinical multifactorial risk prediction models to stratify risk in both clinical trials and clinical implementation studies.

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Fig. 1: Polygenic score distribution in population and cases.
Fig. 2: Measures of a polygenic risk model performance.

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Data availability

The primary data used for graphing Fig. 2 in this Review were re-analysed from Dareng et al.25 and Fritsche et al.29.

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Acknowledgements

This work was supported by the Cancer Research UK grant no. PPRPGM-Nov20\100002, the Gray Foundation and the PERSPECTIVE I&I Project, which the Government of Canada funds through Genome Canada (#13529) and the Canadian Institutes of Health Research (#155865). S.K. is supported by a UK Research and Innovation Future Leaders Fellowship (#MR/T043202/1).

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Authors and Affiliations

  1. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Xin Yang & Antonis C. Antoniou

  2. MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

    Siddhartha Kar

  3. Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK

    Siddhartha Kar

  4. Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Paul D. P. Pharoah

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  1. Xin Yang
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  2. Siddhartha Kar
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  3. Antonis C. Antoniou
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The authors contributed equally to all aspects of the article.

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Correspondence to Paul D. P. Pharoah.

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Related links

CanRisk: https://www.canrisk.org/

Consortium of Investigators of Modifiers of BRCA1/2: https://cimba.ccge.medschl.cam.ac.uk/

The Polygenic Score Catalogue: https://www.pgscatalog.org/

Glossary

313-SNP PGS

A polygenic score with 313 SNPs for breast cancer risk developed by Mavaddat et al.36 using data from a large GWAS with independent validation using data from the UK Biobank.

Common risk alleles

Alleles that are associated with disease risk that have a frequency of at least 1% in the population.

Genetic architecture

The range of risk alleles for a given phenotype as characterized by the risk allele frequencies and their associated risks.

High-penetrance variants

Inherited genetic variants in which carriers of a particular allele are highly likely to develop the disease or trait associated with that variant.

Linkage studies

A type of study designed to identify disease-associated genes, making use of the phenomenon of meiotic linkage (that is, the fact that previously unmapped genes for a disease and nearby genetic markers with known chromosomal position are frequently inherited together in families with a high incidence of the disease).

Lynch syndrome

Also known as hereditary nonpolyposis colorectal cancer, which is an autosomal dominant condition owing to inherited mutations in DNA mismatch repair genes (most commonly MLH1, MSH2, MSH6 or PMS2) that confer high (>50%) lifetime risk of colorectal, endometrial and other cancers.

Narrow-sense heritability

The proportion of variation in a disease or trait that is explained by adding up the average effects of all risk alleles.

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Yang, X., Kar, S., Antoniou, A.C. et al. Polygenic scores in cancer. Nat Rev Cancer 23, 619–630 (2023). https://doi.org/10.1038/s41568-023-00599-x

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