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Review
. 2021 Aug 5;13(16):3953.
doi: 10.3390/cancers13163953.

Risks and Function of Breast Cancer Susceptibility Alleles

Saeideh Torabi Dalivandan  1 , Jasmine Plummer  1 , Simon A Gayther  1
Affiliations
Review

Risks and Function of Breast Cancer Susceptibility Alleles

Saeideh Torabi Dalivandan et al. Cancers (Basel). .

Abstract

Family history remains one of the strongest risk factors for breast cancer. It is well established that women with a first-degree relative affected by breast cancer are twice as likely to develop the disease themselves. Twins studies indicate that this is most likely due to shared genetics rather than shared epidemiological/lifestyle risk factors. Linkage and targeted sequencing studies have shown that rare high- and moderate-penetrance germline variants in genes involved in the DNA damage response (DDR) including BRCA1, BRCA2, PALB2, ATM, and TP53 are responsible for a proportion of breast cancer cases. However, breast cancer is a heterogeneous disease, and there is now strong evidence that different risk alleles can predispose to different subtypes of breast cancer. Here, we review the associations between the different genes and subtype-specificity of breast cancer based on the most comprehensive genetic studies published. Genome-wide association studies (GWAS) have also been used to identify an additional hereditary component of breast cancer, and have identified hundreds of common, low-penetrance susceptibility alleles. The combination of these low penetrance risk variants, summed as a polygenic risk score (PRS), can identify individuals across the spectrum of disease risk. However, there remains a substantial bottleneck between the discovery of GWAS-risk variants and their contribution to tumorigenesis mainly because the majority of these variants map to the non-protein coding genome. A range of functional genomic approaches are needed to identify the causal risk variants and target susceptibility genes and establish their underlying role in disease biology. We discuss how the application of these multidisciplinary approaches to understand genetic risk for breast cancer can be used to identify individuals in the population that may benefit from clinical interventions including screening for early detection and prevention, and treatment strategies to reduce breast cancer-related mortalities.

Keywords: GWAS; breast cancer risk; clinical genetic testing; functional genomics; subtype-specific risk.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the proportional contributions of breast cancer susceptibility risk genes (high- and moderate-penetrance genes), and common risk alleles to breast cancer.
Figure 2
Figure 2
Diagrammatic representation of tumor subtype–associated breast cancer susceptibility genes present in the double-strand DNA break repair pathway based upon the recent study by Breast Cancer Association Consortium et al., 2021 [47]. ER = estrogen receptor. Figures 2–4 were created with Biorender tool (https://biorender.com/, accessed on 6 July 2021).
Figure 3
Figure 3
Illustration of functional follow-up analysis of non-coding low penetrance common risk variants. (a) Integration of genotype and epigenomic data to identify the candidate regulatory targets of risk variants; (b) Integrative analysis of the correlation between genotype to gene expression paired with gene-regulatroy element interaction, identifies putative candidate susceptibility genes; and (c) genome editing, multiomics, and cell biology assays are utilized to functionally evaluate noncoding DNA elements and their potential target genes to uncover their role in neoplastic development.
Figure 4
Figure 4
Breast cancer subtype-specific screening and preventive approaches proposal. (a) Genetic testing to identify risk alleles; (b) stratification of at-risk individuals based on the presence of breast cancer subtype-specific risk alleles; and (c) Subtype-specific care management.
See this image and copyright information in PMC

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