Elucidating the underlying functional mechanisms of breast cancer susceptibility through post-GWAS analyses

Rivandi, M. and Martens, J. W. M. and Hollestelle, A. (2018) Elucidating the underlying functional mechanisms of breast cancer susceptibility through post-GWAS analyses. Frontiers in Genetics, 9 (AUG).

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Abstract

Genome-wide association studies (GWAS) have identified more than 170 single nucleotide polymorphisms (SNPs) associated with the susceptibility to breast cancer. Together, these SNPs explain 18 of the familial relative risk, which is estimated to be nearly half of the total familial breast cancer risk that is collectively explained by low-risk susceptibility alleles. An important aspect of this success has been the access to large sample sizes through collaborative efforts within the Breast Cancer Association Consortium (BCAC), but also collaborations between cancer association consortia. Despite these achievements, however, understanding of each variant's underlying mechanism and how these SNPs predispose women to breast cancer remains limited and represents a major challenge in the field, particularly since the vast majority of the GWAS-identified SNPs are located in non-coding regions of the genome and are merely tags for the causal variants. In recent years, fine-scale mapping studies followed by functional evaluation of putative causal variants have begun to elucidate the biological function of several GWAS-identified variants. In this review, we discuss the findings and lessons learned from these post-GWAS analyses of 22 risk loci. Identifying the true causal variants underlying breast cancer susceptibility and their function not only provides better estimates of the explained familial relative risk thereby improving polygenetic risk scores (PRSs), it also increases our understanding of the biological mechanisms responsible for causing susceptibility to breast cancer. This will facilitate the identification of further breast cancer risk alleles and the development of preventive medicine for those women at increased risk for developing the disease. © 2018 Rivandi, Martens and Hollestelle.

Item Type: Article
Additional Information: Cited By :1 Export Date: 16 February 2020 Correspondence Address: Hollestelle, A.; Department of Medical Oncology, Erasmus MC Cancer InstituteNetherlands; email: a.hollestelle@erasmusmc.nl
Uncontrolled Keywords: Breast cancer Fine-scale mapping Functional analysis Post-GWAS analysis Susceptibility loci allele cancer risk cancer susceptibility chromatin chromatin immunoprecipitation CRISPR-CAS9 system gene expression gene function genetic risk genetic susceptibility genome-wide association study human in vitro study luciferase assay multifactorial inheritance quantitative trait locus Review risk assessment scoring system single nucleotide polymorphism
Subjects: WP Gynecology
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 06 May 2020 12:39
Last Modified: 06 May 2020 12:39
URI: http://eprints.mums.ac.ir/id/eprint/17493

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