A catalog of curated breast cancer genes

Muthiah Bose,Jan Benada,Finn Cilius Nielsen,Jayashree Vijay Thatte,Savvas Kinalis,Bent Ejlertsen,Maria Rossing,Claus Storgaard Sørensen

doi:10.1007/s10549-021-06441-y

Muthiah Bose, Jan Benada + Show 6 more

Open Access

https://doi.org/10.1007/s10549-021-06441-y

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Abstract

PurposeDecades of research have identified multiple genetic variants associated with breast cancer etiology. However, there is no database that archives breast cancer genes and variants responsible for predisposition. We set out to build a dynamic repository of curated breast cancer genes.MethodsA comprehensive literature search was performed in PubMed and Google Scholar, followed by data extraction and harmonization for downstream analysis.ResultsUsing a subset of 345 studies, we cataloged 652 breast cancer-associated loci across the genome. A majority of these were present in the non-coding region (i.e., intergenic (101) and intronic (345)), whereas only 158 were located within an exon. Using the odds ratio, we identified 429 loci to increase the disease risk and 198 to confer protection against breast cancer, whereas 25 were identified to both increase disease risk and confer protection against breast cancer. Chromosomal ideogram analysis indicated that chromosomes 17 and 19 have the highest density of breast cancer loci. We manually annotated and collated breast cancer genes in which a previous association between rare-monogenic variant and breast cancer has been documented. Finally, network and functional enrichment analysis revealed that steroid metabolism and DNA repair pathways were predominant among breast cancer genes and variants.ConclusionsWe have built an online interactive catalog of curated breast cancer genes (https://cbcg.dk). This will expedite clinical diagnostics and support the ongoing efforts in managing breast cancer etiology. Moreover, the database will serve as an essential repository when designing new breast cancer multigene panels.

Highlights

Breast cancer is the most common cancer diagnosed in women and most importantly, it is the leading cause of cancer-related deaths among women worldwide [1, 2]
Genetic variation can predispose to breast cancer through both rare-monogenic variant causing a large increase in disease risk and common-polygenic variant that possess small individual effects on disease, cumulatively cause a large increase in disease risk [7]
Most SNPs are identified through genome-wide association studies (GWAS) and recent studies have suggested that polygenic risk score (PRS) accounts for around 18% of the familial breast cancer risk [10]

Summary

Introduction

Breast cancer is the most common cancer diagnosed in women and most importantly, it is the leading cause of cancer-related deaths among women worldwide [1, 2]. Genetic screens have played a vital role in the identification of genes and variants responsible for breast cancer predisposition. Genetic variation can predispose to breast cancer through both rare-monogenic variant causing a large increase in disease risk and common-polygenic variant (alias SNPs) that possess small individual effects on disease, cumulatively cause a large increase in disease risk [7]. The remaining heritability (around 50%) for breast cancer is most likely caused by yet unidentified moderate-risk genes or a specific cluster of commonpolygenic variants [11]. Identification of these unknown factors responsible for breast cancer etiology is of utmost importance and could expedite personalized breast cancer medicine, including therapeutic and preventive strategies [12]

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Results

Conclusion