AUTHOR=Zanti Maria , Loizidou Maria A. , O’Mahony Denise G. , Dorling Leila , Dennis Joe , Devilee Peter , Easton Douglas F. , Panayiotidis Mihalis I. , Hadjisavvas Andreas , Michailidou Kyriaki 

TITLE=Multi-gene panel testing and association analysis in Cypriot breast cancer cases and controls

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1248492

DOI=10.3389/fgene.2023.1248492

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> It is estimated that around 5% of breast cancer cases carry pathogenic variants in established breast cancer susceptibility genes. However, the underlying prevalence and gene-specific population risk estimates in Cyprus are currently unknown.</p><p><bold>Methods:</bold> We performed sequencing on a population-based case-control study of 990 breast cancer cases and 1094 controls from Cyprus using the BRIDGES sequencing panel. Analyses were conducted separately for protein-truncating and rare missense variants.</p><p><bold>Results:</bold> Protein-truncating variants in established breast cancer susceptibility genes were detected in 3.54% of cases and 0.37% of controls. Protein-truncating variants in <italic>BRCA2</italic> and <italic>ATM</italic> were associated with a high risk of breast cancer, whereas PTVs in <italic>BRCA1</italic> and <italic>PALB2</italic> were associated with a high risk of estrogen receptor (ER)-negative disease. Among participants with a family history of breast cancer, PTVs in <italic>ATM</italic>, <italic>BRCA2</italic>, <italic>BRCA1</italic>, <italic>PALB2</italic> and <italic>RAD50</italic> were associated with an increased risk of breast cancer. Furthermore, an additional 19.70% of cases and 17.18% of controls had at least one rare missense variant in established breast cancer susceptibility genes. For <italic>BRCA1</italic> and <italic>PALB2</italic>, rare missense variants were associated with an increased risk of overall and triple-negative breast cancer, respectively. Rare missense variants in <italic>BRCA1</italic>, <italic>ATM</italic>, <italic>CHEK2</italic> and <italic>PALB2</italic> domains, were associated with increased risk of disease subtypes.</p><p><bold>Conclusion:</bold> This study provides population-based prevalence and gene-specific risk estimates for protein-truncating and rare missense variants. These results may have important clinical implications for women who undergo genetic testing and be pivotal for a substantial proportion of breast cancer patients in Cyprus.</p>