# Screening Mammography and Breast Cancer: Variation in Risk with Rare Deleterious or Predicted Deleterious Variants in DNA Repair Genes

## TL;DR

This study explores how mammograms affect breast cancer risk in women with rare DNA repair gene variants, finding that risk varies depending on the type of gene variant.

## Contribution

The study is the first to investigate the joint effect of mammograms and DNA repair gene variants beyond BRCA1 and BRCA2 in high-risk women.

## Key findings

- Overall, no association was found between ever having a mammogram and breast cancer risk.
- Each additional mammogram increased breast cancer risk by 4%.
- Mammograms doubled the risk for women with variants in genes associated with reduced breast cancer risk.

## Abstract

The association of screening mammography with breast cancer (BC) was investigated in cases with a hereditary predisposition unexplained by BRCA1 or BRCA2 and unrelated controls. Participants reported their lifetime mammography exposures in a questionnaire. Additionally, germline rare deleterious or predicted deleterious variants (D-PDVs) were investigated in 113 DNA repair genes. No association was found between having been exposed to mammograms (never vs. ever) and BC. However, when considering the number of mammograms, an increase in BC risk of 4% (95% CI: 1–6%) per additional exposure was found. When women were grouped according to their D-PDV carrier status and the estimated associated BC risk, mammograms doubled the BC risk of women carrying a D-PDV in a gene associated with BC with an odds ratio (OR) < 0.9, as compared to those carrying a D-PDV in a gene with an OR > 1.1. Even though mammographic screening reduces the risk of mortality from BC, the identification of populations more or less susceptible to ionizing radiation may be clinically relevant.

Background: Women with a familial predisposition to breast cancer (BC) are offered screening at earlier ages and more frequently than women from the general population. Methods: We evaluated the effect of screening mammography in 1552 BC cases with a hereditary predisposition to BC unexplained by BRCA1 or BRCA2 and 1363 unrelated controls. Participants reported their lifetime mammography exposures in a detailed questionnaire. Germline rare deleterious or predicted deleterious variants (D-PDVs) in 113 DNA repair genes were investigated in 82.5% of the women and classified according to the strength of their association with BC. Genes with an odds ratio (OR) < 0.9 was assigned to the Gene Group “Reduced”, those with OR ≥ 0.9 and ≤1.1 to Group “Independent”, and those with OR > 1.1 to Group “Increased”. Results: Overall, having been exposed to mammograms (never vs. ever) was not associated with BC risk. However, an increase in BC risk of 4% (95% CI: 1–6%) per additional exposure was found under the assumption of linearity. When grouped according to D-PDV carrier status, mammograms doubled the BC risk of women carrying a D-PDV in Group “Reduced”, as compared to those carrying a D-PDV in Group “Increased”. Conclusions: Our study is the first to investigate the joint effect of mammogram exposure and variants in DNA repair genes other than BRCA1 and BRCA2 in women at high risk of BC; therefore, further studies are needed to verify our findings. Even though mammographic screening reduces the risk of mortality from BC, the identification of populations that are more or less susceptible to ionizing radiation may be clinically relevant.