16. Xingyan Wang, PhD, MS

Breast cancer (BC) is the most common cancer among women, with Ductal carcinoma in situ (DCIS) accounting for 20-25% of all screen-detected BC in the US. If untreated, 20-30% of DCIS cases may progress to invasive BC within 10 years. Common lifestyle risk factors include obesity, smoking, alcohol consumption and prolonged hormone replacement therapy use. Unlike invasive BC, genetic variants linked to DCIS remain underexplored.
We conducted a genome-wide association analysis (GWAS) for DCIS among women from the UK Biobank, using REGENIE, adjusting for age (at diagnose and at the end of follow-up), age square, the first 20 principal components, assessment centers, and genotype measurement batches. Our analysis included 2,794 cases who were diagnosed with DCIS based on ICD-10 code D05.1 and were free of invasive BC at the time of DCIS diagnosis, and 163,456 controls who were free of any neoplasm-related disease codes. We identified 4 genetic loci associated with DCIS, including ULK4 (lead SNP, rs59043489, P=1.8e-10), MEF2A (rs325385, P=3.05e-08), and two intergenic variants on q13.2 (rs820540, P=2.3e-08) and q13.3 (rs6446966 , P=2.89e-08).
We performed a transcriptome-wide association scan (TWAS) using The Cancer Genome Atlas data, identifying significant genetic effects on TMEM232 (p=1.64e-5) and TUSC3 (p=1.73e-5) gene expression in BC tumor tissues.
We also conducted genetic correlation and Mendelian randomization (MR) analyses using publicly available risk factor GWAS summary statistics, including obesity (BMI and waist-hip ratio), lipids, smoking and drinking behaviors. We identified LDL to be correlated with DCIS (rg = 0.09). MR suggested LDL may contribute to the progression of DCIS to invasive BC (b = -0.46, p = 0.01).
In conclusion, we identified genetic loci associated with DCIS, providing novel insights into disease risk and its relationship with risk factors. These results may inform future management strategies.