A Comparison of POSH and UK Biobank Data in Young-onset Breast Cancer

Abstract

For young women, a breast cancer diagnosis often marks the beginning of a particularly difficult journey. Their cancers are typically more aggressive, harder to treat, and more likely to recur in the opposite breast. Yet the genetic risk prediction tools we use (Polygenic Risk Scores (PRS)) were mostly developed using data from older, postmenopausal women. As a result, they are less effective for younger patients, leaving a critical gap in care. My research aimed to address this gap by assessing how well current PRS perform in young- onset breast cancer (YOBC) and by exploring genetic factors that may be unique to this group. I conducted a genome-wide association study (GWAS), comparing YOBC cases from the Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) with healthy controls from the UK Biobank. However, direct comparisons between these heterogeneously genotyped cohorts showed inflated test statistics and possible technical artifacts. To overcome this, I carried out a UK Biobank-only analysis, which identified 159 genome-wide significant SNPs. I also evaluated the widely used PRS313 model in YOBC. While it provided some population- level risk stratification, its individual predictive accuracy was modest (AUC = 0.59), highlighting its limited utility for younger women. These findings underscore the need for PRS specifically tailored to YOBC. Developing age- specific models that capture the unique genetic architecture and aggressive biology of these cancers could improve early detection, enable more personalised treatment strategies, and ultimately enhance survival and quality of life. This work represents an important step toward ensuring that young women receive accurate risk predictions and the care they deserve.