| الوصف: |
INTRODUCTION Polygenic risk scores (PRS) have demonstrated their potential to predict the likelihood of developing cancer. This allows risk stratification and, therefore, improved screening programs. Among these, PRS313 is the best-performing PRS for breast cancer in women of European ancestry.1 The NAGENMx project aims to provide the necessary evidence to implement a personalized breast cancer screening program based on this PRS in Navarra. Therefore, prior validation in our population is essential to ensure accurate stratification. AIM The aim of this study was to evaluate the applicability of PRS313 for breast cancer in Navarra. RESULTS A total of 803 WGS samples from NAGEN projects were available. After applying the selection criteria, 213 samples were included: 213 in the control group, 91 in the moderate-risk group, and 35 in the high-risk group. Exploratory analysis showed 2 SNPs present in a single sample (Figure 1), and 12 samples with fewer than 300 SNPs available (Figure 2). Additionally, significant differences from the frequencies described by Mavaddat were observed in 27 SNPs. To deal with these missing SNPs, several approaches described in the literature were tested. So far, substitution by effect allele frequency yielded the best results. Genotype imputation will also be tested. Then, the optimum number of substituted SNPs in all samples was explored (Figure 3), with the aim of maximizing the distance (delta) between the groups. Figure 4 shows a significant difference between the means of the moderate risk group and the control one (p < 0.05). Another approach will be to adapt the weights of each SNP by logistic regression. CONCLUSIONS Missing SNPs pose a major limitation when applying existing PRSs to new populations. On the other hand, the greater separation between the control and moderate-risk groups could suggest a higher polygenic burden in this group, while the high-risk group with family history could be explained by rare mutations not covered by the PRS313. These results highlight the need to adapt and develop an alternative PRS appropriate to our target population and existing data. |