Assessing the risk stratification of breast cancer polygenic risk scores in two Brazilian samples

Polygenic risk scores (PRS) for breast cancer (BC) have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium (LD) and differences in variant frequency (AF-diff). Thus, locally-sourced population-based phenotypic and genomic datasets are essential to assess the validity of PRS derived from signals detected across populations. Here, assess the transferability of a BC PRS composed of 313 risk variants (313-PRS) in two Brazilian tri-hybrid admixed ancestries (European, African and Native American) whole-genome sequenced cohorts. We computed 313-PRS in both cohorts (n=753 and n=853) versus the UK Biobank (UKBB, n=264,307) as reference. We show that although the Brazilian cohorts have a high European (EA) component, with AF-diff and to a lesser extent LD patterns like those found in EA populations, the 313-PRS distribution is inflated when compared to that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. Interestingly, we find that case-controls lead to equivalent predictive power when compared to UKBB-EA samples with AUROC values of 0.66-0.62 compared to 0.63 for UKBB. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding for Michel Naslavsky, Mayana Zatz and Yeda Duarte at University of São Paulo was provided by grants and fellowships from São Paulo Research Foundation (FAPESP) (CEPID 2013/08028-1, SABE 2014/50649-6, INCT 2014/50931-3), and Conselho Nacional de Desenvolvimento Científico e Tecnol ógico - CNPq (INCT 465355/2014-5). Funding for Helena Brentani and Catarina S. Gomes at University of São Paulo was provided by grants and fellowships from FAPESP (grant #2020/16376-3 and #2018/18560-6), and the Conselho Nacional de Desenvolvimento Científico e Tecnol ógico - Brasil (CNPq) grant #310823/2021-8. The Rare Genomes Project is an initiative of Hospital Israelita Albert Einstein in partnership with the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (PROADI-SUS) from the Brazilian Ministry of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants signed written consent forms. SABE and UKBB PRS studies were approved by Albert Einstein Israelite Hospital ethical committee (37924920.9.0000.0071). GRAR studies were approved by Albert Einstein Israelite Hospital ethical committee (29567220.4.1001.0071). This research has been conducted using the UK Biobank Resource under Application Number 74348. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Scripts to replicate these analyses are available at: https://github.com/Varstation/313prs-bc-grar-sabe. SABE genomic data is available at https://ega-archive.org/studies/EGAS00001005052 under reasonable request and after Data Access Agreement is signed by User and User Institution