INTERVENE - May 2025

Project title:
Assessment for breast cancer risk prediction using the combined risk coming from both polygenic risk score (PRS) and rare variants

Project leaders:
Alessandra Renieri, University of Siena

Project Description:

Within the INTERVENE project in the Siana cohort, we run Whole exome sequencing and genome-wide PRS assessment on 213 female patients with breast cancer. Patients were stratified into four risk categories for rare variants: i) high (>1,25) (ii) medium (<1,25 >-1,26) iii) low (<-1,26) iv) no P/LP variants in known cancer driver genes, and three risk categories for PRS: high (10 percentile), low (90 percentile) and intermediate.

The data show strong contribution from both the PRS and the rare variant, with the OR remaining close to 1 in both the absence of a rare variant with high PRS and in the case of a high-penetrance rare variant (e.g., BRCA 1/2) with low PRS (OR 1.68; 95% CI: 1.41-2; p < 0.001). Furthermore, patients with rare variants of intermediate (e.g., CHEK2) or low penetrance, but with high PRS, show a very high OR (e.g., 6.58; 95% CI: 5.52-7.85; p < 0.001), higher than that observed for BRCA1/2 with low PRS. Finally, the risk increases with age and differ significantly depending on PRS category and the specific rare variant.

The INTERVENE project will end in December 2025.

In this last 6 months counselling and segregation in family members is planned as well as replication study in 200 patients from Turin and 800 patients from Helsinki (on Helsinki patients the Finland PRS will be used).

Start date: May 2025

Duration: 2 years

Funder: INTERVENE project (https://www.interveneproject.eu/)