The role of polygenic risk and susceptibility genes in breast cancer over the course of life
Nina Mars, Elisabeth Widén, Sini Kerminen, Tuomo J Meretoja, Matti Pirinen, Pietro Della Briotta Parolo, Priit Palta, FinnGen, Aki S. Havulinna, Amanda Elliott, Anastasia Shcherban, Andrea Ganna, Anu Jalanko, Arto Lehistö, Elina Kilpeläinen, Georg Brein, Awaisa Ghazal, Hannele Laivuori, Henrike Heyne, Jarmo Harju, Jiwoo Lee, Juha Karjalainen, Jukka Koskela, Kalle Pärn, Kati Donner, Kristin Tsuo, Manuel González Jiménez, Mari Kaunisto, Mari Niemi, Mary Pat Reeve, Mervi Aavikko, Mitja Kurki, Oluwaseun Alexander Dada, Pietro Della Briotta Parolo, Risto Kajanne, Sina Rüeger, Susanna Lemmelä, Taru Tukiainen, Tiinamaija Tuomi, Timo P. Sipilä, Tuomo Kiiskinen, Vincent Llorens, Adam Ziemann, Anne Lehtonen, Apinya Lertratanakul, Bob Georgantas, Bridget Riley‐Gillis, Danjuma Quarless, Fedik Rahimov, Howard J. Jacob, Jeffrey F. Waring, J. Wade Davis, Nizar Smaoui, Relja Popovic, Sahar Esmaeeli, Athena Matakidou, Ben Challis, David A. Close, Eleonor Wigmore, Slavé Petrovski, Chia‐Yen Chen, Ellen Tsai, Heiko Runz, Jimmy Z. Liu, Paola G. Bronson, Sally John, Sanni Lahdenperä, Stephanie Loomis, Susan Eaton, Yunfeng Huang, Erika Kvikstad, Minal Çalışkan, Samir Wadhawan, Elmutaz Shaikho Elhaj Mohammed, Janet van Adelsberg, Joseph Maranville, Marla Hochfeld, Robert M. Plenge, Shameek Biswas, Steven M. Greenberg, Andrew S. Peterson, David F. Choy, Diana Chang, Edmond Teng, Erich C. Strauss, Geoff Kerchner, Hao Chen, Hubert Chen, Jennifer L. Schutzman, John A. Michon, Julie Hunkapiller, Mark I. McCarthy, Natalie Bowers, Sarah A. Pendergrass, Tushar Bhangale, David Pulford, Dawn Waterworth, Diptee Kulkarni, Fanli Xu, Jo Betts
Abstract
Abstract Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10–90 th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49–61%), which increases to 84% (71–97%) with a high PRS ( > 90 th percentile), and decreases to 49% (30–68%) with a low PRS ( < 10 th percentile). Similarly, for c.1100delC in CHEK2 (3.7–fold enrichment; 1648 carriers), the respective lifetime risks are 29% (27–32%), 59% (52–66%), and 9% (5–14%). The PRS also refines the risk assessment of women with first-degree relatives diagnosed with breast cancer, particularly among women with positive family history of early-onset breast cancer. Here we demonstrate the opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.