The role of polygenic risk and susceptibility genes in breast cancer over the course of life
Authors: Mars Nina , Widén Elisabeth , Kerminen Sini , Meretoja Tuomo , Pirinen Matti , della Briotta Parolo Pietro , Palta Priit ,   FinnGen, Havulinna Aki , Elliott Amanda , Shcherban Anastasia , Ganna Andrea , Jalanko Anu , Lehisto Arto , Kilpeläinen Elina , Brein Georg , Awaisa Ghazal , Laivuori Hannele , Heyne Henrike , Harju Jarmo , Lee Jiwoo , Karjalainen Juha , Koskela Jukka , Pärn Kalle , Donner Kati , Tsuo Kristin , Jiménez Manuel González , Kaunisto Mari , Niemi Mari E. , Reeve Mary Pat , Aavikko Mervi , Kurki Mitja , Dada Oluwaseun A. , della Briotta Parolo Pietro , Kajanne Risto , Rüeger Sina , Lemmelä Susanna , Tukiainen Taru , Tuomi Tiinamaija , Sipilä Timo P. , Kiiskinen Tuomo , Llorens Vincent , Ziemann Adam , Lehtonen Anne , Lertratanakul Apinya , Georgantas Bob , Riley-Gillis Bridget , Quarless Danjuma , Rahimov Fedik , Jacob Howard , Waring Jeffrey , Davis Justin Wade , Smaoui Nizar , Popovic Relja , Esmaeeli Sahar , Matakidou Athena , Challis Ben , Close David , Wigmore Eleonor , Petrovski Slavé , Chen Chia-Yen , Tsai Ellen , Runz Heiko , Liu Jimmy , Bronson Paola , John Sally , Lahdenperä Sanni , Loomis Stephanie , Eaton Susan , Huang Yunfeng , Kvikstad Erika , Caliskan Minal , Wadhawan Samir , Mohammed Elmutaz Shaikho Elhaj , van Adelsberg Janet , Maranville Joseph , Hochfeld Marla , Plenge Robert , Biswas Shameek , Greenberg Steven , Peterson Andrew , Choy David , Chang Diana , Teng Edmond , Strauss Erich , Kerchner Geoff , Chen Hao , Chen Hubert , Schutzman Jennifer , Michon John , Hunkapiller Julie , McCarthy Mark , Bowers Natalie , Pendergrass Sarah , Bhangale Tushar , Pulford David , Waterworth Dawn , Kulkarni Diptee , Xu Fanli , Betts Jo , Gordillo Jorge Esparza , Hoffman Joshua , King Karen S. , Ehm Meg , Ghosh Soumitra , Loerch Patrick , Fleuren Wilco , Cummings Beryl , Brauer Matt , Graham Robert , Behrens Tim , Loboda Andrey , Podgornaia Anna , Chhibber Aparna , Chu Audrey , Fox Caroline , Diogo Dorothee , Holzinger Emily , Eicher John , Gormley Padhraig , Mehta Vinay , Malarstig Anders , Hedman Åsa , Marshall Catherine , Whelan Christopher , Lehtonen Heli , Parkkinen Jaakko , Linden Kari , Kalpala Kirsi , Miller Melissa , Bing Nan , McDonough Stefan , Chen Xing , Hu Xinli , Wu Ying , Muslin Anthony , Wang Clarence , Chatelain Clement , Rajpal Deepak , Liu Dongyu , Xu Ethan , Auge Franck , Call Katherine , Klinger Kathy , Crohns Marika , Gossel Matthias , Xia Tai-he , Hendolin Minna , Tuovila Outi , Tuovila Outi , Pakkanen Raimo , Karlsson Antti , Pulkki Kari , Kallio Lila , Virolainen Petri , Mannermaa Arto , Heikkinen Sami , Kosma Veli-Matti , Laakkonen Eija , Laukkanen Jari , Kuopio Teijo , Kujala Urho , Kangasniemi Eeva , Mäkelä Johanna , Ritari Jarmo , Partanen Jukka , Hyvärinen Kati , Arvas Mikko , Pitkäranta Anne , Loukola Anu , Punkka Eero , Koskinen Miika , Carpén Olli , Salminen Aino , Rice David , Mattson Johanna , Turunen Joni A. , Sinisalo Juha , Hannula-Jouppi Katariina , Aaltonen Lauri , Taskinen Marja-Riitta , Färkkilä Martti , Kauppi Paula , Nieminen Pekka , Tienari Pentti , Pussinen Pirkko , Pikkarainen Sampsa , Seitsonen Sanna , Ollila Terhi , Tuomi Tiinamaija , Salo Tuula , Palotie Ulla , Rinne Juha , Metsärinne Kaj , Elenius Klaus , Koulu Leena , Voutilainen Markku , Juonala Markus , Peltonen Sirkku , Gursoy Ulvi , Aaltonen Vesa , Kettunen Johannes , Pylkäs Katri , Kalaoja Marita , Turpeinen Miia , Karjalainen Minna , Serpi Raisa , Hinttala Reetta , Kaarteenaho Riitta , Vainio Seppo , Mantere Tuomo , Remes Anne , Junttila Juhani , Tasanen Kaisa , Sipilä Kirsi , Huilaja Laura , Luodonpää Marja , Hautala Nina , Karihtala Peeter , Kauppila Saila , Harju Terttu , Blomster Timo , Anttonen Vuokko , Soininen Hilkka , Harvima Ilkka , Pihlajamäki Jussi , Kaarniranta Kai , Suominen Liisa , Pelkonen Margit , Siponen Maria , Laakso Markku , Hiltunen Mikko , Kiviniemi Mikko , Auvinen Päivi , Mäntylä Päivi , Kälviäinen Reetta , Julkunen Valtteri , Auranen Annika , Jussila Airi , Uusitalo-Järvinen Hannele , Kankaanranta Hannu , Uusitalo Hannu , Peltola Jukka , Kähönen Mika , Laitinen Tarja , Salmi Teea , Järvensivu Elina , Kaiharju Essi , Mattsson Hannele , Kristiansson Kati , Männikkö Lotta , Laukkanen Markku , Perola Markus , Laiho Päivi , Wong Regis , Lähteenmäki Sini , Soini Sirpa , Niiranen Teemu , Paajanen Teemu , Kilpi Terhi , Hiekkalinna Tero , Sistonen Tuuli , Salomaa Veikko , Kanai Masahiro , Zhou Wei , Mäkelä Tomi , Rivas Manuel , Palin Kimmo , Siirtola Harri , Garcia-Tabuenca Javier , Sipeky Csilla , Jambulingam Dhanaprakash , Schleutker Johanna , Heron Samuel , Rathinakannan Venkat Subramaniam , Palotie Aarno , Kaprio Jaakko , Joensuu Heikki , Daly Mark , Ripatti Samuli 
Published: December 2020

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 (10–90th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49–61%), which increases to 84% (71–97%) with a high PRS ( > 90th percentile), and decreases to 49% (30–68%) with a low PRS ( < 10th 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.