University of Oulu

Mars, N., Widén, E., Kerminen, S. et al. The role of polygenic risk and susceptibility genes in breast cancer over the course of life. Nat Commun 11, 6383 (2020). https://doi.org/10.1038/s41467-020-19966-5

The role of polygenic risk and susceptibility genes in breast cancer over the course of life

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Author: Mars, Nina1; Widén, Elisabeth1; Kerminen, Sini1;
Organizations: 1Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
2Breast Surgery Unit, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland
3University of Helsinki, Helsinki, Finland
4Helsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland
5Department of Public Health, University of Helsinki, Helsinki, Finland
6Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
7Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
8Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021111655679
Language: English
Published: Springer Nature, 2020
Publish Date: 2021-11-16
Description:

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 (10–90th 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.

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FinnGen

Aarno Palotie1,7,8, Aki Havulinna1, Amanda Elliott1,8, Anastasia Shcherban1, Andrea Ganna1, Anu Jalanko1, Arto Lehisto1, Elina Kilpeläinen1, Georg Brein1, Ghazal Awaisa1, Hannele Laivuori1, Henrike Heyne1, Jaakko Kaprio1,5, Jarmo Harju1, Jiwoo Lee1,8, Juha Karjalainen1,8, Jukka Koskela1, Kalle Pärn1, Kati Donner1, Kristin Tsuo1,8, Manuel González Jiménez1, Mark Daly1,8, Mari Kaunisto1, Mari E. Niemi1, Mary Pat Reeve1, Mervi Aavikko1, Mitja Kurki1,8, Nina Mars1, Oluwaseun A. Dada1, Pietro della Briotta Parolo1, Priit Palta1,6, Risto Kajanne1, Samuli Ripatti1,6,8, Sina Rüeger1, Susanna Lemmelä1, Taru Tukiainen1, Tiinamaija Tuomi1, Timo P. Sipilä1, Tuomo Kiiskinen1, Vincent Llorens1, Adam Ziemann10, Anne Lehtonen10, Apinya Lertratanakul10, Bob Georgantas10, Bridget Riley-Gillis10, Danjuma Quarless10, Fedik Rahimov10, Howard Jacob10, Jeffrey Waring10, Justin Wade Davis10, Nizar Smaoui10, Relja Popovic10, Sahar Esmaeeli10, Athena Matakidou11, Ben Challis11, David Close11, Eleonor Wigmore11, Slavé Petrovski11, Chia-Yen Chen12, Ellen Tsai12, Heiko Runz12, Jimmy Liu12, Paola Bronson12, Sally John12, Sanni Lahdenperä12, Stephanie Loomis12, Susan Eaton12, Yunfeng Huang12, Erika Kvikstad13, Minal Caliskan13, Samir Wadhawan13, Elmutaz Shaikho Elhaj Mohammed14, Janet van Adelsberg14, Joseph Maranville14, Marla Hochfeld14, Robert Plenge14, Shameek Biswas14, Steven Greenberg14, Andrew Peterson15, David Choy15, Diana Chang15, Edmond Teng15, Erich Strauss15, Geoff Kerchner15, Hao Chen15, Hubert Chen15, Jennifer Schutzman15, John Michon15, Julie Hunkapiller15, Mark McCarthy15, Natalie Bowers15, Sarah Pendergrass15, Tushar Bhangale15, David Pulford16, Dawn Waterworth16, Diptee Kulkarni16, Fanli Xu16, Jo Betts16, Jorge Esparza Gordillo16, Joshua Hoffman16, Karen S. King16, Meg Ehm16, Soumitra Ghosh16, Patrick Loerch17, Wilco Fleuren17, Beryl Cummings18, Matt Brauer18, Robert Graham18, Tim Behrens18, Andrey Loboda19, Anna Podgornaia19, Aparna Chhibber19, Audrey Chu19, Caroline Fox19, Dorothee Diogo19, Emily Holzinger19, John Eicher19, Padhraig Gormley19, Vinay Mehta19, Anders Malarstig20, Åsa Hedman20, Catherine Marshall20, Christopher Whelan20, Heli Lehtonen20, Jaakko Parkkinen20, Kari Linden20, Kirsi Kalpala20, Melissa Miller20, Nan Bing20, Stefan McDonough20, Xing Chen20, Xinli Hu20, Ying Wu20, Anthony Muslin21, Clarence Wang21, Clement Chatelain21, Deepak Rajpal21, Dongyu Liu21, Ethan Xu21, Franck Auge21, Katherine Call21, Kathy Klinger21, Marika Crohns21, Matthias Gossel21, Tai-he Xia21, Minna Hendolin22, Outi Tuovila22, Outi Tuovila22, Raimo Pakkanen22, Antti Karlsson23, Kari Pulkki23, Lila Kallio23, Petri Virolainen23, Arto Mannermaa24, Sami Heikkinen24, Veli-Matti Kosma24, Eija Laakkonen25, Jari Laukkanen25, Teijo Kuopio25, Urho Kujala25, Eeva Kangasniemi26, Johanna Mäkelä26, Jarmo Ritari27, Jukka Partanen27, Kati Hyvärinen27, Mikko Arvas27, Anne Pitkäranta28, Anu Loukola28, Eero Punkka28, Miika Koskinen28, Olli Carpén28,29, Aino Salminen29, David Rice29, Heikki Joensuu3,9 & Johanna Mattson29, Joni A. Turunen29, Juha Sinisalo29, Katariina Hannula-Jouppi29, Lauri Aaltonen29, Marja-Riitta Taskinen29, Martti Färkkilä29, Paula Kauppi29, Pekka Nieminen29, Pentti Tienari29, Pirkko Pussinen29, Sampsa Pikkarainen29, Sanna Seitsonen29, Terhi Ollila29, Tiinamaija Tuomi29, Tuomo Meretoja2,3, Tuula Salo29, Ulla Palotie29, Juha Rinne30, Kaj Metsärinne30, Klaus Elenius30, Leena Koulu30, Markku Voutilainen30, Markus Juonala30, Sirkku Peltonen30, Ulvi Gursoy30, Vesa Aaltonen30, Johannes Kettunen31, Katri Pylkäs31, Marita Kalaoja31, Miia Turpeinen31, Minna Karjalainen31, Raisa Serpi31, Reetta Hinttala31, Riitta Kaarteenaho31, Seppo Vainio31, Tuomo Mantere31, Anne Remes32, Juhani Junttila32, Kaisa Tasanen32, Kirsi Sipilä32, Laura Huilaja32, Marja Luodonpää32, Nina Hautala32, Peeter Karihtala32, Saila Kauppila32, Terttu Harju32, Timo Blomster32, Vuokko Anttonen32, Hilkka Soininen33, Ilkka Harvima33, Jussi Pihlajamäki33, Kai Kaarniranta33, Liisa Suominen33, Margit Pelkonen33, Maria Siponen33, Markku Laakso33, Mikko Hiltunen33, Mikko Kiviniemi33, Päivi Auvinen33, Päivi Mäntylä33, Reetta Kälviäinen33, Valtteri Julkunen33, Annika Auranen34, Airi Jussila34, Hannele Uusitalo-Järvinen34, Hannu Kankaanranta34, Hannu Uusitalo34, Jukka Peltola34, Mika Kähönen34, Tarja Laitinen26,34, Teea Salmi34, Elina Järvensivu35, Essi Kaiharju35, Hannele Mattsson35, Kati Kristiansson35, Lotta Männikkö35, Markku Laukkanen35, Markus Perola35, Päivi Laiho35, Regis Wong35, Sini Lähteenmäki35, Sirpa Soini35, Teemu Niiranen35, Teemu Paajanen35, Terhi Kilpi35, Tero Hiekkalinna35, Tuuli Sistonen35, Veikko Salomaa35, Masahiro Kanai8, Wei Zhou8, Tomi Mäkelä36, Manuel Rivas37, Kimmo Palin3, Harri Siirtola38, Javier Garcia-Tabuenca38, Csilla Sipeky39, Dhanaprakash Jambulingam39, Johanna Schleutker23,39, Samuel Heron39 & Venkat Subramaniam Rathinakannan39

1Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland. 2Breast Surgery Unit, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. 3University of Helsinki, Helsinki, Finland. 4Helsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. 5Department of Public Health, University of Helsinki, Helsinki, Finland. 6Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia. 7Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. 8Broad Institute of MIT and Harvard, Cambridge, MA, USA. 9Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. 10Abbvie, North Waukegan Road, North Chicago, Chicago, IL 60064, USA. 11Astra Zeneca, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK. 12Biogen, 225 Binney Street Cambridge, Cambridge, MA 02142, USA. 13Bristol-Meyers-Squibb, 430 East 29th Street, New York, NY 10016, USA. 14Celgene, 86 Morris Avenue, Summit, NJ 07901, USA. 15Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. 16GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. 17Janssen Biotech, 800/850 Ridgeview Drive, Horsham, PA 19044, USA. 18Maze Therapeutics, 171 Oyster Point Blvd Suite 300, South San Francisco, CA 94080, USA. 19Merck, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. 20Pfizer, 235 East 42nd Street, New York, NY 10017, USA. 21Sanofi, The Finnish Institute for Health and Welfare, Paris, France. 22Business Finland, Porkkalankatu 1, 00180 Helsinki, Finland. 23Auria Biobank, University of Turku, Hospital District of Southwest Finland, Yliopistonmäki, FI-20014 Turku, Finland. 24Biobank of Eastern Finland, University of Eastern Finland, Northern Savo Hospital District, P.O. Box 100, FI-70029 KYS Kuopio, Finland. 25Central Finland Biobank, University of Jyväskylä, Central Finland Health Care District, Keskussairaalantie 19, FI-40620 Jyväskylä, Finland. 26Finnish Clinical Biobank Tampere, University of Tampere, Pirkanmaa Hospital District, P.O. Box 2000, FI-33521 Tampere, Finland. 27Finnish Red Cross Blood Service, Finnish Hematology Registry and Clinical Biobank, Kivihaantie 7, FI-00310 Helsinki, Finland. 28Helsinki Biobank, Helsinki University and Hospital District of Helsinki and Uusimaa, P.O. Box 400, FI-00029 HUS Helsinki, Finland. 29Hospital District of Helsinki and Uusimaa, P.O. Box 400, FI-00029 HUS Helsinki, Finland. 30Hospital District of Southwest Finland, P.O. Box 52, FI-20521 Turku, Finland. 31Northern Finland Biobank Borealis, University of Oulu, Northern Ostrobothnia Hospital District, P.O. Box 50, FI-90029 Oulu, Finland. 32Northern Ostrobothnia Hospital District, P.O. Box 10, FI-90029 OYS Oulu, Finland. 33Northern Savo Hospital District, P.O. Box 100, FI-70029 KYS Kuopio, Finland. 34Pirkanmaa Hospital District, P.O. Box 2000, FI-33521 Tampere, Finland. 35THL Biobank/The Finnish Institute for Health and Welfare, P.O. Box 30, 00271 Helsinki, Finland. 36HiLIFE, University of Helsinki, P.O.Box 3, FI-00014 Helsinki, Finland. 37University of Stanford, 1265 Welch Road MC5464, MSOB West Wing, Third Floor, Stanford, CA 94305‐5464, USA. 38University of Tampere, P.O. Box 2000, FI-33521 Tampere, Finland. 39University of Turku, Yliopistonmäki, FI-20014 Turku, Finland

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 11
Issue: 1
Article number: 6383
DOI: 10.1038/s41467-020-19966-5
OADOI: https://oadoi.org/10.1038/s41467-020-19966-5
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Subjects:
Funding: Following biobanks are acknowledged for collecting the FinnGen project samples: Auria Biobank (https://www.auria.fi/biopankki), THL Biobank (https://thl.fi/fi/web/thl-biopankki), Helsinki Biobank (https://www.terveyskyla.fi/helsinginbiopankki), Biobank Borealis of Northern Finland (https://www.oulu.fi/university/node/38474), Finnish Clinical Biobank Tampere (https://www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (https://ita-suomenbiopankki.fi), Central Finland Biobank (https://www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (https://www.veripalvelu.fi/verenluovutus/biopankkitoiminta) and Terveystalo Biobank (https://www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). We also thank study participants for their generous participation at THL Biobank and the National FINRISK study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and by twelve industry partners (AbbVie Inc, AstraZeneca UK Ltd, Biogen MA Inc, Celgene Corporation, Celgene International II Sàrl, Genentech Inc, Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., SanofiUS Services Inc., Maze Therapeutics Inc.,Janssen Biotech Inc and Novartis AG). This work was supported by the Sigrid Jusélius Foundation (to S.R., A.P., M.P., and H.J.); University of Helsinki HiLIFE Fellow grants 2017-2020 (to S.R.); Academy of Finland Center of Excellence in Complex Disease Genetics (grant number 312062 to S.R., 312074 to A.P., 312075 to M.D; 312073 to J.K.; 312076 to M.P.); Academy of Finland (grant number 331671 to N.M., grant number 285380 to S.R., 128650 to A.P., 308248 to J.K., 288509 to M.P., 218068 and 131449 to H.J.); The Finnish Innovation Fund Tekes (grant number 2273/31/2017 to E.W.); Foundation and the Horizon 2020 Research and Innovation Programme (grant number 667301 (COSYN) to A.P.); Cancer Foundation Finland sr (to T.M.); Cancer Society of Finland (to H.J.); and Jane and Aatos Erkko Foundation (to H.J.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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