. 2023 Aug;12(15):16142-16162.

doi: 10.1002/cam4.6272. Epub 2023 Jul 3.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Anna Morra¹, Maartje A C Schreurs², Irene L Andrulis^{3

4}, Hoda Anton-Culver⁵, Annelie Augustinsson⁶, Matthias W Beckmann⁷, Sabine Behrens⁸, Stig E Bojesen^{9

10

11}, Manjeet K Bolla¹², Hiltrud Brauch^{13

14

15}, Annegien Broeks¹, Saundra S Buys¹⁶, Nicola J Camp¹⁶, Jose E Castelao¹⁷, Melissa H Cessna¹⁸, Jenny Chang-Claude^{8

19}, Wendy K Chung²⁰; NBCS Collaborators^{21

22

23

24

25

26

27

28

29

30}; Sarah V Colonna¹⁶, Fergus J Couch³¹, Angela Cox³², Simon S Cross³³, Kamila Czene³⁴, Mary B Daly³⁵, Joe Dennis¹², Peter Devilee^{36

37}, Thilo Dörk³⁸, Alison M Dunning³⁹, Miriam Dwek⁴⁰, Douglas F Easton^{12

39}, Diana M Eccles⁴¹, Mikael Eriksson³⁴, D Gareth Evans^{42

43}, Peter A Fasching⁷, Tanja N Fehm⁴⁴, Jonine D Figueroa^{45

46

47}, Henrik Flyger⁴⁸, Marike Gabrielson³⁴, Manuela Gago-Dominguez⁴⁹, Montserrat García-Closas⁴⁷, José A García-Sáenz⁵⁰, Jeanine Genkinger^{51

52}, Felix Grassmann^{34

53}, Melanie Gündert^{54

55

56}, Eric Hahnen^{57

58}, Christopher A Haiman⁵⁹, Ute Hamann⁶⁰, Patricia A Harrington³⁹, Jaana M Hartikainen^{61

62}, Reiner Hoppe^{13

63}, John L Hopper⁶⁴, Richard S Houlston⁶⁵, Anthony Howell⁶⁶; ABCTB Investigators⁶⁷; kConFab Investigators^{68

69}; Anna Jakubowska^{70

71}, Wolfgang Janni⁷², Helena Jernström⁶, Esther M John^{73

74}, Nichola Johnson⁷⁵, Michael E Jones⁶⁵, Vessela N Kristensen^{22

28}, Allison W Kurian^{73

74}, Diether Lambrechts^{76

77}, Loic Le Marchand⁷⁸, Annika Lindblom^{79

80}, Jan Lubiński⁷⁰, Michael P Lux⁷, Arto Mannermaa^{61

62

81}, Dimitrios Mavroudis⁸², Anna Marie Mulligan^{83

84}, Taru A Muranen⁸⁵, Heli Nevanlinna⁸⁵, Ines Nevelsteen⁸⁶, Patrick Neven⁸⁶, William G Newman^{42

43}, Nadia Obi⁸⁷, Kenneth Offit^{88

89}, Andrew F Olshan⁹⁰, Tjoung-Won Park-Simon³⁸, Alpa V Patel⁹¹, Paolo Peterlongo⁹², Kelly-Anne Phillips^{64

93

94}, Dijana Plaseska-Karanfilska⁹⁵, Eric C Polley⁹⁶, Nadege Presneau⁴⁰, Katri Pylkäs^{97

98}, Brigitte Rack⁷², Paolo Radice⁹⁹, Muhammad U Rashid^{60

100}, Valerie Rhenius³⁹, Mark Robson⁸⁹, Atocha Romero¹⁰¹, Emmanouil Saloustros¹⁰², Elinor J Sawyer¹⁰³, Rita K Schmutzler^{57

58

104}, Sabine Schuetze⁷², Christopher Scott⁹⁶, Mitul Shah³⁹, Snezhana Smichkoska¹⁰⁵, Melissa C Southey^{106

107

108}, William J Tapper⁴¹, Lauren R Teras⁹¹, Rob A E M Tollenaar¹⁰⁹, Katarzyna Tomczyk⁷⁵, Ian Tomlinson¹¹⁰, Melissa A Troester⁹⁰, Celine M Vachon¹¹¹, Elke M van Veen^{42

43}, Qin Wang¹², Camilla Wendt^{112

113}, Hans Wildiers⁸⁶, Robert Winqvist^{97

98}, Argyrios Ziogas⁵, Per Hall^{34

113}, Paul D P Pharoah^{12

39}, Muriel A Adank¹¹⁴, Antoinette Hollestelle², Marjanka K Schmidt^{1

115}, Maartje J Hooning²

Collaborators, Affiliations

Collaborators

Kristine K Sahlberg, Anne-Lise Børresen-Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, Grethe I Grenaker Alnaes, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, J Dinny Graham, Mythily Sachchithananthan, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed

Affiliations

¹ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
² Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
³ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁵ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California, USA.
⁶ Oncology, Clinical Sciences in Lund, Lund University, Lund, Sweden.
⁷ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁰ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹¹ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹³ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
¹⁴ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
¹⁵ German Cancer Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Tübingen, Germany.
¹⁶ Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
¹⁷ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
¹⁸ Intermountain Healthcare, Salt Lake City, Utah, USA.
¹⁹ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁰ Departments of Pediatrics and Medicine, Columbia University, New York, New York, USA.
²¹ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
²² Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²³ Department of Research, Vestre Viken Hospital, Drammen, Norway.
²⁴ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
²⁵ Division of Surgery, Cancer and Transplantation Medicine, Department of Oncology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
²⁶ Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
²⁷ Oslo Breast Cancer Research Consortium, Oslo University Hospital, Oslo, Norway.
²⁸ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
²⁹ Department of Community Medicine, The Arctic University of Norway, Tromsø, Norway.
³⁰ Core Facility for Biobanking, The Arctic University of Norway, Tromsø, Norway.
³¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
³² Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
³³ Department of Neuroscience, Academic Unit of Pathology, University of Sheffield, Sheffield, UK.
³⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁵ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
³⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
³⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
³⁸ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³⁹ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁴⁰ School of Life Sciences, University of Westminster, London, UK.
⁴¹ Faculty of Medicine, University of Southampton, Southampton, UK.
⁴² Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁴³ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴⁴ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
⁴⁵ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁴⁶ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁴⁷ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴⁸ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁹ Cancer Genetics and Epidemiology Group, SERGAS, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain.
⁵⁰ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁵¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
⁵² Herbert Irving Comprehensive Cancer Center, New York, New York, USA.
⁵³ Health and Medical University, Potsdam, Germany.
⁵⁴ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵⁵ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁵⁶ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵⁷ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁸ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁶⁰ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶¹ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁶² Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁶³ University of Tübingen, Tübingen, Germany.
⁶⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁶⁵ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁶ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁶⁷ Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
⁶⁸ Research Department, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
⁶⁹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷⁰ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁷¹ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁷² Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁷³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.
⁷⁴ Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁷⁵ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁷⁶ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁷⁷ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁷⁸ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
⁷⁹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁸⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁸¹ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁸² Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
⁸³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁸⁴ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
⁸⁵ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸⁶ Department of Oncology, Leuven Multidisciplinary Breast Center, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
⁸⁷ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸⁸ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁸⁹ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁹⁰ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁹¹ Department of Population Science, American Cancer Society, Atlanta, Georgia, USA.
⁹² IFOM ETS - The AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy.
⁹³ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁹⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
⁹⁵ Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁹⁶ Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
⁹⁷ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹⁸ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
⁹⁹ Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, "Predictive Medicine: Molecular Bases of Genetic Risk", Milan, Italy.
¹⁰⁰ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹⁰¹ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹⁰² Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹⁰³ School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
¹⁰⁴ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰⁵ Medical Faculty, University Clinic of Radiotherapy and Oncology, Ss. Cyril and Methodius University in Skopje, Skopje, Republic of North Macedonia.
¹⁰⁶ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
¹⁰⁷ Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰⁸ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹⁰⁹ Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
¹¹⁰ Cancer Research Centre, The University of Edinburgh, Edinburgh, UK.
¹¹¹ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
¹¹² Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹¹³ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
¹¹⁴ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹¹⁵ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

PMID: 37401034
PMCID: PMC10469654
DOI: 10.1002/cam4.6272

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Anna Morra et al. Cancer Med. 2023 Aug.

. 2023 Aug;12(15):16142-16162.

doi: 10.1002/cam4.6272. Epub 2023 Jul 3.

Authors

Collaborators

Kristine K Sahlberg, Anne-Lise Børresen-Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, Grethe I Grenaker Alnaes, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, J Dinny Graham, Mythily Sachchithananthan, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, Milita Zaheed

Affiliations

¹ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
² Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
³ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁵ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California, USA.
⁶ Oncology, Clinical Sciences in Lund, Lund University, Lund, Sweden.
⁷ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁰ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹¹ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹³ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
¹⁴ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
¹⁵ German Cancer Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Tübingen, Germany.
¹⁶ Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
¹⁷ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
¹⁸ Intermountain Healthcare, Salt Lake City, Utah, USA.
¹⁹ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁰ Departments of Pediatrics and Medicine, Columbia University, New York, New York, USA.
²¹ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
²² Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²³ Department of Research, Vestre Viken Hospital, Drammen, Norway.
²⁴ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
²⁵ Division of Surgery, Cancer and Transplantation Medicine, Department of Oncology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
²⁶ Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
²⁷ Oslo Breast Cancer Research Consortium, Oslo University Hospital, Oslo, Norway.
²⁸ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
²⁹ Department of Community Medicine, The Arctic University of Norway, Tromsø, Norway.
³⁰ Core Facility for Biobanking, The Arctic University of Norway, Tromsø, Norway.
³¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
³² Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
³³ Department of Neuroscience, Academic Unit of Pathology, University of Sheffield, Sheffield, UK.
³⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁵ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
³⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
³⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
³⁸ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³⁹ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁴⁰ School of Life Sciences, University of Westminster, London, UK.
⁴¹ Faculty of Medicine, University of Southampton, Southampton, UK.
⁴² Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁴³ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴⁴ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
⁴⁵ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁴⁶ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁴⁷ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴⁸ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁹ Cancer Genetics and Epidemiology Group, SERGAS, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS) Foundation, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain.
⁵⁰ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁵¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
⁵² Herbert Irving Comprehensive Cancer Center, New York, New York, USA.
⁵³ Health and Medical University, Potsdam, Germany.
⁵⁴ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵⁵ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁵⁶ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵⁷ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁸ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁶⁰ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶¹ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁶² Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁶³ University of Tübingen, Tübingen, Germany.
⁶⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁶⁵ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁶ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁶⁷ Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
⁶⁸ Research Department, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
⁶⁹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷⁰ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁷¹ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁷² Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁷³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.
⁷⁴ Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁷⁵ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁷⁶ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁷⁷ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁷⁸ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
⁷⁹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁸⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁸¹ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁸² Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
⁸³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁸⁴ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
⁸⁵ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸⁶ Department of Oncology, Leuven Multidisciplinary Breast Center, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
⁸⁷ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸⁸ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁸⁹ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁹⁰ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁹¹ Department of Population Science, American Cancer Society, Atlanta, Georgia, USA.
⁹² IFOM ETS - The AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy.
⁹³ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁹⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
⁹⁵ Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁹⁶ Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
⁹⁷ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹⁸ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
⁹⁹ Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, "Predictive Medicine: Molecular Bases of Genetic Risk", Milan, Italy.
¹⁰⁰ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹⁰¹ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹⁰² Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹⁰³ School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
¹⁰⁴ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰⁵ Medical Faculty, University Clinic of Radiotherapy and Oncology, Ss. Cyril and Methodius University in Skopje, Skopje, Republic of North Macedonia.
¹⁰⁶ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
¹⁰⁷ Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰⁸ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹⁰⁹ Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
¹¹⁰ Cancer Research Centre, The University of Edinburgh, Edinburgh, UK.
¹¹¹ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
¹¹² Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹¹³ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
¹¹⁴ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹¹⁵ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

PMID: 37401034
PMCID: PMC10469654
DOI: 10.1002/cam4.6272

Abstract

Background: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.

Aim: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.

Methods: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.

Results: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].

Conclusion: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Keywords: CHEK2 c.1100delC germline genetic variant; contralateral breast cancer risk; radiotherapy; survival; systemic treatment.

PubMed Disclaimer

Conflict of interest statement

Matthias W. Beckmann and Peter A. Fasching conduct research funded by Amgen, Novartis and Pfizer (not related to this study). Peter A. Fasching received Honoraria from Roche, Novartis and Pfizer (not related to this study). Allison W. Kurian's institution received a research funding from Myriad genetics for an unrelated project (not related to this study). Emmanouil Saloustros reported the following: honoraria from Amgen Hellas, Pfizer Hellas, and IPSEN (not related to this study) and support from Merck Greece and Pfizer Hellas for attending meetings (not related to this study); he participated in advisory boards in Greece (MSD Greece, AstraZeneca Greece, Gilead Sciences Hellas, Pfizer Hellas, Genesis Pharma), not related to this study; he is a PI in sponsored clinical trials: MSD Greece (not related to this study). The other authors declare no conflict of interest.

Figures

**FIGURE 1**
Data flowchart of inclusion and exclusion of patients with breast cancer from the Breast Cancer Association Consortium (BCAC) database.

**FIGURE 2**
Graphical representation of the multi‐state model. BC, breast cancer; CBC, contralateral breast cancer.

See this image and copyright information in PMC

Cited by

Breast, Colorectal, and Pancreatic Cancer Mortality With Pathogenic Variants in ATM, CHEK2, or PALB2.
Veenstra CM, Abrahamse P, Hamilton AS, Ward KC, Gomez SL, Liu L, Katz SJ, Hofer TP, Kurian AW. Veenstra CM, et al. J Clin Oncol. 2025 May;43(13):1587-1596. doi: 10.1200/JCO-24-02442. Epub 2025 Feb 28. J Clin Oncol. 2025. PMID: 40020204
Revealing roles of PANoptosis-related genes in prognosis and molecular subtypes in lung squamous cell carcinoma by integrated bioinformatic analyses and experiments.
Chen Y, Wang M. Chen Y, et al. Clin Exp Med. 2025 May 12;25(1):154. doi: 10.1007/s10238-025-01696-x. Clin Exp Med. 2025. PMID: 40353888 Free PMC article.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209‐249. - PubMed
1. CHEK2 Breast Cancer Case‐Control Consortium . CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet. 2004;74:1175‐1182. - PMC - PubMed
1. Schmidt MK, Hogervorst F, van Hien R, et al. Age‐ and tumor subtype‐specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol. 2016;34:2750‐2760. - PMC - PubMed
1. Weischer M, Nordestgaard BG, Pharoah P, et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer‐specific death, and increased risk of a second breast cancer. J Clin Oncol. 2012;30:4308‐4316. - PMC - PubMed
1. Thompson D, Seal S, Schutte M, et al. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol Biomarkers Prev. 2006;15:2542‐2545. - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Collaborators

Affiliations

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical