Cancers (Jun 2023)
Spectrum and Frequency of Germline <i>FANCM</i> Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases
- Gisella Figlioli,
- Amandine Billaud,
- Qin Wang,
- Manjeet K. Bolla,
- Joe Dennis,
- Michael Lush,
- Anders Kvist,
- Muriel A. Adank,
- Thomas U. Ahearn,
- Natalia N. Antonenkova,
- Päivi Auvinen,
- Sabine Behrens,
- Marina Bermisheva,
- Natalia V. Bogdanova,
- Stig E. Bojesen,
- Bernardo Bonanni,
- Thomas Brüning,
- Nicola J. Camp,
- Archie Campbell,
- Jose E. Castelao,
- Melissa H. Cessna,
- NBCS Collaborators,
- Kamila Czene,
- Peter Devilee,
- Thilo Dörk,
- Mikael Eriksson,
- Peter A. Fasching,
- Henrik Flyger,
- Marike Gabrielson,
- Manuela Gago-Dominguez,
- Montserrat García-Closas,
- Gord Glendon,
- Encarna B. Gómez Garcia,
- Anna González-Neira,
- Felix Grassmann,
- Pascal Guénel,
- Eric Hahnen,
- Ute Hamann,
- Peter Hillemanns,
- Maartje J. Hooning,
- Reiner Hoppe,
- Anthony Howell,
- Keith Humphreys,
- kConFab Investigators,
- Anna Jakubowska,
- Elza K. Khusnutdinova,
- Vessela N. Kristensen,
- Annika Lindblom,
- Maria A. Loizidou,
- Jan Lubiński,
- Arto Mannermaa,
- Tabea Maurer,
- Dimitrios Mavroudis,
- William G. Newman,
- Nadia Obi,
- Mihalis I. Panayiotidis,
- Paolo Radice,
- Muhammad U. Rashid,
- Valerie Rhenius,
- Matthias Ruebner,
- Emmanouil Saloustros,
- Elinor J. Sawyer,
- Marjanka K. Schmidt,
- Rita K. Schmutzler,
- Mitul Shah,
- Melissa C. Southey,
- Ian Tomlinson,
- Thérèse Truong,
- Elke M. van Veen,
- Camilla Wendt,
- Xiaohong R. Yang,
- Kyriaki Michailidou,
- Alison M. Dunning,
- Paul D. P. Pharoah,
- Douglas F. Easton,
- Irene L. Andrulis,
- D. Gareth Evans,
- Antoinette Hollestelle,
- Jenny Chang-Claude,
- Roger L. Milne,
- Paolo Peterlongo
Affiliations
- Gisella Figlioli
- Genome Diagnostics Program, IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milan, Italy
- Amandine Billaud
- Genome Diagnostics Program, IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milan, Italy
- Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Manjeet K. Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Michael Lush
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Anders Kvist
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, 22185 Lund, Sweden
- Muriel A. Adank
- The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, Family Cancer Clinic, 1066 CX Amsterdam, The Netherlands
- Thomas U. Ahearn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD 20892, USA
- Natalia N. Antonenkova
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040 Minsk, Belarus
- Päivi Auvinen
- Translational Cancer Research Area, University of Eastern Finland, 70210 Kuopio, Finland
- Sabine Behrens
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Marina Bermisheva
- Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia
- Natalia V. Bogdanova
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040 Minsk, Belarus
- Stig E. Bojesen
- Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, 2730 Herlev, Denmark
- Bernardo Bonanni
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
- Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789 Bochum, Germany
- Nicola J. Camp
- Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
- Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
- Jose E. Castelao
- Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312 Vigo, Spain
- Melissa H. Cessna
- Intermountain Health, Salt Lake City, UT 84111, USA
- NBCS Collaborators
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, 0379 Oslo, Norway
- Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden
- Peter Devilee
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
- Mikael Eriksson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden
- Peter A. Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
- Henrik Flyger
- Department of Breast Surgery, Copenhagen University Hospital, Herlev and Gentofte Hospital, 2730 Herlev, Denmark
- Marike Gabrielson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden
- Manuela Gago-Dominguez
- Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS) Foundation, IDIS Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Complejo Hospitalario Universitario de Santiago, SERGAS, 15706 Santiago de Compostela, Spain
- Montserrat García-Closas
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD 20892, USA
- Gord Glendon
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON M5G 1X5, Canada
- Encarna B. Gómez Garcia
- Department of Clinical Genetics, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands
- Anna González-Neira
- Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
- Felix Grassmann
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden
- Pascal Guénel
- CESP U1018, Inserm “Exposome, Heredity, Cancer and Health” Team, UVSQ, University Paris-Saclay, Gustave Roussy, 94805 Villejuif, France
- Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Ute Hamann
- German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, 69120 Heidelberg, Germany
- Peter Hillemanns
- Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
- Maartje J. Hooning
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands
- Reiner Hoppe
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany
- Anthony Howell
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
- Keith Humphreys
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden
- kConFab Investigators
- Research Department, Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia
- Anna Jakubowska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
- Elza K. Khusnutdinova
- Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia
- Vessela N. Kristensen
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway
- Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Maria A. Loizidou
- Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 2371 Nicosia, Cyprus
- Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
- Arto Mannermaa
- Translational Cancer Research Area, University of Eastern Finland, 70210 Kuopio, Finland
- Tabea Maurer
- Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Dimitrios Mavroudis
- Department of Medical Oncology, University Hospital of Heraklion, 711 10 Heraklion, Greece
- William G. Newman
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
- Nadia Obi
- University Medical Center Hamburg-Eppendorf, Institute for Medical Biometry and Epidemiology, 20246 Hamburg, Germany
- Mihalis I. Panayiotidis
- Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 2371 Nicosia, Cyprus
- Paolo Radice
- Unit of ‘Predictive Medicine: Molecular Bases of Genetic Risk’, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy
- Muhammad U. Rashid
- German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, 69120 Heidelberg, Germany
- Valerie Rhenius
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
- Matthias Ruebner
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
- Emmanouil Saloustros
- Department of Oncology, University Hospital of Larissa, 411 10 Larissa, Greece
- Elinor J. Sawyer
- King’s College London, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy’s Campus, London SE1 9RT, UK
- Marjanka K. Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Rita K. Schmutzler
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
- Melissa C. Southey
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
- Ian Tomlinson
- Cancer Research Centre, The University of Edinburgh, Edinburgh EH4 2XU, UK
- Thérèse Truong
- CESP U1018, Inserm “Exposome, Heredity, Cancer and Health” Team, UVSQ, University Paris-Saclay, Gustave Roussy, 94805 Villejuif, France
- Elke M. van Veen
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
- Camilla Wendt
- Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, 118 83 Stockholm, Sweden
- Xiaohong R. Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD 20892, USA
- Kyriaki Michailidou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Alison M. Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
- Paul D. P. Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Douglas F. Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Irene L. Andrulis
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON M5G 1X5, Canada
- D. Gareth Evans
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
- Antoinette Hollestelle
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands
- Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Roger L. Milne
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
- Paolo Peterlongo
- Genome Diagnostics Program, IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milan, Italy
- DOI
- https://doi.org/10.3390/cancers15133313
- Journal volume & issue
-
Vol. 15,
no. 13
p. 3313
Abstract
FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.
Keywords
- breast cancer predisposition
- breast cancer risk factors
- <i>FANCM</i> PTVs spectrum
- protein truncating variants
- PTVs
