Spectrum and Frequency of Germline FANCM 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; 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; Anna Jakubowska; Elza K. Khusnutdinova; Vessela N. Kristensen; Annika Lindblom; Maria A. Loizidou; Jan Lubinski; Arto Mannermaa; Tabea Maurer; Paolo Peterlongo; KConFab Investigators; NBCS Collaborators

doi:10.3390/cancers15133313

Spectrum and Frequency of Germline FANCM 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. CastelaoMelissa H. Cessna, 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, Anna Jakubowska, Elza K. Khusnutdinova, Vessela N. Kristensen, Annika Lindblom, Maria A. Loizidou, Jan Lubinski, Arto Mannermaa, Tabea Maurer, Paolo Peterlongo^*, KConFab Investigators, NBCS Collaborators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	3313
Number of pages	16
Journal	Cancers
Volume	15
Issue number	13
DOIs	https://doi.org/10.3390/cancers15133313
Publication status	Published - 1 Jul 2023

Keywords

breast cancer predisposition
breast cancer risk factors
FANCM PTVs spectrum
protein truncating variants
PTVs

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10.3390/cancers15133313Licence: CC BY

Cite this

Figlioli, G., Billaud, A., Wang, Q., Bolla, M. K., Dennis, J., Lush, M., Kvist, A., Adank, M. A., Ahearn, T. U., Antonenkova, N. N., Auvinen, P., Behrens, S., Bermisheva, M., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Brüning, T., Camp, N. J., Campbell, A., ... NBCS Collaborators (2023). Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases. Cancers, 15(13), Article 3313. https://doi.org/10.3390/cancers15133313

@article{0727e901a9b440aaa40b73c2b4fed528,

title = "Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases",

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, FANCM PTVs spectrum, protein truncating variants, PTVs",

author = "Gisella Figlioli and Amandine Billaud and Qin Wang and Bolla, {Manjeet K.} and Joe Dennis and Michael Lush and Anders Kvist and Adank, {Muriel A.} and Ahearn, {Thomas U.} and Antonenkova, {Natalia N.} and P{\"a}ivi Auvinen and Sabine Behrens and Marina Bermisheva and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Bernardo Bonanni and Thomas Br{\"u}ning and Camp, {Nicola J.} and Archie Campbell and Castelao, {Jose E.} and Cessna, {Melissa H.} and Kamila Czene and Peter Devilee and Thilo D{\"o}rk and Mikael Eriksson and Fasching, {Peter A.} and Henrik Flyger and Marike Gabrielson and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Gord Glendon and {G{\'o}mez Garcia}, {Encarna B.} and Anna Gonz{\'a}lez-Neira and Felix Grassmann and Pascal Gu{\'e}nel and Eric Hahnen and Ute Hamann and Peter Hillemanns and Hooning, {Maartje J.} and Reiner Hoppe and Anthony Howell and Keith Humphreys and Anna Jakubowska and Khusnutdinova, {Elza K.} and Kristensen, {Vessela N.} and Annika Lindblom and Loizidou, {Maria A.} and Jan Lubinski and Arto Mannermaa and Tabea Maurer and Paolo Peterlongo and {KConFab Investigators} and {NBCS Collaborators}",

note = "Funding Information: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCS thanks the Blood bank Sanquin, The Netherlands. BIGGS thanks Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones. The BREOGAN study would not have been possible without the contributions of the following: Manuela Gago-Dominguez, Jose Esteban Castelao, Angel Carracedo, Victor Mu{\~n}oz Garz{\'o}n, Alejandro Novo Dom{\'i}nguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Pe{\~n}a Fern{\'a}ndez, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), Jos{\'e} Ant{\'u}nez, M{\'a}ximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigaci{\'o}n Sanitaria de Santiago, IDIS, Xerencia de Xestion Integrada de Santiago-SERGAS; Joaqu{\'i}n Gonz{\'a}lez-Carrer{\'o} and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigacion Biomedica Galicia Sur, SERGAS, Vigo, Spain. The BSUCH study acknowledges the Principal Investigator, Barbara Burwinkel, and, thanks Peter Bugert, Medical Faculty Mannheim. CCGP thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. CGPS thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldg{\aa}rd Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. The Danish Breast Cancer Cooperative Group (DBCG) are acknowledged for their provision of clinical case data. CNIO-BCS thanks Guillermo Pita, Charo Alonso, Nuria {\'A}lvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO). FHRISK and PROCAS thank NIHR for funding. The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of T{\"u}bingen, Germany [RH, Hiltrud Brauch, Wing-Yee Lo], Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [UH], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. The Hereditary Breast and Ovarian Cancer Research Group Netherlands ( HEBON ) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.K. Schmidt, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, D.J. Stommel-Jenner, R. de Groot; Erasmus Medical Center, Rotterdam, NL: J.M. Coll{\'e}e, I. Geurts-Giele, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. G{\'o}mez Garc{\'i}a, M.J. Blok, M. de Boer; University of Groningen, NL: L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): Q.J.M. Voorham. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. HUBCS thanks Darya Prokofyeva and Shamil Gantsev. KARMA and SASBAC thank the Swedish Medical Research Counsel. KBCP thanks Eija My{\"o}h{\"a}nen. kConFab/AOCS wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. The following are the KConFab investigators: 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, Sophie Nightingale, Shona O{\textquoteright}Connell, Sarah O{\textquoteright}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, 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. MARIE thanks Petra Seibold, Nadia Obi, Sabine Behrens, Ursula Eilber and Muhabbet Celik. MASTOS thanks all the study participants and express appreciation to the doctors: Yiola Marcou, Eleni Kakouri, Panayiotis Papadopoulos, Simon Malas and Maria Daniel, as well as to all the nurses and volunteers who provided valuable help towards the recruitment of the study participants. MBCSG (Milan Breast Cancer Study Group): Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Erica Rosina, Daniela Zaffaroni, Irene Feroce, Mariarosaria Calvello, Aliana Guerrieri Gonzaga, Monica Marabelli, Davide Bondavalli and the personnel of the Cogentech Cancer Genetic Test Laboratory. The MCCS was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on follow-up, and the many thousands of Melbourne residents who continue to participate in the study. The following are NBCS Collaborators: Kristine K. Sahlberg), Anne-Lise B{\o}rresen-Dale, Lars Ottestad, Rolf K{\aa}resen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebr{\aa}ten, Bj{\o}rn Naume, Alexander Foss{\aa}, Cecile E. Kiserud, Kristin V. Reinertsen, {\AA}slaug Helland, Margit Riis, J{\"u}rgen Geisler, OSBREAC and Grethe I. Grenaker Aln{\ae}s. NBHS and SBCGS thank study participants and research staff for their contributions and commitment to the studies. The OFBCR thanks Teresa Selander, Nayana Weerasooriya and Steve Gallinger. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. The RBCS thanks Jannet Blom, Saskia Pelders, Wendy J.C. Prager–van der Smissen and the Erasmus MC Family Cancer Clinic. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed. We thank the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. UBCS thanks all study participants as well as the ascertainment, laboratory, analytics and informatics teams at Huntsman Cancer Institute and Intermountain Healthcare for their important contributions to this study. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = jul,

day = "1",

doi = "10.3390/cancers15133313",

language = "English",

volume = "15",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "13",

}

Figlioli, G, Billaud, A, Wang, Q, Bolla, MK, Dennis, J, Lush, M, Kvist, A, Adank, MA, Ahearn, TU, Antonenkova, NN, Auvinen, P, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bonanni, B, Brüning, T, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Czene, K, Devilee, P, Dörk, T, Eriksson, M, Fasching, PA, Flyger, H, Gabrielson, M, Gago-Dominguez, M, García-Closas, M, Glendon, G, Gómez Garcia, EB, González-Neira, A, Grassmann, F, Guénel, P, Hahnen, E, Hamann, U, Hillemanns, P, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jakubowska, A, Khusnutdinova, EK, Kristensen, VN, Lindblom, A, Loizidou, MA, Lubinski, J, Mannermaa, A, Maurer, T, Peterlongo, P, KConFab Investigators & NBCS Collaborators 2023, 'Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases', Cancers, vol. 15, no. 13, 3313. https://doi.org/10.3390/cancers15133313

TY - JOUR

T1 - Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

AU - Figlioli, Gisella

AU - Billaud, Amandine

AU - Wang, Qin

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Lush, Michael

AU - Kvist, Anders

AU - Adank, Muriel A.

AU - Ahearn, Thomas U.

AU - Antonenkova, Natalia N.

AU - Auvinen, Päivi

AU - Behrens, Sabine

AU - Bermisheva, Marina

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Brüning, Thomas

AU - Camp, Nicola J.

AU - Campbell, Archie

AU - Castelao, Jose E.

AU - Cessna, Melissa H.

AU - Czene, Kamila

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Eriksson, Mikael

AU - Fasching, Peter A.

AU - Flyger, Henrik

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - Glendon, Gord

AU - Gómez Garcia, Encarna B.

AU - González-Neira, Anna

AU - Grassmann, Felix

AU - Guénel, Pascal

AU - Hahnen, Eric

AU - Hamann, Ute

AU - Hillemanns, Peter

AU - Hooning, Maartje J.

AU - Hoppe, Reiner

AU - Howell, Anthony

AU - Humphreys, Keith

AU - Jakubowska, Anna

AU - Khusnutdinova, Elza K.

AU - Kristensen, Vessela N.

AU - Lindblom, Annika

AU - Loizidou, Maria A.

AU - Lubinski, Jan

AU - Mannermaa, Arto

AU - Maurer, Tabea

AU - Peterlongo, Paolo

AU - KConFab Investigators

AU - NBCS Collaborators

N1 - Funding Information: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCS thanks the Blood bank Sanquin, The Netherlands. BIGGS thanks Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones. The BREOGAN study would not have been possible without the contributions of the following: Manuela Gago-Dominguez, Jose Esteban Castelao, Angel Carracedo, Victor Muñoz Garzón, Alejandro Novo Domínguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Peña Fernández, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), José Antúnez, Máximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigación Sanitaria de Santiago, IDIS, Xerencia de Xestion Integrada de Santiago-SERGAS; Joaquín González-Carreró and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigacion Biomedica Galicia Sur, SERGAS, Vigo, Spain. The BSUCH study acknowledges the Principal Investigator, Barbara Burwinkel, and, thanks Peter Bugert, Medical Faculty Mannheim. CCGP thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. CGPS thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. The Danish Breast Cancer Cooperative Group (DBCG) are acknowledged for their provision of clinical case data. CNIO-BCS thanks Guillermo Pita, Charo Alonso, Nuria Álvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO). FHRISK and PROCAS thank NIHR for funding. The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Germany [RH, Hiltrud Brauch, Wing-Yee Lo], Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [UH], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. The Hereditary Breast and Ovarian Cancer Research Group Netherlands ( HEBON ) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.K. Schmidt, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, D.J. Stommel-Jenner, R. de Groot; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, I. Geurts-Giele, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez García, M.J. Blok, M. de Boer; University of Groningen, NL: L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): Q.J.M. Voorham. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. HUBCS thanks Darya Prokofyeva and Shamil Gantsev. KARMA and SASBAC thank the Swedish Medical Research Counsel. KBCP thanks Eija Myöhänen. kConFab/AOCS wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. The following are the KConFab investigators: 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, 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, 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. MARIE thanks Petra Seibold, Nadia Obi, Sabine Behrens, Ursula Eilber and Muhabbet Celik. MASTOS thanks all the study participants and express appreciation to the doctors: Yiola Marcou, Eleni Kakouri, Panayiotis Papadopoulos, Simon Malas and Maria Daniel, as well as to all the nurses and volunteers who provided valuable help towards the recruitment of the study participants. MBCSG (Milan Breast Cancer Study Group): Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Erica Rosina, Daniela Zaffaroni, Irene Feroce, Mariarosaria Calvello, Aliana Guerrieri Gonzaga, Monica Marabelli, Davide Bondavalli and the personnel of the Cogentech Cancer Genetic Test Laboratory. The MCCS was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on follow-up, and the many thousands of Melbourne residents who continue to participate in the study. The following are NBCS Collaborators: Kristine K. Sahlberg), Anne-Lise Børresen-Dale, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E. Kiserud, Kristin V. Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, OSBREAC and Grethe I. Grenaker Alnæs. NBHS and SBCGS thank study participants and research staff for their contributions and commitment to the studies. The OFBCR thanks Teresa Selander, Nayana Weerasooriya and Steve Gallinger. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. The RBCS thanks Jannet Blom, Saskia Pelders, Wendy J.C. Prager–van der Smissen and the Erasmus MC Family Cancer Clinic. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed. We thank the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. UBCS thanks all study participants as well as the ascertainment, laboratory, analytics and informatics teams at Huntsman Cancer Institute and Intermountain Healthcare for their important contributions to this study. Publisher Copyright: © 2023 by the authors.

PY - 2023/7/1

Y1 - 2023/7/1

N2 - 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.

AB - 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.

KW - breast cancer predisposition

KW - breast cancer risk factors

KW - FANCM PTVs spectrum

KW - protein truncating variants

KW - PTVs

U2 - 10.3390/cancers15133313

DO - 10.3390/cancers15133313

M3 - Article

C2 - 37444426

SN - 2072-6694

VL - 15

JO - Cancers

JF - Cancers

IS - 13

M1 - 3313

ER -

Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

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