FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women
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FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. / Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U; Antonenkova, Natalia N; Becher, Heiko; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blok, Marinus J; Bogdanova, Natalia V; Bonanni, Bernardo; Burwinkel, Barbara; Camp, Nicola J; Campbell, Archie; Castelao, Jose E; Cessna, Melissa H; Chanock, Stephen J; Czene, Kamila; Devilee, Peter; Dörk, Thilo; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine D; Gabrielson, Marike; Gago-Dominguez, Manuela; García-Closas, Montserrat; González-Neira, Anna; Grassmann, Felix; Guénel, Pascal; Gündert, Melanie; Hadjisavvas, Andreas; Hahnen, Eric; Hall, Per; Hamann, Ute; Harrington, Patricia A; He, Wei; Hillemanns, Peter; Hollestelle, Antoinette; Hooning, Maartje J; Hoppe, Reiner; Howell, Anthony; Humphreys, Keith; Jager, Agnes; Jakubowska, Anna; Khusnutdinova, Elza K; Ko, Yon-Dschun; Kristensen, Vessela N; Lindblom, Annika; Lissowska, Jolanta; Lubiński, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Mavroudis, Dimitrios; Newman, William G; Obi, Nadia; Panayiotidis, Mihalis I; Rashid, Muhammad U; Rhenius, Valerie; Rookus, Matti A; Saloustros, Emmanouil; Sawyer, Elinor J; Schmutzler, Rita K; Shah, Mitul; Sironen, Reijo; Southey, Melissa C; Suvanto, Maija; Tollenaar, Rob A E M; Tomlinson, Ian; Truong, Thérèse; van der Kolk, Lizet E; van Veen, Elke M; Wappenschmidt, Barbara; Yang, Xiaohong R; Bolla, Manjeet K; Dennis, Joe; Dunning, Alison M; Easton, Douglas F; Lush, Michael; Michailidou, Kyriaki; Pharoah, Paul D P; Adank, Muriel A; Schmidt, Marjanka K; Andrulis, Irene L; Chang-Claude, Jenny; Nevanlinna, Heli; Chenevix-Trench, Georgia; Evans, D Gareth; Milne, Roger L; Radice, Paolo; Peterlongo, Paolo; NBCS Collaborators.
in: EUR J HUM GENET, Jahrgang 31, Nr. 5, 05.2023, S. 578-587.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women
AU - Figlioli, Gisella
AU - Billaud, Amandine
AU - Ahearn, Thomas U
AU - Antonenkova, Natalia N
AU - Becher, Heiko
AU - Beckmann, Matthias W
AU - Behrens, Sabine
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Blok, Marinus J
AU - Bogdanova, Natalia V
AU - Bonanni, Bernardo
AU - Burwinkel, Barbara
AU - Camp, Nicola J
AU - Campbell, Archie
AU - Castelao, Jose E
AU - Cessna, Melissa H
AU - Chanock, Stephen J
AU - Czene, Kamila
AU - Devilee, Peter
AU - Dörk, Thilo
AU - Engel, Christoph
AU - Eriksson, Mikael
AU - Fasching, Peter A
AU - Figueroa, Jonine D
AU - Gabrielson, Marike
AU - Gago-Dominguez, Manuela
AU - García-Closas, Montserrat
AU - González-Neira, Anna
AU - Grassmann, Felix
AU - Guénel, Pascal
AU - Gündert, Melanie
AU - Hadjisavvas, Andreas
AU - Hahnen, Eric
AU - Hall, Per
AU - Hamann, Ute
AU - Harrington, Patricia A
AU - He, Wei
AU - Hillemanns, Peter
AU - Hollestelle, Antoinette
AU - Hooning, Maartje J
AU - Hoppe, Reiner
AU - Howell, Anthony
AU - Humphreys, Keith
AU - Jager, Agnes
AU - Jakubowska, Anna
AU - Khusnutdinova, Elza K
AU - Ko, Yon-Dschun
AU - Kristensen, Vessela N
AU - Lindblom, Annika
AU - Lissowska, Jolanta
AU - Lubiński, Jan
AU - Mannermaa, Arto
AU - Manoukian, Siranoush
AU - Margolin, Sara
AU - Mavroudis, Dimitrios
AU - Newman, William G
AU - Obi, Nadia
AU - Panayiotidis, Mihalis I
AU - Rashid, Muhammad U
AU - Rhenius, Valerie
AU - Rookus, Matti A
AU - Saloustros, Emmanouil
AU - Sawyer, Elinor J
AU - Schmutzler, Rita K
AU - Shah, Mitul
AU - Sironen, Reijo
AU - Southey, Melissa C
AU - Suvanto, Maija
AU - Tollenaar, Rob A E M
AU - Tomlinson, Ian
AU - Truong, Thérèse
AU - van der Kolk, Lizet E
AU - van Veen, Elke M
AU - Wappenschmidt, Barbara
AU - Yang, Xiaohong R
AU - Bolla, Manjeet K
AU - Dennis, Joe
AU - Dunning, Alison M
AU - Easton, Douglas F
AU - Lush, Michael
AU - Michailidou, Kyriaki
AU - Pharoah, Paul D P
AU - Adank, Muriel A
AU - Schmidt, Marjanka K
AU - Andrulis, Irene L
AU - Chang-Claude, Jenny
AU - Nevanlinna, Heli
AU - Chenevix-Trench, Georgia
AU - Evans, D Gareth
AU - Milne, Roger L
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - NBCS Collaborators
N1 - © 2023. The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
AB - Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
U2 - 10.1038/s41431-022-01257-w
DO - 10.1038/s41431-022-01257-w
M3 - SCORING: Journal article
C2 - 36707629
VL - 31
SP - 578
EP - 587
JO - EUR J HUM GENET
JF - EUR J HUM GENET
SN - 1018-4813
IS - 5
ER -