FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

G. Figlioli; A. Billaud; T.U. Ahearn; N.N. Antonenkova; H. Becher; M.W. Beckmann; S. Behrens; J. Benitez; M. Bermisheva; M.J. Blok; N.V. Bogdanova; B. Bonanni; B. Burwinkel; N.J. Camp; A. Campbell; J.E. Castelao; M.H. Cessna; S.J. Chanock; K. Czene; P. Devilee; T. Dork; C. Engel; M. Eriksson; P.A. Fasching; J.D. Figueroa; M. Gabrielson; M. Gago-Dominguez; M. Garcia-Closas; A. Gonzalez-Neira; F. Grassmann; P. Guenel; M. Gundert; A. Hadjisavvas; E. Hahnen; P. Hall; U. Hamann; P.A. Harrington; W. He; P. Hillemanns; A. Hollestelle; M.J. Hooning; R. Hoppe; A. Howell; K. Humphreys; A. Jager; A. Jakubowska; E.K. Khusnutdinova; Y.D. Ko; V.N. Kristensen; A. Lindblom; KConFab Investigators; NBCS Collaborators; Paolo Peterlongo

doi:10.1038/s41431-022-01257-w

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

G. Figlioli, A. Billaud, T.U. Ahearn, N.N. Antonenkova, H. Becher, M.W. Beckmann, S. Behrens, J. Benitez, M. Bermisheva, M.J. Blok, N.V. Bogdanova, B. Bonanni, B. Burwinkel, N.J. Camp, A. Campbell, J.E. Castelao, M.H. Cessna, S.J. Chanock, K. Czene, P. DevileeT. Dork, C. Engel, M. Eriksson, P.A. Fasching, J.D. Figueroa, M. Gabrielson, M. Gago-Dominguez, M. Garcia-Closas, A. Gonzalez-Neira, F. Grassmann, P. Guenel, M. Gundert, A. Hadjisavvas, E. Hahnen, P. Hall, U. Hamann, P.A. Harrington, W. He, P. Hillemanns, A. Hollestelle, M.J. Hooning, R. Hoppe, A. Howell, K. Humphreys, A. Jager, A. Jakubowska, E.K. Khusnutdinova, Y.D. Ko, V.N. Kristensen, A. Lindblom, KConFab Investigators, NBCS Collaborators, Paolo Peterlongo^*

^*Corresponding author for this work

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

Abstract

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.

Original language	English
Pages (from-to)	578-587
Number of pages	10
Journal	European Journal of Human Genetics
Volume	31
Issue number	5
Early online date	1 Jan 2023
DOIs	https://doi.org/10.1038/s41431-022-01257-w
Publication status	Published - 1 May 2023

Keywords

C.5791C-GREATER-THAN-T
FRAMEWORK
GENE
PATHOGENICITY
Pathogenicity
Gene
C.5791c-greater-than-t
Framework

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Figlioli, G., Billaud, A., Ahearn, T. U., Antonenkova, N. N., Becher, H., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Blok, M. J., Bogdanova, N. V., Bonanni, B., Burwinkel, B., Camp, N. J., Campbell, A., Castelao, J. E., Cessna, M. H., Chanock, S. J., Czene, K., ... Peterlongo, P. (2023). FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European Journal of Human Genetics, 31(5), 578-587. https://doi.org/10.1038/s41431-022-01257-w

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title = "FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women",

abstract = "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.",

keywords = "C.5791C-GREATER-THAN-T, FRAMEWORK, GENE, PATHOGENICITY, Pathogenicity, Gene, C.5791c-greater-than-t, Framework",

author = "G. Figlioli and A. Billaud and T.U. Ahearn and N.N. Antonenkova and H. Becher and M.W. Beckmann and S. Behrens and J. Benitez and M. Bermisheva and M.J. Blok and N.V. Bogdanova and B. Bonanni and B. Burwinkel and N.J. Camp and A. Campbell and J.E. Castelao and M.H. Cessna and S.J. Chanock and K. Czene and P. Devilee and T. Dork and C. Engel and M. Eriksson and P.A. Fasching and J.D. Figueroa and M. Gabrielson and M. Gago-Dominguez and M. Garcia-Closas and A. Gonzalez-Neira and F. Grassmann and P. Guenel and M. Gundert and A. Hadjisavvas and E. Hahnen and P. Hall and U. Hamann and P.A. Harrington and W. He and P. Hillemanns and A. Hollestelle and M.J. Hooning and R. Hoppe and A. Howell and K. Humphreys and A. Jager and A. Jakubowska and E.K. Khusnutdinova and Y.D. Ko and V.N. Kristensen and A. Lindblom and {KConFab Investigators} and {NBCS Collaborators} and Paolo Peterlongo",

note = "Publisher Copyright: {\textcopyright} 2023. The Author(s).",

year = "2023",

month = may,

day = "1",

doi = "10.1038/s41431-022-01257-w",

language = "English",

volume = "31",

pages = "578--587",

journal = "European Journal of Human Genetics",

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Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, NV, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Dork, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, YD, Kristensen, VN, Lindblom, A, KConFab Investigators, NBCS Collaborators & Peterlongo, P 2023, 'FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women', European Journal of Human Genetics, vol. 31, no. 5, pp. 578-587. https://doi.org/10.1038/s41431-022-01257-w

TY - JOUR

T1 - FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

AU - Figlioli, G.

AU - Billaud, A.

AU - Ahearn, T.U.

AU - Antonenkova, N.N.

AU - Becher, H.

AU - Beckmann, M.W.

AU - Behrens, S.

AU - Benitez, J.

AU - Bermisheva, M.

AU - Blok, M.J.

AU - Bogdanova, N.V.

AU - Bonanni, B.

AU - Burwinkel, B.

AU - Camp, N.J.

AU - Campbell, A.

AU - Castelao, J.E.

AU - Cessna, M.H.

AU - Chanock, S.J.

AU - Czene, K.

AU - Devilee, P.

AU - Dork, T.

AU - Engel, C.

AU - Eriksson, M.

AU - Fasching, P.A.

AU - Figueroa, J.D.

AU - Gabrielson, M.

AU - Gago-Dominguez, M.

AU - Garcia-Closas, M.

AU - Gonzalez-Neira, A.

AU - Grassmann, F.

AU - Guenel, P.

AU - Gundert, M.

AU - Hadjisavvas, A.

AU - Hahnen, E.

AU - Hall, P.

AU - Hamann, U.

AU - Harrington, P.A.

AU - He, W.

AU - Hillemanns, P.

AU - Hollestelle, A.

AU - Hooning, M.J.

AU - Hoppe, R.

AU - Howell, A.

AU - Humphreys, K.

AU - Jager, A.

AU - Jakubowska, A.

AU - Khusnutdinova, E.K.

AU - Ko, Y.D.

AU - Kristensen, V.N.

AU - Lindblom, A.

AU - KConFab Investigators

AU - NBCS Collaborators

AU - Peterlongo, Paolo

PY - 2023/5/1

Y1 - 2023/5/1

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.

KW - C.5791C-GREATER-THAN-T

KW - FRAMEWORK

KW - GENE

KW - PATHOGENICITY

KW - Pathogenicity

KW - Gene

KW - C.5791c-greater-than-t

KW - Framework

U2 - 10.1038/s41431-022-01257-w

DO - 10.1038/s41431-022-01257-w

M3 - Article

C2 - 36707629

SN - 1018-4813

VL - 31

SP - 578

EP - 587

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 5

ER -

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

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Keywords

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