FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women
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Authors
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.
Devilee, P.
Dörk, T.
Engel, C.
Eriksson, M.
Fasching, P. A.
Figueroa, J. D.
Gabrielson, M.
Gago-Dominguez, M.
García-Closas, M.
González-Neira, A.
Grassmann, F.
Guénel, P.
Gündert, M.
Hadjisavvas, A.
Hahnen, E.
Hall, P.
Hamann, U.
Harrington, P. A.
He, W.
Hillemanns, P.
Hollestelle, A.
Hooning, M. J.
Hoppe, R.
Howell, Anthony
Humphreys, K.
Jager, A.
Jakubowska, A.
Khusnutdinova, E. K.
Ko, Y. D.
Kristensen, V. N.
Lindblom, A.
Lissowska, J.
Lubiński, J.
Mannermaa, A.
Manoukian, S.
Margolin, S.
Mavroudis, D.
Newman, W. G.
Obi, N.
Panayiotidis, M. I.
Rashid, M. U.
Rhenius, V.
Rookus, M. A.
Saloustros, E.
Sawyer, E. J.
Schmutzler, R. K.
Shah, M.
Sironen, R.
Southey, M. C.
Suvanto, M.
Tollenaar, R.
Tomlinson, I.
Truong, T.
van der Kolk, L. E.
van Veen, E. M.
Wappenschmidt, B.
Yang, X. R.
Bolla, M. K.
Dennis, J.
Dunning, A. M.
Easton, D. F.
Lush, M.
Michailidou, K.
Pharoah, P. D. P.
Wang, Q.
Adank, M. A.
Schmidt, M. K.
Andrulis, I. L.
Chang-Claude, J.
Nevanlinna, H.
Chenevix-Trench, G.
Evans, D. G.
Milne, R. L.
Radice, P.
Peterlongo, P.
Affiliation
IFOM ETS - The AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, ItalyIssue Date
2023
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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.Citation
Figlioli G, Billaud A, Ahearn TU, Antonenkova NN, Becher H, Beckmann MW, et al. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European journal of human genetics : EJHG. 2023 Jan 27. PubMed PMID: 36707629. Epub 2023/01/28. eng.Journal
European Journal of Human GeneticsDOI
10.1038/s41431-022-01257-wPubMed ID
36707629Additional Links
https://dx.doi.org/10.1038/s41431-022-01257-wType
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41431-022-01257-w
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