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Meta-Analysis
. 2023 May;31(5):578-587.
doi: 10.1038/s41431-022-01257-w. Epub 2023 Jan 27.

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

Gisella Figlioli  1 , Amandine Billaud  1 , Thomas U Ahearn  2 , Natalia N Antonenkova  3 , Heiko Becher  4 , Matthias W Beckmann  5 , Sabine Behrens  6 , Javier Benitez  7   8 , Marina Bermisheva  9 , Marinus J Blok  10 , Natalia V Bogdanova  3   11   12 , Bernardo Bonanni  13 , Barbara Burwinkel  14   15 , Nicola J Camp  16 , Archie Campbell  17   18 , Jose E Castelao  19 , Melissa H Cessna  20 , Stephen J Chanock  2 ; NBCS Collaborators; Kamila Czene  21 , Peter Devilee  22   23 , Thilo Dörk  12 , Christoph Engel  24   25 , Mikael Eriksson  21 , Peter A Fasching  5 , Jonine D Figueroa  2   18   26 , Marike Gabrielson  21 , Manuela Gago-Dominguez  27   28 , Montserrat García-Closas  2 , Anna González-Neira  29 , Felix Grassmann  21   30 , Pascal Guénel  31 , Melanie Gündert  14   15   32 , Andreas Hadjisavvas  33 , Eric Hahnen  34   35 , Per Hall  21   36 , Ute Hamann  37 , Patricia A Harrington  38 , Wei He  21 , Peter Hillemanns  12 , Antoinette Hollestelle  39 , Maartje J Hooning  39 , Reiner Hoppe  40   41 , Anthony Howell  42 , Keith Humphreys  21 ; KConFab Investigators; Agnes Jager  39 , Anna Jakubowska  43   44 , Elza K Khusnutdinova  9   45 , Yon-Dschun Ko  46 , Vessela N Kristensen  47 , Annika Lindblom  48   49 , Jolanta Lissowska  50 , Jan Lubiński  43 , Arto Mannermaa  51   52   53 , Siranoush Manoukian  54 , Sara Margolin  36   55 , Dimitrios Mavroudis  56 , William G Newman  57   58 , Nadia Obi  4 , Mihalis I Panayiotidis  33 , Muhammad U Rashid  37   59 , Valerie Rhenius  38 , Matti A Rookus  60 , Emmanouil Saloustros  61 , Elinor J Sawyer  62 , Rita K Schmutzler  34   35   63 , Mitul Shah  38 , Reijo Sironen  51   52   64 , Melissa C Southey  65   66   67 , Maija Suvanto  68 , Rob A E M Tollenaar  69 , Ian Tomlinson  70 , Thérèse Truong  31 , Lizet E van der Kolk  71 , Elke M van Veen  57   58 , Barbara Wappenschmidt  34   35 , Xiaohong R Yang  2 , Manjeet K Bolla  72 , Joe Dennis  72 , Alison M Dunning  38 , Douglas F Easton  38   72 , Michael Lush  72 , Kyriaki Michailidou  72   73 , Paul D P Pharoah  38   72 , Qin Wang  72 , Muriel A Adank  71 , Marjanka K Schmidt  60   74 , Irene L Andrulis  75   76 , Jenny Chang-Claude  6   77 , Heli Nevanlinna  68 , Georgia Chenevix-Trench  78 , D Gareth Evans  57   58 , Roger L Milne  65   67   79 , Paolo Radice  80 , Paolo Peterlongo  81
Collaborators, Affiliations
Meta-Analysis

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

Gisella Figlioli et al. Eur J Hum Genet. 2023 May.

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.

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Conflict of interest statement

MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer; he received Honoraria from Roche, Novartis and Pfizer. All the other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Representation of the 673 FANCM rare missense variants (MVs) with respect to the 2048 amino acid long FANCM protein.
Functional and binding domains (MPH1, ATP-dependent DNA helicase; MHF, domain of interaction with the Histone Fold 1 and 2 (MHF1/2); MM1, motif of interaction with FANCF within the Fanconi Anemia core complex; MM2, motif of interaction with RecQ-Mediated genome Instability protein 1 (RMI1); MM3, highly conserved motif of still unknown function; FAAP24, domain of interaction with the Fanconi Anemia core complex-Associated Protein 24) are shown in dark grey and their boundaries indicated. The MVs are shown according to their position, the number of carriers in cases and controls, and by their in silico scores of pathogenicity according to BayesDel, CADD, Helix and REVEL tools; in grey are MVs predicted benign by all the tools; in black, MVs predicted pathogenic by one tool; in blue; MVs predicted pathogenic by two tools; in red, MVs predicted pathogenic by three or four tools.
Fig. 2
Fig. 2. Meta-analysis of studies testing the association of FANCM MVs with familial breast cancer risk and based on the analysis of 14,543 familial breast cancer cases and 42,211 controls.
OR odds ratio, CI confidence interval, I2 percentage of heterogeneity among the studies; Phet, p value calculated using the Cochran’s Q-test for heterogeneity; P, p value of association from Z-test.
See this image and copyright information in PMC

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