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000306176 0247_ $$2doi$$a10.1016/j.breast.2025.104619
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000306176 1001_ $$aBillaud, Amandine$$b0
000306176 245__ $$aLarge-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer.
000306176 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2025
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000306176 520__ $$aThe breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.
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000306176 650_7 $$2Other$$aBreast cancer risk
000306176 650_7 $$2Other$$aCRISPR-Cas9
000306176 650_7 $$2Other$$aFANCM
000306176 650_7 $$2Other$$aGene editing
000306176 650_7 $$2Other$$aGenetic predisposition
000306176 650_7 $$2Other$$aMeta-analysis
000306176 7001_ $$aFiglioli, Gisella$$b1
000306176 7001_ $$aMooser, Clémence$$b2
000306176 7001_ $$aCasamassima, Irene$$b3
000306176 7001_ $$aAzzoni, Violette$$b4
000306176 7001_ $$aSrivatsa, Jahnavi$$b5
000306176 7001_ $$aColombo, Mara$$b6
000306176 7001_ $$aCaleca, Laura$$b7
000306176 7001_ $$aAhearn, Thomas U$$b8
000306176 7001_ $$aAndrulis, Irene L$$b9
000306176 7001_ $$aAntoniou, Antonis C$$b10
000306176 7001_ $$aBeckmann, Matthias W$$b11
000306176 7001_ $$0P:(DE-He78)6b04712f3afe72044d496a25505cb1ea$$aBehrens, Sabine$$b12$$udkfz
000306176 7001_ $$aBermisheva, Marina$$b13
000306176 7001_ $$aBogdanova, Natalia V$$b14
000306176 7001_ $$aBolla, Manjeet K$$b15
000306176 7001_ $$aBonanni, Bernardo$$b16
000306176 7001_ $$aBrüning, Thomas$$b17
000306176 7001_ $$aCamp, Nicola J$$b18
000306176 7001_ $$aCampbell, Archie$$b19
000306176 7001_ $$aCastelao, Jose E$$b20
000306176 7001_ $$aCessna, Melissa H$$b21
000306176 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b22
000306176 7001_ $$aNBCS Collaborators$$b23$$eCollaboration Author
000306176 7001_ $$aCzene, Kamila$$b24
000306176 7001_ $$aDennis, Joe$$b25
000306176 7001_ $$aDevilee, Peter$$b26
000306176 7001_ $$aDörk, Thilo$$b27
000306176 7001_ $$aDunning, Alison M$$b28
000306176 7001_ $$aEriksson, Mikael$$b29
000306176 7001_ $$aEvans, D Gareth$$b30
000306176 7001_ $$aFasching, Peter A$$b31
000306176 7001_ $$aFigueroa, Jonine D$$b32
000306176 7001_ $$aGabrielson, Marike$$b33
000306176 7001_ $$aGago-Dominguez, Manuela$$b34
000306176 7001_ $$aGonzález-Neira, Anna$$b35
000306176 7001_ $$aGuénel, Pascal$$b36
000306176 7001_ $$aHadjisavvas, Andreas$$b37
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000306176 7001_ $$aHillemanns, Peter$$b40
000306176 7001_ $$aHollestelle, Antoinette$$b41
000306176 7001_ $$aHooning, Maartje J$$b42
000306176 7001_ $$aHoppe, Reiner$$b43
000306176 7001_ $$aHowell, Anthony$$b44
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000306176 7001_ $$aJakubowska, Anna$$b46
000306176 7001_ $$aKristensen, Vessela N$$b47
000306176 7001_ $$aLubiński, Jan$$b48
000306176 7001_ $$aLush, Michael$$b49
000306176 7001_ $$aManoukian, Siranoush$$b50
000306176 7001_ $$aMavroudis, Dimitrios$$b51
000306176 7001_ $$aMilne, Roger L$$b52
000306176 7001_ $$aMulligan, Anna Marie$$b53
000306176 7001_ $$aNewman, William G$$b54
000306176 7001_ $$aObi, Nadia$$b55
000306176 7001_ $$aPanayiotidis, Mihalis I$$b56
000306176 7001_ $$aPita, Guillermo$$b57
000306176 7001_ $$0P:(DE-HGF)0$$aRashid, Muhammad U$$b58
000306176 7001_ $$aRhenius, Valerie$$b59
000306176 7001_ $$aSaloustros, Emmanouil$$b60
000306176 7001_ $$aSawyer, Elinor J$$b61
000306176 7001_ $$aSchmutzler, Rita K$$b62
000306176 7001_ $$aShah, Mitul$$b63
000306176 7001_ $$aSouthey, Melissa C$$b64
000306176 7001_ $$aSpurdle, Amanda B$$b65
000306176 7001_ $$aTomlinson, Ian$$b66
000306176 7001_ $$aTruong, Thérèse$$b67
000306176 7001_ $$aWang, Qin$$b68
000306176 7001_ $$aWendt, Camilla$$b69
000306176 7001_ $$aAuer, Paul L$$b70
000306176 7001_ $$aBoddicker, Nicholas J$$b71
000306176 7001_ $$aBodelon, Clara$$b72
000306176 7001_ $$aBurnside, Elizabeth S$$b73
000306176 7001_ $$aChen, Fei$$b74
000306176 7001_ $$aCouch, Fergus J$$b75
000306176 7001_ $$aDomchek, Susan M$$b76
000306176 7001_ $$aEliassen, Heather A$$b77
000306176 7001_ $$aHaiman, Christopher$$b78
000306176 7001_ $$aHodge, James M$$b79
000306176 7001_ $$aHu, Chunling$$b80
000306176 7001_ $$aHuang, Hongyan$$b81
000306176 7001_ $$aLindstrom, Sara$$b82
000306176 7001_ $$aMartinez, Maria Elena$$b83
000306176 7001_ $$aNathanson, Katherine L$$b84
000306176 7001_ $$aNeuhausen, Susan L$$b85
000306176 7001_ $$aO'Brien, Katie M$$b86
000306176 7001_ $$aOlson, Janet E$$b87
000306176 7001_ $$aPalmer, Julie R$$b88
000306176 7001_ $$aPatel, Alpa V$$b89
000306176 7001_ $$aRuddy, Kathryn J$$b90
000306176 7001_ $$aSandler, Dale P$$b91
000306176 7001_ $$aTeras, Lauren R$$b92
000306176 7001_ $$aWeinberg, Clarice R$$b93
000306176 7001_ $$aWeitzel, Jeffrey N$$b94
000306176 7001_ $$aWinham, Stacey J$$b95
000306176 7001_ $$aYadav, Siddhartha$$b96
000306176 7001_ $$aYao, Song$$b97
000306176 7001_ $$aZirpoli, Gary$$b98
000306176 7001_ $$aJanatova, Marketa$$b99
000306176 7001_ $$aKleibl, Zdenek$$b100
000306176 7001_ $$aKleiblova, Petra$$b101
000306176 7001_ $$aSoukupova, Jana$$b102
000306176 7001_ $$aconsortium, CZECANCA$$b103$$eCollaboration Author
000306176 7001_ $$aZhao, Qihong$$b104
000306176 7001_ $$aDevereux, Lisa$$b105
000306176 7001_ $$aJames, Paul A$$b106
000306176 7001_ $$aCampbell, Ian G$$b107
000306176 7001_ $$aNguyen-Dumont, Tu$$b108
000306176 7001_ $$aDowty, James G$$b109
000306176 7001_ $$aAndrieu, Nadine$$b110
000306176 7001_ $$aLesueur, Fabienne$$b111
000306176 7001_ $$aStoppa-Lyonnet, Dominique$$b112
000306176 7001_ $$aGENESIS$$b113$$eCollaboration Author
000306176 7001_ $$aHoya, Miguel de la$$b114
000306176 7001_ $$aRadice, Paolo$$b115
000306176 7001_ $$aSørensen, Claus Storgaard$$b116
000306176 7001_ $$aPeterlongo, Paolo$$b117
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