TY  - JOUR
AU  - Billaud, Amandine
AU  - Figlioli, Gisella
AU  - Mooser, Clémence
AU  - Casamassima, Irene
AU  - Azzoni, Violette
AU  - Srivatsa, Jahnavi
AU  - Colombo, Mara
AU  - Caleca, Laura
AU  - Ahearn, Thomas U
AU  - Andrulis, Irene L
AU  - Antoniou, Antonis C
AU  - Beckmann, Matthias W
AU  - Behrens, Sabine
AU  - Bermisheva, Marina
AU  - Bogdanova, Natalia V
AU  - Bolla, Manjeet K
AU  - Bonanni, Bernardo
AU  - Brüning, Thomas
AU  - Camp, Nicola J
AU  - Campbell, Archie
AU  - Castelao, Jose E
AU  - Cessna, Melissa H
AU  - Chang-Claude, Jenny
AU  - Czene, Kamila
AU  - Dennis, Joe
AU  - Devilee, Peter
AU  - Dörk, Thilo
AU  - Dunning, Alison M
AU  - Eriksson, Mikael
AU  - Evans, D Gareth
AU  - Fasching, Peter A
AU  - Figueroa, Jonine D
AU  - Gabrielson, Marike
AU  - Gago-Dominguez, Manuela
AU  - González-Neira, Anna
AU  - Guénel, Pascal
AU  - Hadjisavvas, Andreas
AU  - Hahnen, Eric
AU  - Hamann, Ute
AU  - Hillemanns, Peter
AU  - Hollestelle, Antoinette
AU  - Hooning, Maartje J
AU  - Hoppe, Reiner
AU  - Howell, Anthony
AU  - Jakubowska, Anna
AU  - Kristensen, Vessela N
AU  - Lubiński, Jan
AU  - Lush, Michael
AU  - Manoukian, Siranoush
AU  - Mavroudis, Dimitrios
AU  - Milne, Roger L
AU  - Mulligan, Anna Marie
AU  - Newman, William G
AU  - Obi, Nadia
AU  - Panayiotidis, Mihalis I
AU  - Pita, Guillermo
AU  - Rashid, Muhammad U
AU  - Rhenius, Valerie
AU  - Saloustros, Emmanouil
AU  - Sawyer, Elinor J
AU  - Schmutzler, Rita K
AU  - Shah, Mitul
AU  - Southey, Melissa C
AU  - Spurdle, Amanda B
AU  - Tomlinson, Ian
AU  - Truong, Thérèse
AU  - Wang, Qin
AU  - Wendt, Camilla
AU  - Auer, Paul L
AU  - Boddicker, Nicholas J
AU  - Bodelon, Clara
AU  - Burnside, Elizabeth S
AU  - Chen, Fei
AU  - Couch, Fergus J
AU  - Domchek, Susan M
AU  - Eliassen, Heather A
AU  - Haiman, Christopher
AU  - Hodge, James M
AU  - Hu, Chunling
AU  - Huang, Hongyan
AU  - Lindstrom, Sara
AU  - Martinez, Maria Elena
AU  - Nathanson, Katherine L
AU  - Neuhausen, Susan L
AU  - O'Brien, Katie M
AU  - Olson, Janet E
AU  - Palmer, Julie R
AU  - Patel, Alpa V
AU  - Ruddy, Kathryn J
AU  - Sandler, Dale P
AU  - Teras, Lauren R
AU  - Weinberg, Clarice R
AU  - Weitzel, Jeffrey N
AU  - Winham, Stacey J
AU  - Yadav, Siddhartha
AU  - Yao, Song
AU  - Zirpoli, Gary
AU  - Janatova, Marketa
AU  - Kleibl, Zdenek
AU  - Kleiblova, Petra
AU  - Soukupova, Jana
AU  - Zhao, Qihong
AU  - Devereux, Lisa
AU  - James, Paul A
AU  - Campbell, Ian G
AU  - Nguyen-Dumont, Tu
AU  - Dowty, James G
AU  - Andrieu, Nadine
AU  - Lesueur, Fabienne
AU  - Stoppa-Lyonnet, Dominique
AU  - Hoya, Miguel de la
AU  - Radice, Paolo
AU  - Sørensen, Claus Storgaard
AU  - Peterlongo, Paolo
TI  - Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer.
JO  - The breast
VL  - 85
SN  - 0960-9776
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DKFZ-2025-02416
SP  - 104619
PY  - 2025
AB  - The 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.
KW  - Breast cancer risk (Other)
KW  - CRISPR-Cas9 (Other)
KW  - FANCM (Other)
KW  - Gene editing (Other)
KW  - Genetic predisposition (Other)
KW  - Meta-analysis (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41223770
DO  - DOI:10.1016/j.breast.2025.104619
UR  - https://inrepo02.dkfz.de/record/306176
ER  -