Mavaddat, Nasim, Dorling, Leila, Carvalho, Sara, Allen, Jamie, Gonzalez-Neira, Anna, Keeman, Renske, Bolla, Manjeet K., Dennis, Joe, Wang, Qin, Ahearn, Thomas U., Andrulis, Irene L., Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia, V, Bojesen, Stig E., Briceno, Ignacio, Bruning, Thomas, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Christiansen, Hans, Czene, Kamila, Dork, Thilo, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine D., Flyger, Henrik, Gabrielson, Marike ORCID: 0000-0002-3171-1556, Gago-Dominguez, Manuela, Geisler, Jurgen, Giles, Graham G., Guenel, Pascal ORCID: 0000-0002-8359-518X, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Hartikainen, Jaana M., Hartman, Mikael, Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Jung, Audrey ORCID: 0000-0003-0875-6673, Khusnutdinova, Elza K., Kristensen, Vessela N., Li, Jingmei ORCID: 0000-0001-8587-7511, Lim, Swee Ho, Lindblom, Annika, Loizidou, Maria A., Lophatananon, Artitaya, Lubinski, Jan, Madsen, Michael J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara ORCID: 0000-0002-5526-5570, Mavroudis, Dimitrios, Milne, Roger L., Taib, Nur Aishah Mohd ORCID: 0000-0001-8419-0478, Morra, Anna, Muir, Kenneth, Obi, Nadia, Osorio, Ana ORCID: 0000-0001-8124-3984, Park-Simon, Tjoung-Won, Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Radice, Paolo, Saloustros, Emmanouil ORCID: 0000-0002-0485-0120, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sim, Xueling, Southey, Melissa C., Thorne, Heather, Tomlinson, Ian, Torres, Diana, Truong, Therese, Yip, Cheng Har, Spurdle, Amanda B., Vreeswijk, Maaike P. G., Dunning, Alison M., Garcia-Closas, Montserrat ORCID: 0000-0003-1033-2650, Pharoah, Paul D. P., Kvist, Anders, Muranen, Taru A., Nevanlinna, Heli, Teo, Soo Hwang, Devilee, Peter, Schmidt, Marjanka K. and Easton, Douglas F. (2022). Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes. JAMA Oncol., 8 (3). CHICAGO: AMER MEDICAL ASSOC. ISSN 2374-2445

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Abstract

IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1(11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)(+)ERBB2(-) high-grade subtype (OR, 4.99; 95% CI. 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR(+)ERBB2(+) and HR(-)ERBB2(+) subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mavaddat, NasimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorling, LeilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carvalho, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allen, JamieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Neira, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keeman, RenskeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolla, Manjeet K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, QinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahearn, Thomas U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckmann, Matthias W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrens, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bermisheva, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blomqvist, CarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogdanova, Natalia, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojesen, Stig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Briceno, IgnacioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruning, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Camp, Nicola J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, ArchieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castelao, Jose E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang-Claude, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chanock, Stephen J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christiansen, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Czene, KamilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dork, ThiloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eriksson, MikaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, D. GarethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fasching, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueroa, Jonine D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flyger, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabrielson, MarikeUNSPECIFIEDorcid.org/0000-0002-3171-1556UNSPECIFIED
Gago-Dominguez, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geisler, JurgenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giles, Graham G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenel, PascalUNSPECIFIEDorcid.org/0000-0002-8359-518XUNSPECIFIED
Hadjisavvas, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hall, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartikainen, Jaana M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartman, MikaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ReinerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howell, AnthonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jung, AudreyUNSPECIFIEDorcid.org/0000-0003-0875-6673UNSPECIFIED
Khusnutdinova, Elza K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kristensen, Vessela N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, JingmeiUNSPECIFIEDorcid.org/0000-0001-8587-7511UNSPECIFIED
Lim, Swee HoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loizidou, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lophatananon, ArtitayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubinski, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madsen, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannermaa, ArtoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manoochehri, MehdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Margolin, SaraUNSPECIFIEDorcid.org/0000-0002-5526-5570UNSPECIFIED
Mavroudis, DimitriosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milne, Roger L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taib, Nur Aishah MohdUNSPECIFIEDorcid.org/0000-0001-8419-0478UNSPECIFIED
Morra, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muir, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Obi, NadiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osorio, AnaUNSPECIFIEDorcid.org/0000-0001-8124-3984UNSPECIFIED
Park-Simon, Tjoung-WonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Radice, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saloustros, EmmanouilUNSPECIFIEDorcid.org/0000-0002-0485-0120UNSPECIFIED
Sawyer, Elinor J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, MitulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sim, XuelingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorne, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Truong, ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yip, Cheng HarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vreeswijk, Maaike P. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dunning, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Closas, MontserratUNSPECIFIEDorcid.org/0000-0003-1033-2650UNSPECIFIED
Pharoah, Paul D. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kvist, AndersUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muranen, Taru A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo HwangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Marjanka K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699385
DOI: 10.1001/jamaoncol.2021.6744
Journal or Publication Title: JAMA Oncol.
Volume: 8
Number: 3
Date: 2022
Publisher: AMER MEDICAL ASSOC
Place of Publication: CHICAGO
ISSN: 2374-2445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INTERNATIONAL EXPERT CONSENSUS; BRCA2 MUTATION CARRIERS; PRIMARY THERAPY; MOLECULAR PORTRAITS; SUBTYPES; EXPRESSION; ACTIVATION; SUBCLASSES; PALB2; CHK2Multiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69938

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