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@ARTICLE{Consortium:178655,
author = {N. Mavaddat and L. Dorling and S. Carvalho and J. Allen and
A. González-Neira and R. Keeman and M. K. Bolla and J.
Dennis and Q. Wang and T. U. Ahearn and I. L. Andrulis and
M. W. Beckmann and S. Behrens$^*$ and J. Benitez and M.
Bermisheva and C. Blomqvist and N. V. Bogdanova and S. E.
Bojesen and I. Briceno and T. Brüning and N. J. Camp and A.
Campbell and J. E. Castelao and J. Chang-Claude$^*$ and S.
J. Chanock and G. Chenevix-Trench and H. Christiansen and K.
Czene and T. Dörk and M. Eriksson and D. G. Evans and P. A.
Fasching and J. D. Figueroa and H. Flyger and M. Gabrielson
and M. Gago-Dominguez and J. Geisler and G. G. Giles and P.
Guénel and A. Hadjisavvas and E. Hahnen and P. Hall and U.
Hamann$^*$ and J. M. Hartikainen and M. Hartman and R. Hoppe
and A. Howell and A. Jakubowska and A. Jung$^*$ and E. K.
Khusnutdinova and V. N. Kristensen and J. Li and S. H. Lim
and A. Lindblom and M. A. Loizidou and A. Lophatananon and
J. Lubinski and M. J. Madsen and A. Mannermaa and M.
Manoochehri$^*$ and S. Margolin and D. Mavroudis and R. L.
Milne and N. A. Mohd Taib and A. Morra and K. Muir and N.
Obi and A. Osorio and T.-W. Park-Simon and P. Peterlongo and
P. Radice and E. Saloustros and E. J. Sawyer and R. K.
Schmutzler and M. Shah and X. Sim and M. C. Southey and H.
Thorne and I. Tomlinson and D. Torres and T. Truong and C.
H. Yip and A. B. Spurdle and M. P. G. Vreeswijk and A. M.
Dunning and M. García-Closas and P. D. P. Pharoah and A.
Kvist and T. A. Muranen and H. Nevanlinna and S. H. Teo and
P. Devilee and M. K. Schmidt and D. F. Easton},
collaboration = {B. C. A. Consortium},
title = {{P}athology of {T}umors {A}ssociated {W}ith {P}athogenic
{G}ermline {V}ariants in 9 {B}reast {C}ancer
{S}usceptibility {G}enes.},
journal = {JAMA oncology},
volume = {8},
number = {3},
issn = {2374-2437},
address = {Chicago, Ill.},
publisher = {American Medical Association},
reportid = {DKFZ-2022-00184},
pages = {e216744},
year = {2022},
note = {2022 Mar 1;8(3):e216744},
abstract = {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.To characterize tumors
associated with BC susceptibility genes in large-scale
population- or hospital-based studies.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 1991 and 2016. Sequencing and
analysis took place between 2016 and 2021.Protein-truncating
variants and likely pathogenic missense variants in ATM,
BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and
TP53.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.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.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.},
cin = {C020 / B072 / B070},
ddc = {610},
cid = {I:(DE-He78)C020-20160331 / I:(DE-He78)B072-20160331 /
I:(DE-He78)B070-20160331},
pnm = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
pid = {G:(DE-HGF)POF4-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:35084436},
doi = {10.1001/jamaoncol.2021.6744},
url = {https://inrepo02.dkfz.de/record/178655},
}
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