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@ARTICLE{Blechter:305046,
author = {B. Blechter and X. Wang and J. Dai and C. Karsonaki and J.
Shi and K. Shiraishi and J. Choi and K. Matsuo and T.-Y.
Chen and R. J. Hung and K. Chen and X.-O. Shu and Y. T. Kim
and P. P. Choudhury and J. Williams and M. T. Landi and D.
Lin and W. Zheng and Z. Yin and B. Zhou and J. Wang and W.
J. Seow and L. Song and I.-S. Chang and W. Hu and L.-H.
Chien and Q. Cai and Y.-C. Hong and H. N. Kim and Y.-L. Wu
and M. P. Wong and B. D. Richardson and S. Li and T. Zhang
and C. Breeze and Z. Wang and B. A. Bassig and J. H. Kim and
D. Albanes and J. Y. Wong Sm and M.-H. Shin and L. P. Chung
and Y. Yang and H. Zheng and H. Dai and Y. Yatabe and X.-C.
Zhang and Y.-C. Kim and N. E. Caporaso and J. Chang and J.
C. M. Ho and Y. Daigo and Y. Momozawa and Y. Kamatani and M.
Kobayashi and K. Okubo and T. Honda and H. D. Hosgood and H.
Kunitoh and S.-I. Watanabe and Y. Miyagi and S. Matsumoto
and H. Horinouchi and M. Tsuboi and R. Hamamoto and K. Goto
and A. Takahashi and A. Goto and Y. Minamiya and M. Hara and
Y. Nishida and K. Takeuchi and K. Wakai and K. Matsuda and
Y. Murakami and K. Shimizu and H. Suzuki and M. Saito and Y.
Ohtaki and K. Tanaka and T. Wu and F. Wei and M. J. Machiela
and Y. H. Kim and I.-J. Oh and V. H. F. Lee and G.-C. Chang
and K.-Y. Chen and W.-C. Su and Y.-M. Chen and A. Seow and
J. Y. Park and S.-S. Kweon and Y.-T. Gao and J. Liu and A.
G. Schwartz and R. Houlston and I. P. Gorlov and X. Wu and
P. Yang and S. Lam and A. Tardon and C. Chen and S. E.
Bojesen and M. Johansson and A. Risch$^*$ and H.
Bickeböller and B.-T. Ji and H.-E. Wichmann and D. C.
Christiani and G. Rennert and S. M. Arnold and P. Brennan
and J. McKay and J. K. Field and M. P. A. Davies and S. S.
Shete and L. Le Marchand and G. Liu and A. S. Andrew and L.
A. Kiemeney and S. Zienolddiny-Narui and K. Grankvist and A.
Cox and F. Taylor and J.-M. Yuan and P. Lazarus and M. B.
Schabath and M. C. Aldrich and H.-S. Jeon and S. S. Jiang
and C.-H. Chen and C.-F. Hsiao and Z. Hu and L. Burdett and
M. Yeager and A. Hutchinson and B. Hicks and J. Liu and S.
I. Berndt and W. Wu and J. Wang and Y. Li and J. E. Choi and
K. H. Park and S. W. Sung and C. H. Kang and W.-C. Wang and
J. Xu and P. Guan and W. Tan and C.-J. Yu and G. Yang and A.
D. L. Sihoe and Y. Y. Choi and I. K. Park and H.-H. Hung and
R. C. H. Vermeulen and I. Cheng and J. Wu and F.-Y. Tsai and
J. K. C. Chan and J. Li and H.-C. Lin and J. Liu and B. Song
and N. Sawada and T. Yamaji and K. Wyatt and H. Ma and M.
Zhu and Y. Wang and T. Qi and X. Li and Y. Ren and A. Chao
and M. Iwasaki and J. Zhu and G. Wu and C.-Y. Chen and C. C.
ScD and P.-C. Yang and V. L. Stevens and J. F. Fraumeni and
K. Lin and R. G. Walters and Z. Chen and N. Chatterjee and
O. Y. Gorlova and C. I. Amos and H. Shen and C. A. Hsiung
and S. J. Chanock and N. Rothman and T. Kohno and Q. Lan and
H. Zhang},
title = {{S}tratifying lung adenocarcinoma risk with multi-ancestry
polygenic risk scores in {E}ast {A}sian never-smokers.},
journal = {Journal of the National Cancer Institute},
volume = {nn},
issn = {0027-8874},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {DKFZ-2025-02022},
pages = {nn},
year = {2025},
note = {ISSN 1460-2105 / epub},
abstract = {Lung adenocarcinoma (LUAD) in never-smokers is a major
public health burden, especially among East Asian women.
Polygenic risk scores (PRSs) are promising for risk
stratification but are primarily developed in
European-ancestry populations. We aimed to develop and
validate single- and multi-ancestry PRSs for East Asian
never-smokers to improve LUAD risk prediction.PRSs were
developed using genome-wide association study summary
statistics from East Asian (8,002 cases; 20,782 controls)
and European (2,058 cases; 5,575 controls) populations.
Single-ancestry models included PRS-25, PRS-CT, and LDpred2;
multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx,
and CT-SLEB. Performance was evaluated in independent East
Asian data from the Female Lung Cancer Consortium (FLCCA)
and externally validated in the Nanjing Lung Cancer Cohort
(NJLCC). We assessed predictive accuracy via AUC, with
10-year and (age 30-80) absolute risks estimates.The best
multi-ancestry PRS, using East Asian and European data via
CT-SLEB (clumping and thresholding, super learning,
empirical Bayes), outperformed the best East Asian-only PRS
(LDpred2; AUC = 0.629, $95\%$ CI:0.618,0.641), achieving an
AUC of 0.640 $(95\%$ CI : 0.629,0.653) and odds ratio of
1.71 $(95\%$ CI : 1.61,1.82) per SD increase. NJLCC
Validation confirmed robust performance (AUC =0.649, $95\%$
CI: 0.623, 0.676). The top $20\%$ PRS group had a 3.92-fold
higher LUAD risk than the bottom $20\%.$ Further, the top
$5\%$ PRS group reached a $6.69\%$ lifetime absolute risk.
Notably, this group reached the average population 10-year
LUAD risk at age 50 $(0.42\%)$ by age 41, nine years
earlier.Multi-ancestry PRS approaches enhance LUAD risk
stratification in East Asian never-smokers, with consistent
external validation, suggesting future clinical utility.},
keywords = {East Asian never smokers (Other) / Genome-wide association
studies (Other) / Lifetime absolute risk (Other) / Lung
adenocarcinoma (Other) / Polygenic risk scores (Other)},
cin = {B370},
ddc = {610},
cid = {I:(DE-He78)B370-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41032288},
doi = {10.1093/jnci/djaf272},
url = {https://inrepo02.dkfz.de/record/305046},
}