TY  - JOUR
AU  - Güler, Murat
AU  - Canzian, Federico
TI  - Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: a multi-trait genome-wide association study.
JO  - Blood cancer journal
VL  - 15
IS  - 1
SN  - 2044-5385
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01813
SP  - 147
PY  - 2025
N1  - #EA:C055#LA:C055#
AB  - Lymphoid neoplasms (LNs) are heterogeneous malignancies arising from lymphoid cells, displaying diverse clinical and molecular features. Although LNs are collectively frequent, individual subtypes are rare, posing challenges for genetic association studies. Indeed, genome-wide association studies (GWAS) explained only a fraction of the heritability. Shared genetic susceptibility and overlapping risk factors suggest a partially common etiology across subtypes. We employed a multi-trait GWAS strategy to improve discovery power by leveraging pleiotropy among LN subtypes. We defined LN phenoclusters based on cell of origin, somatic mutation profiles, and approved therapeutic agents. Using data from three large cohorts-the UK Biobank, Million Veteran Program, and FinnGen-we analyzed 31,937 LN cases and 1.2 million controls across 8 individual subtypes and 7 phenoclusters. We replicated the novel associations in two independent cohorts (All of Us and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) with 2892 LN cases and 165,791 controls. We identified 76 genome-wide significant loci for individual subtypes or subtype clusters, including 20 novel associations. We identified the subtypes contributing to each locus, putative candidate causal variants, and genes underlying the associations, and found enrichment of specific cell types, biological processes, and drugs associated with LN risk genes. Overall, this study identified new LN genetic risk loci and candidate genes, providing insights that may inform novel therapeutic approaches.
KW  - Humans
KW  - Genome-Wide Association Study
KW  - Mutation
KW  - Female
KW  - Male
KW  - Genetic Predisposition to Disease
KW  - Middle Aged
KW  - Aged
LB  - PUB:(DE-HGF)16
C6  - pmid:40883272
C2  - pmc:PMC12397487
DO  - DOI:10.1038/s41408-025-01351-4
UR  - https://inrepo02.dkfz.de/record/304272
ER  -