Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions.
Journal
Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089
Informations de publication
Date de publication:
08 06 2023
08 06 2023
Historique:
received:
15
06
2022
revised:
07
11
2022
accepted:
14
02
2023
medline:
9
6
2023
pubmed:
18
3
2023
entrez:
17
3
2023
Statut:
ppublish
Résumé
The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
Sections du résumé
BACKGROUND
The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.
METHODS
We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.
RESULTS
We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.
CONCLUSIONS
Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
Identifiants
pubmed: 36929942
pii: 7079819
doi: 10.1093/jnci/djad043
pmc: PMC10248849
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
712-732Subventions
Organisme : NCI NIH HHS
ID : U01 CA182883
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101782
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA164930
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206110
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH090951
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES013678
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101820
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA006227
Pays : United States
Organisme : Cancer Research UK
ID : 25514
Pays : United Kingdom
Organisme : NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NIH HHS
ID : T32 ES013678
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101810
Pays : United States
Organisme : NIH HHS
ID : S10 OD028685
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101819
Pays : United States
Organisme : Cancer Research UK
ID : 29017
Pays : United Kingdom
Organisme : NIH HHS
ID : U01 CA122839
Pays : United States
Organisme : NIH HHS
ID : U19 CA148065
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH090936
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA261339
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008C
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242218
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH101825
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH090948
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH090941
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194393
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101822
Pays : United States
Organisme : CCR NIH HHS
ID : HHSN261200800001C
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH090937
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States
Organisme : Cancer Research UK
ID : 4584
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG18033
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201000029C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101814
Pays : United States
Organisme : NIH HHS
ID : R01 CA189184
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148107
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG018033
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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