Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.
Journal
JNCI cancer spectrum
ISSN: 2515-5091
Titre abrégé: JNCI Cancer Spectr
Pays: England
ID NLM: 101721827
Informations de publication
Date de publication:
31 Oct 2023
31 Oct 2023
Historique:
received:
07
06
2023
revised:
18
09
2023
accepted:
18
10
2023
medline:
27
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.
Sections du résumé
BACKGROUND
BACKGROUND
This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung).
METHODS
METHODS
A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type.
RESULTS
RESULTS
Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected).
CONCLUSIONS
CONCLUSIONS
There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.
Identifiants
pubmed: 37862240
pii: 7325356
doi: 10.1093/jncics/pkad088
pmc: PMC10653584
pii:
doi:
Types de publication
Meta-Analysis
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Investigateurs
Elnaz Naderi
(E)
Miguel E Aguado-Barrera
(ME)
Line M H Schack
(LMH)
Leila Dorling
(L)
Tim Rattay
(T)
Laura Fachal
(L)
Holly Summersgill
(H)
Laura Martínez-Calvo
(L)
Ceilidh Welsh
(C)
Tom Dudding
(T)
Yasmin Odding
(Y)
Ana Varela-Pazos
(A)
Rajesh Jena
(R)
David J Thomson
(DJ)
Roel J H M Steenbakkers
(RJHM)
Joe Dennis
(J)
Ramón Lobato-Busto
(R)
Jan Alsner
(J)
Andy Ness
(A)
Chris Nutting
(C)
Antonio Gómez-Caamaño
(A)
Jesper G Eriksen
(JG)
Steve J Thomas
(SJ)
Amy M Bates
(AM)
Adam J Webb
(AJ)
Ananya Choudhury
(A)
Barry S Rosenstein
(BS)
Begona Taboada-Valladares
(B)
Carsten Herskind
(C)
David Azria
(D)
David P Dearnaley
(DP)
Dirk de Ruysscher
(D)
Elena Sperk
(E)
Emma Hall
(E)
Hilary Stobart
(H)
Jenny Chang-Claude
(J)
Kim De Ruyck
(K)
Liv Veldeman
(L)
Manuel Altabas
(M)
Maria Carmen De Santis
(MC)
Marie-Pierre Farcy-Jacquet
(MP)
Marlon R Veldwijk
(MR)
Matthew R Sydes
(MR)
Matthew Parliament
(M)
Nawaid Usmani
(N)
Neil G Burnet
(NG)
Petra Seibold
(P)
R Paul Symonds
(RP)
Rebecca M Elliott
(RM)
Renée Bultijnck
(R)
Sara Gutiérrez-Enríquez
(S)
Meritxell Mollà
(M)
Sarah L Gulliford
(SL)
Sheryl Green
(S)
Tiziana Rancati
(T)
Victoria Reyes
(V)
Ana Carballo
(A)
Paula Peleteiro
(P)
Paloma Sosa-Fajardo
(P)
Chris Parker
(C)
Valérie Fonteyne
(V)
Kerstie Johnson
(K)
Maarten Lambrecht
(M)
Ben Vanneste
(B)
Riccardo Valdagni
(R)
Alexandra Giraldo
(A)
Mónica Ramos
(M)
Brenda Diergaarde
(B)
Geoffrey Liu
(G)
Suzanne M Leal
(SM)
Melvin L K Chua
(MLK)
Miranda Pring
(M)
Jens Overgaard
(J)
Luis M Cascallar-Caneda
(LM)
Fréderic Duprez
(F)
Christopher J Talbot
(CJ)
Gillian C Barnett
(GC)
Alison M Dunning
(AM)
Ana Vega
(A)
Christian Nicolaj Andreassen
(CN)
Johannes A Langendijk
(JA)
Catharine M L West
(CML)
Behrooz Z Alizadeh
(BZ)
Sarah L Kerns
(SL)
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press.
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