Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.
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:
01 02 2020
01 02 2020
Historique:
received:
30
11
2018
revised:
20
03
2019
accepted:
29
04
2019
pubmed:
17
5
2019
medline:
17
5
2019
entrez:
17
5
2019
Statut:
ppublish
Résumé
A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
Sections du résumé
BACKGROUND
A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies.
METHODS
We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.
RESULTS
Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.
CONCLUSIONS
This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
Identifiants
pubmed: 31095341
pii: 5490201
doi: 10.1093/jnci/djz075
pmc: PMC7019089
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
179-190Subventions
Organisme : NCI NIH HHS
ID : K07 CA187546
Pays : United States
Organisme : Cancer Research UK
ID : C5047/A7357
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C16913/A6135
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1094/A18504
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5047/A10692
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C147/A25254
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM114434
Pays : United States
Organisme : Cancer Research UK
ID : 12518
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12023/28
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 7253
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A16563
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : U01 CA188392
Pays : United States
Organisme : Cancer Research UK
ID : C5047/A3354
Pays : United Kingdom
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201500043C
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148537
Pays : United States
Organisme : Cancer Research UK
ID : C8197/A16565
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press.
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