Radiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer RadiotherapyCitation formats

Standard

Radiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer Radiotherapy. / Radiogenomics Consortium; Elliott, Rebecca; Burnet, Neil; West, Catharine; et al.

In: Journal National Cancer Institute, Vol. 112, No. 2, 16.05.2019, p. 179–190.

Research output: Contribution to journalArticlepeer-review

Harvard

Radiogenomics Consortium, Elliott, R, Burnet, N, West, C & et al. 2019, 'Radiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer Radiotherapy', Journal National Cancer Institute, vol. 112, no. 2, pp. 179–190. https://doi.org/10.1093/jnci/djz075

APA

Vancouver

Author

Radiogenomics Consortium ; Elliott, Rebecca ; Burnet, Neil ; West, Catharine ; et al. / Radiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer Radiotherapy. In: Journal National Cancer Institute. 2019 ; Vol. 112, No. 2. pp. 179–190.

Bibtex

@article{1ea65e16fc9e4a7490d42d87e6c0f14b,
title = "Radiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer Radiotherapy",
abstract = "BACKGROUND: 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 = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ∼6 million genotyped/imputed variants (time to first ≥grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 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 (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). 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 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 multi-national radiogenomics studies in larger cohorts are worthwhile.",
author = "{Radiogenomics Consortium} and Rebecca Elliott and Neil Burnet and Catharine West and {et al.}",
note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press.",
year = "2019",
month = may,
day = "16",
doi = "10.1093/jnci/djz075",
language = "English",
volume = "112",
pages = "179–190",
journal = "National Cancer Institute. Journal ",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "2",

}

RIS

TY - JOUR

T1 - Radiogenomics Consortium Genome-Wide Association Study Meta-analysis of Late Toxicity after Prostate Cancer Radiotherapy

AU - Radiogenomics Consortium

AU - Elliott, Rebecca

AU - Burnet, Neil

AU - West, Catharine

AU - et al.,

N1 - © The Author(s) 2019. Published by Oxford University Press.

PY - 2019/5/16

Y1 - 2019/5/16

N2 - BACKGROUND: 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 = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ∼6 million genotyped/imputed variants (time to first ≥grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 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 (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). 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 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 multi-national radiogenomics studies in larger cohorts are worthwhile.

AB - BACKGROUND: 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 = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ∼6 million genotyped/imputed variants (time to first ≥grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 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 (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). 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 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 multi-national radiogenomics studies in larger cohorts are worthwhile.

U2 - 10.1093/jnci/djz075

DO - 10.1093/jnci/djz075

M3 - Article

C2 - 31095341

VL - 112

SP - 179

EP - 190

JO - National Cancer Institute. Journal

JF - National Cancer Institute. Journal

SN - 0027-8874

IS - 2

ER -