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Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer

View Article: PubMed Central - PubMed

ABSTRACT

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10− 8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.

No MeSH data available.


Related in: MedlinePlus

Regional plots for two loci. Loci tagged by rs17599026 (a) and rs7720298 (b) with points representing the tag SNP reported in this paper shown in purple circles. Points representing nearby SNPs are color coded according to linkage disequilibrium r2 value as indicated in the legends. The recombination rate is estimated from samples from the International HapMap project.
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f0010: Regional plots for two loci. Loci tagged by rs17599026 (a) and rs7720298 (b) with points representing the tag SNP reported in this paper shown in purple circles. Points representing nearby SNPs are color coded according to linkage disequilibrium r2 value as indicated in the legends. The recombination rate is estimated from samples from the International HapMap project.

Mentions: Regions of linkage disequilibrium (LD) were defined for the three loci tagged by SNPs reaching genome-wide significance. rs17599026, associated with urinary frequency, tags a 106 kb region of LD (base position 137,657,783–137,763,798; Fig. 2A) containing part of KDM3B (including the promoter region through exon 20), the upstream FAM53C, and part of the upstream CDC25C (the promoter region through exon 6). rs7720298, associated with decreased urine stream, tags a 39 kb region of LD (base position 13,858,328–13,897,362; Fig. 2B) that contains exons 16 through 30 of DNAH5. rs11230328 was not in strong linkage disequilibrium with any other common SNPs found in the more recent release of the 1000 Genomes population data, and this locus may represent a spurious association. rs11230328 lies within a LINE element, and may be difficult to map in the genome due to its location within a region of high homology. Imputation coverage (i.e. the number of SNPs successfully imputed in the study datasets out of common SNPs (MAF ≥ 0.05) within the 1000 Genomes European population) was high within the regions tagged (correlation r2 ≥ 0.5) by rs17599026 (173/183, 94.5%) and rs7720298 (130/136, 95.6%).


Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer
Regional plots for two loci. Loci tagged by rs17599026 (a) and rs7720298 (b) with points representing the tag SNP reported in this paper shown in purple circles. Points representing nearby SNPs are color coded according to linkage disequilibrium r2 value as indicated in the legends. The recombination rate is estimated from samples from the International HapMap project.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036513&req=5

f0010: Regional plots for two loci. Loci tagged by rs17599026 (a) and rs7720298 (b) with points representing the tag SNP reported in this paper shown in purple circles. Points representing nearby SNPs are color coded according to linkage disequilibrium r2 value as indicated in the legends. The recombination rate is estimated from samples from the International HapMap project.
Mentions: Regions of linkage disequilibrium (LD) were defined for the three loci tagged by SNPs reaching genome-wide significance. rs17599026, associated with urinary frequency, tags a 106 kb region of LD (base position 137,657,783–137,763,798; Fig. 2A) containing part of KDM3B (including the promoter region through exon 20), the upstream FAM53C, and part of the upstream CDC25C (the promoter region through exon 6). rs7720298, associated with decreased urine stream, tags a 39 kb region of LD (base position 13,858,328–13,897,362; Fig. 2B) that contains exons 16 through 30 of DNAH5. rs11230328 was not in strong linkage disequilibrium with any other common SNPs found in the more recent release of the 1000 Genomes population data, and this locus may represent a spurious association. rs11230328 lies within a LINE element, and may be difficult to map in the genome due to its location within a region of high homology. Imputation coverage (i.e. the number of SNPs successfully imputed in the study datasets out of common SNPs (MAF ≥ 0.05) within the 1000 Genomes European population) was high within the regions tagged (correlation r2 ≥ 0.5) by rs17599026 (173/183, 94.5%) and rs7720298 (130/136, 95.6%).

View Article: PubMed Central - PubMed

ABSTRACT

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10− 8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.

No MeSH data available.


Related in: MedlinePlus