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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.

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Forest plots of significant SNPs. SNPs with meta-p-value < 5 × 10− 8 associated with: (a) urinary frequency (rs17599026); (b) decreased urine stream (rs7720298); and (c) overall toxicity (rs11230328). p-Values are from meta-analysis of regression coefficients and standard errors from regression analysis performed in each study. Odds ratios (OR; urinary frequency and decreased urine stream) or regression beta coefficient (STAT score) are shown for each individual study as well as the meta-analysis (Summary). The size of the box marking each odds ratio or beta is proportional to the precision of estimate for the given study. Lines on the boxes denote 95% confidence intervals. ‘Toxicity’ and ‘No toxicity’ (rs17599026 and rs7720298) was defined as ≥ 1 point increase in toxicity grade versus no change in toxicity grade from pre-radiotherapy scores. Overall toxicity was analyzed as a continuous variable (STAT).
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f0005: Forest plots of significant SNPs. SNPs with meta-p-value < 5 × 10− 8 associated with: (a) urinary frequency (rs17599026); (b) decreased urine stream (rs7720298); and (c) overall toxicity (rs11230328). p-Values are from meta-analysis of regression coefficients and standard errors from regression analysis performed in each study. Odds ratios (OR; urinary frequency and decreased urine stream) or regression beta coefficient (STAT score) are shown for each individual study as well as the meta-analysis (Summary). The size of the box marking each odds ratio or beta is proportional to the precision of estimate for the given study. Lines on the boxes denote 95% confidence intervals. ‘Toxicity’ and ‘No toxicity’ (rs17599026 and rs7720298) was defined as ≥ 1 point increase in toxicity grade versus no change in toxicity grade from pre-radiotherapy scores. Overall toxicity was analyzed as a continuous variable (STAT).

Mentions: Meta-analysis Q-Q plots (Fig. S1) show no genomic inflation, suggesting that population structure was adequately controlled using principal components analysis to exclude outliers with non-European ancestry. The most statistically significant SNPs associated with late toxicity are listed in Table 5, Table 6, Table 7, Table 8, which show several SNPs had meta-p-values reaching or approaching significance (p-value ≤ 5 × 10− 6) with concordant effect direction across the individual studies. Three SNPs reached genome-wide significance: rs17599026 on 5q31.2 with urinary frequency (3.12, 95% CI 2.08–4.69, p-value 4.16 × 10− 8); rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8); and rs11230328 on 11q12.2 with STAT score (Beta 0.31, 95% CI 0.21–0.41, p-value = 6.27 × 10− 10). rs17599026 was directly genotyped in the GenePARE and CCI studies and imputed in the RADIOGEN (information score = 0.90) and RAPPER (information score = 0.87) studies. rs7720298 was imputed in all four studies (RADIOGEN information score = 0.91, RAPPER information score = 0.93, GenePARE information score = 0.94, and CCI information score = 0.95) and rs11230328 was imputed in all four studies (RADIOGEN information score = 0.68, RAPPER information score = 0.61, GenePARE information score = 0.88, and CCI information score = 0.97). To provide a more interpretable effect size for rs11230328, STAT score was dichotomized at the mean and analyzed using logistic regression, which resulted in an OR of 1.59 (95% CI 1.25–2.02). There were no genome-wide significant SNPs associated with rectal bleeding, and though several approached significance, these require investigation in future larger studies. Fig. 1 shows forest plots for the SNPs that reached the genome-wide significance threshold.


Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer
Forest plots of significant SNPs. SNPs with meta-p-value < 5 × 10− 8 associated with: (a) urinary frequency (rs17599026); (b) decreased urine stream (rs7720298); and (c) overall toxicity (rs11230328). p-Values are from meta-analysis of regression coefficients and standard errors from regression analysis performed in each study. Odds ratios (OR; urinary frequency and decreased urine stream) or regression beta coefficient (STAT score) are shown for each individual study as well as the meta-analysis (Summary). The size of the box marking each odds ratio or beta is proportional to the precision of estimate for the given study. Lines on the boxes denote 95% confidence intervals. ‘Toxicity’ and ‘No toxicity’ (rs17599026 and rs7720298) was defined as ≥ 1 point increase in toxicity grade versus no change in toxicity grade from pre-radiotherapy scores. Overall toxicity was analyzed as a continuous variable (STAT).
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f0005: Forest plots of significant SNPs. SNPs with meta-p-value < 5 × 10− 8 associated with: (a) urinary frequency (rs17599026); (b) decreased urine stream (rs7720298); and (c) overall toxicity (rs11230328). p-Values are from meta-analysis of regression coefficients and standard errors from regression analysis performed in each study. Odds ratios (OR; urinary frequency and decreased urine stream) or regression beta coefficient (STAT score) are shown for each individual study as well as the meta-analysis (Summary). The size of the box marking each odds ratio or beta is proportional to the precision of estimate for the given study. Lines on the boxes denote 95% confidence intervals. ‘Toxicity’ and ‘No toxicity’ (rs17599026 and rs7720298) was defined as ≥ 1 point increase in toxicity grade versus no change in toxicity grade from pre-radiotherapy scores. Overall toxicity was analyzed as a continuous variable (STAT).
Mentions: Meta-analysis Q-Q plots (Fig. S1) show no genomic inflation, suggesting that population structure was adequately controlled using principal components analysis to exclude outliers with non-European ancestry. The most statistically significant SNPs associated with late toxicity are listed in Table 5, Table 6, Table 7, Table 8, which show several SNPs had meta-p-values reaching or approaching significance (p-value ≤ 5 × 10− 6) with concordant effect direction across the individual studies. Three SNPs reached genome-wide significance: rs17599026 on 5q31.2 with urinary frequency (3.12, 95% CI 2.08–4.69, p-value 4.16 × 10− 8); rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8); and rs11230328 on 11q12.2 with STAT score (Beta 0.31, 95% CI 0.21–0.41, p-value = 6.27 × 10− 10). rs17599026 was directly genotyped in the GenePARE and CCI studies and imputed in the RADIOGEN (information score = 0.90) and RAPPER (information score = 0.87) studies. rs7720298 was imputed in all four studies (RADIOGEN information score = 0.91, RAPPER information score = 0.93, GenePARE information score = 0.94, and CCI information score = 0.95) and rs11230328 was imputed in all four studies (RADIOGEN information score = 0.68, RAPPER information score = 0.61, GenePARE information score = 0.88, and CCI information score = 0.97). To provide a more interpretable effect size for rs11230328, STAT score was dichotomized at the mean and analyzed using logistic regression, which resulted in an OR of 1.59 (95% CI 1.25–2.02). There were no genome-wide significant SNPs associated with rectal bleeding, and though several approached significance, these require investigation in future larger studies. Fig. 1 shows forest plots for the SNPs that reached the genome-wide significance threshold.

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&ndash;4.69, p-value 4.16&nbsp;&times;&nbsp;10&minus;&nbsp;8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90&ndash;3.86, p-value&nbsp;=&nbsp;3.21&nbsp;&times;&nbsp;10&minus;&nbsp;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