16 research outputs found
Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer
Background and purpose: We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC). Materials and methods: We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNP-based heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS. Results: From 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 Ă 10-8). In-silico functional analyses identified â3âČ-5'-exoribonuclease activityâ (FDR = 1.6e-10) for dysphagia, âinositol phosphate-mediated signallingâ for mucositis (FDR = 2.20e-09), and âdrug catabolic processâ for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (±standard error) was 29 ± 0.08 % for dysphagia, 9 ± 0.12 % (mucositis) and 27 ± 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %). Conclusion: In HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be replicated in larger studies
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
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Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types
Recommended from our members
Large-scale metaâgenome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types
Acknowledgements: The study sponsors were not involved in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. We thank all patients who participated in the study and the participating clinic staff for their contribution to data collection. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding, and the NIHR Senior Investigator award to Professor Andy Ness. Genotyping was funded by World Cancer Research Fund Pilot Grant (grant No. 2018/1792), Above and Beyond, Wellcome Trust Research Training Fellowship (201237/Z/16/Z), and Cancer Research UK Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant No. C18281/A19169). The VHIO authors acknowledge the Cellex Foundation for providing research equipment and facilities and thank CERCA Program/Generalitat de Catalunya for institutional support.Funder: National Institute for Health Research; DOI: https://doi.org/10.13039/501100000272Funder: The Taylor Family FoundationFunder: Cancer Research UK; DOI: https://doi.org/10.13039/501100000289Funder: National Medical Research Council; DOI: https://doi.org/10.13039/501100001349Background: 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: 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 (SNVâformerly SNP)âbased heritability of rSTATacute in all patients and for each cancer type. 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 Ă 10â8 < P < 1.0 Ă 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 Ă 10â7), 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 âRNA splicing via endonucleolytic cleavage and ligationâ (P = 5.1 Ă 10â6, 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: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future metaâgenome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types