Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

On the behalf of the Radiogenomics Consortium; Elnaz Naderi; Miguel E Aguado-Barrera; Line M H Schack; Leila Dorling; Tim Rattay; Laura Fachal; Holly Summersgill; Laura Martínez-Calvo; Ceilidh Welsh; Tom Dudding; Yasmin Odding; Ana Varela-Pazos; Rajesh Jena; David J Thomson; Roel J H M Steenbakkers; Joe Dennis; Ramón Lobato-Busto; Jan Alsner; Andy Ness; Chris Nutting; Antonio Gómez-Caamaño; Jesper G Eriksen; Steve J Thomas; Amy M Bates; Adam J Webb; Ananya Choudhury; Barry S Rosenstein; Begona Taboada-Valladares; Carsten Herskind; David Azria; David P Dearnaley; Dirk de Ruysscher; Elena Sperk; Emma Hall; Hilary Stobart; Jenny Chang-Claude; Kim De Ruyck; Liv Veldeman; Manuel Altabas; Maria Carmen De Santis; Marie-Pierre Farcy-Jacquet; Marlon R Veldwijk; Matthew R Sydes; Matthew Parliament; Nawaid Usmani; Neil G Burnet; Petra Seibold; R Paul Symonds; Johannes A Langendijk; Behrooz Z Alizadeh

doi:10.1093/jncics/pkad088

Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

On the behalf of the Radiogenomics Consortium, Elnaz Naderi, Miguel E Aguado-Barrera, Line M H Schack, Leila Dorling, Tim Rattay, Laura Fachal, Holly Summersgill, Laura Martínez-Calvo, Ceilidh Welsh, Tom Dudding, Yasmin Odding, Ana Varela-Pazos, Rajesh Jena, David J Thomson, Roel J H M Steenbakkers, Joe Dennis, Ramón Lobato-Busto, Jan Alsner, Andy NessChris Nutting, Antonio Gómez-Caamaño, Jesper G Eriksen, Steve J Thomas, Amy M Bates, Adam J Webb, Ananya Choudhury, Barry S Rosenstein, Begona Taboada-Valladares, Carsten Herskind, David Azria, David P Dearnaley, Dirk de Ruysscher, Elena Sperk, Emma Hall, Hilary Stobart, Jenny Chang-Claude, Kim De Ruyck, Liv Veldeman, Manuel Altabas, Maria Carmen De Santis, Marie-Pierre Farcy-Jacquet, Marlon R Veldwijk, Matthew R Sydes, Matthew Parliament, Nawaid Usmani, Neil G Burnet, Petra Seibold, R Paul Symonds, Johannes A Langendijk, Behrooz Z Alizadeh

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BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).

METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.

RESULTS: Shared SNP-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 SNPs with rSTATacute (5.0x10-8<P-value<1.0x10-5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size -0.17; P-value=1.7x10-7), 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 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 x10-6, Pcorrected =0.079) as the top gene set associated with rSTATacute among all patients. In-silico gene expression analysis showed the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed Pcorrected=0.004; sun exposed Pcorrected=0.026).

CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

Originele taal-2	English
Artikelnummer	pkad088
Aantal pagina's	11
Tijdschrift	JNCI cancer spectrum
Volume	7
Nummer van het tijdschrift	6
Vroegere onlinedatum	20-okt.-2023
DOI's	https://doi.org/10.1093/jncics/pkad088
Status	Published - dec.-2023

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10.1093/jncics/pkad088Licentie: CC BY-NC

Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types Final publisher's version, 1,19 MBLicentie: CC BY-NC

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On the behalf of the Radiogenomics Consortium, Naderi, E., Aguado-Barrera, M. E., Schack, L. M. H., Dorling, L., Rattay, T., Fachal, L., Summersgill, H., Martínez-Calvo, L., Welsh, C., Dudding, T., Odding, Y., Varela-Pazos, A., Jena, R., Thomson, D. J., Steenbakkers, R. J. H. M., Dennis, J., Lobato-Busto, R., Alsner, J., ... Alizadeh, B. Z. (2023). Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers. JNCI cancer spectrum, 7(6), Artikel pkad088. https://doi.org/10.1093/jncics/pkad088

@article{17d65d70ac9b4bf9bccad6c1e48b74ad,

title = "Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers",

abstract = "BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-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 SNPs with rSTATacute (5.0x10-8CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.",

author = "{On the behalf of the Radiogenomics Consortium} and Elnaz Naderi and Aguado-Barrera, {Miguel E} and Schack, {Line M H} and Leila Dorling and Tim Rattay and Laura Fachal and Holly Summersgill and Laura Mart{\'i}nez-Calvo and Ceilidh Welsh and Tom Dudding and Yasmin Odding and Ana Varela-Pazos and Rajesh Jena and Thomson, {David J} and Steenbakkers, {Roel J H M} and Joe Dennis and Ram{\'o}n Lobato-Busto and Jan Alsner and Andy Ness and Chris Nutting and Antonio G{\'o}mez-Caama{\~n}o and Eriksen, {Jesper G} and Thomas, {Steve J} and Bates, {Amy M} and Webb, {Adam J} and Ananya Choudhury and Rosenstein, {Barry S} and Begona Taboada-Valladares and Carsten Herskind and David Azria and Dearnaley, {David P} and {de Ruysscher}, Dirk and Elena Sperk and Emma Hall and Hilary Stobart and Jenny Chang-Claude and {De Ruyck}, Kim and Liv Veldeman and Manuel Altabas and {De Santis}, {Maria Carmen} and Marie-Pierre Farcy-Jacquet and Veldwijk, {Marlon R} and Sydes, {Matthew R} and Matthew Parliament and Nawaid Usmani and Burnet, {Neil G} and Petra Seibold and Symonds, {R Paul} and Langendijk, {Johannes A} and Alizadeh, {Behrooz Z}",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press.",

year = "2023",

month = dec,

doi = "10.1093/jncics/pkad088",

language = "English",

volume = "7",

journal = "JNCI cancer spectrum",

issn = "2515-5091",

publisher = "Oxford University Press",

number = "6",

}

On the behalf of the Radiogenomics Consortium, Naderi, E, Aguado-Barrera, ME, Schack, LMH, Dorling, L, Rattay, T, Fachal, L, Summersgill, H, Martínez-Calvo, L, Welsh, C, Dudding, T, Odding, Y, Varela-Pazos, A, Jena, R, Thomson, DJ, Steenbakkers, RJHM, Dennis, J, Lobato-Busto, R, Alsner, J, Ness, A, Nutting, C, Gómez-Caamaño, A, Eriksen, JG, Thomas, SJ, Bates, AM, Webb, AJ, Choudhury, A, Rosenstein, BS, Taboada-Valladares, B, Herskind, C, Azria, D, Dearnaley, DP, de Ruysscher, D, Sperk, E, Hall, E, Stobart, H, Chang-Claude, J, De Ruyck, K, Veldeman, L, Altabas, M, De Santis, MC, Farcy-Jacquet, M-P, Veldwijk, MR, Sydes, MR, Parliament, M, Usmani, N, Burnet, NG, Seibold, P, Symonds, RP, Langendijk, JA & Alizadeh, BZ 2023, 'Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers', JNCI cancer spectrum, vol. 7, nr. 6, pkad088. https://doi.org/10.1093/jncics/pkad088

TY - JOUR

T1 - Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

AU - On the behalf of the Radiogenomics Consortium

AU - Naderi, Elnaz

AU - Aguado-Barrera, Miguel E

AU - Schack, Line M H

AU - Dorling, Leila

AU - Rattay, Tim

AU - Fachal, Laura

AU - Summersgill, Holly

AU - Martínez-Calvo, Laura

AU - Welsh, Ceilidh

AU - Dudding, Tom

AU - Odding, Yasmin

AU - Varela-Pazos, Ana

AU - Jena, Rajesh

AU - Thomson, David J

AU - Steenbakkers, Roel J H M

AU - Dennis, Joe

AU - Lobato-Busto, Ramón

AU - Alsner, Jan

AU - Ness, Andy

AU - Nutting, Chris

AU - Gómez-Caamaño, Antonio

AU - Eriksen, Jesper G

AU - Thomas, Steve J

AU - Bates, Amy M

AU - Webb, Adam J

AU - Choudhury, Ananya

AU - Rosenstein, Barry S

AU - Taboada-Valladares, Begona

AU - Herskind, Carsten

AU - Azria, David

AU - Dearnaley, David P

AU - de Ruysscher, Dirk

AU - Sperk, Elena

AU - Hall, Emma

AU - Stobart, Hilary

AU - Chang-Claude, Jenny

AU - De Ruyck, Kim

AU - Veldeman, Liv

AU - Altabas, Manuel

AU - De Santis, Maria Carmen

AU - Farcy-Jacquet, Marie-Pierre

AU - Veldwijk, Marlon R

AU - Sydes, Matthew R

AU - Parliament, Matthew

AU - Usmani, Nawaid

AU - Burnet, Neil G

AU - Seibold, Petra

AU - Symonds, R Paul

AU - Langendijk, Johannes A

AU - Alizadeh, Behrooz Z

PY - 2023/12

Y1 - 2023/12

N2 - BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-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 SNPs with rSTATacute (5.0x10-8CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

AB - BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity (RIT) across four cancer types (prostate, head and neck, breast, and lung).METHODS: A GWAS meta-analysis was performed using 19 cohorts including 12,042 patients. Acute standardized total average toxicity (rSTATacute) was modelled using a generalized linear regression model for additive effect of genetic variants adjusted for demographic and clinical covariates. LD score regression estimated shared SNP-based heritability of rSTATacute in all patients and for each cancer type.RESULTS: Shared SNP-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 SNPs with rSTATacute (5.0x10-8CONCLUSIONS: There is shared SNP-based heritability for acute RIT across and within individual cancer sites. Future meta-GWAS among large radiotherapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

U2 - 10.1093/jncics/pkad088

DO - 10.1093/jncics/pkad088

M3 - Article

C2 - 37862240

SN - 2515-5091

VL - 7

JO - JNCI cancer spectrum

JF - JNCI cancer spectrum

IS - 6

M1 - pkad088

ER -

Large-Scale Meta-GWAS Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancers

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