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Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

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, et al.
(2023) JNCI CANCER SPECTRUM. 7(6).
Author
Organization
Abstract
Background 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 (SNV—formerly SNP)–based 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 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), 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 × 10‒6, 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 meta–genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.
Keywords
Cancer Research, Oncology

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Citation

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MLA
Naderi, Elnaz, et al. “Large-Scale Meta–Genome-Wide Association Study Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancer Types.” JNCI CANCER SPECTRUM, vol. 7, no. 6, Oxford University Press (OUP), 2023, doi:10.1093/jncics/pkad088.
APA
Naderi, E., Aguado-Barrera, M. E., Schack, L. M. H., Dorling, L., Rattay, T., Fachal, L., … Radiogenomics Consortium, [missing]. (2023). Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types. JNCI CANCER SPECTRUM, 7(6). https://doi.org/10.1093/jncics/pkad088
Chicago author-date
Naderi, Elnaz, Miguel E Aguado-Barrera, Line M H Schack, Leila Dorling, Tim Rattay, Laura Fachal, Holly Summersgill, et al. 2023. “Large-Scale Meta–Genome-Wide Association Study Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancer Types.” JNCI CANCER SPECTRUM 7 (6). https://doi.org/10.1093/jncics/pkad088.
Chicago author-date (all authors)
Naderi, Elnaz, 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, Rebecca M Elliott, Renée Bultijnck, Sara Gutiérrez-Enríquez, Meritxell Mollà, Sarah L Gulliford, Sheryl Green, Tiziana Rancati, Victoria Reyes, Ana Carballo, Paula Peleteiro, Paloma Sosa-Fajardo, Chris Parker, Valerie Fonteyne, Kerstie Johnson, Maarten Lambrecht, Ben Vanneste, Riccardo Valdagni, Alexandra Giraldo, Mónica Ramos, Brenda Diergaarde, Geoffrey Liu, Suzanne M Leal, Melvin L K Chua, Miranda Pring, Jens Overgaard, Luis M Cascallar-Caneda, Fréderic Duprez, Christopher J Talbot, Gillian C Barnett, Alison M Dunning, Ana Vega, Christian Nicolaj Andreassen, Johannes A Langendijk, Catharine M L West, Behrooz Z Alizadeh, Sarah L Kerns, and [missing] Radiogenomics Consortium. 2023. “Large-Scale Meta–Genome-Wide Association Study Reveals Common Genetic Factors Linked to Radiation-Induced Acute Toxicities across Cancer Types.” JNCI CANCER SPECTRUM 7 (6). doi:10.1093/jncics/pkad088.
Vancouver
1.
Naderi E, Aguado-Barrera ME, Schack LMH, Dorling L, Rattay T, Fachal L, et al. Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types. JNCI CANCER SPECTRUM. 2023;7(6).
IEEE
[1]
E. Naderi et al., “Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types,” JNCI CANCER SPECTRUM, vol. 7, no. 6, 2023.
@article{01HGD978FSVB0BEKZ1MBN4XYXK,
  abstract     = {{Background
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 (SNV—formerly SNP)–based 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 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), 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 × 10‒6, 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 meta–genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.}},
  articleno    = {{pkad088}},
  author       = {{Naderi, Elnaz and Aguado-Barrera, Miguel E and Schack, Line M H and Dorling, Leila and Rattay, Tim and Fachal, Laura and Summersgill, Holly and Martínez-Calvo, Laura and Welsh, Ceilidh and Dudding, Tom and Odding, Yasmin and Varela-Pazos, Ana and Jena, Rajesh and Thomson, David J and Steenbakkers, Roel J H M and Dennis, Joe and Lobato-Busto, Ramón and Alsner, Jan and Ness, Andy and Nutting, Chris and Gómez-Caamaño, Antonio and Eriksen, Jesper G and Thomas, Steve J and Bates, Amy M and Webb, Adam J and Choudhury, Ananya and Rosenstein, Barry S and Taboada-Valladares, Begona and Herskind, Carsten and Azria, David and Dearnaley, David P and de Ruysscher, Dirk and Sperk, Elena and Hall, Emma and Stobart, Hilary and Chang-Claude, Jenny and De Ruyck, Kim and Veldeman, Liv and Altabas, Manuel and De Santis, Maria Carmen and Farcy-Jacquet, Marie-Pierre and Veldwijk, Marlon R and Sydes, Matthew R and Parliament, Matthew and Usmani, Nawaid and Burnet, Neil G and Seibold, Petra and Symonds, R Paul and Elliott, Rebecca M and Bultijnck, Renée and Gutiérrez-Enríquez, Sara and Mollà, Meritxell and Gulliford, Sarah L and Green, Sheryl and Rancati, Tiziana and Reyes, Victoria and Carballo, Ana and Peleteiro, Paula and Sosa-Fajardo, Paloma and Parker, Chris and Fonteyne, Valerie and Johnson, Kerstie and Lambrecht, Maarten and Vanneste, Ben and Valdagni, Riccardo and Giraldo, Alexandra and Ramos, Mónica and Diergaarde, Brenda and Liu, Geoffrey and Leal, Suzanne M and Chua, Melvin L K and Pring, Miranda and Overgaard, Jens and Cascallar-Caneda, Luis M and Duprez, Fréderic and Talbot, Christopher J and Barnett, Gillian C and Dunning, Alison M and Vega, Ana and Andreassen, Christian Nicolaj and Langendijk, Johannes A and West, Catharine M L and Alizadeh, Behrooz Z and Kerns, Sarah L and Radiogenomics Consortium, [missing]}},
  issn         = {{2515-5091}},
  journal      = {{JNCI CANCER SPECTRUM}},
  keywords     = {{Cancer Research,Oncology}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{11}},
  publisher    = {{Oxford University Press (OUP)}},
  title        = {{Large-scale meta–genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types}},
  url          = {{http://doi.org/10.1093/jncics/pkad088}},
  volume       = {{7}},
  year         = {{2023}},
}
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