TY - JOUR
T1 - Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer
AU - Naderi, Elnaz
AU - Schack, Line M.H.
AU - Welsh, Ceilidh
AU - Sim, Adelene Y.L.
AU - Aguado-Barrera, Miguel E.
AU - Dudding, Tom
AU - Summersgil, Holly
AU - Martínez-Calvo, Laura
AU - Ong, Enya H.W.
AU - Odding, Yasmin
AU - Varela-Pazos, Ana
AU - Steenbakkers, Roel J.H.M.
AU - Crijns, Anne P.G.
AU - Jena, Rajesh
AU - Pring, Miranda
AU - Dennis, Joe
AU - Lobato-Busto, Ramón
AU - Alsner, Jan
AU - Ness, Andy
AU - Nutting, Christopher
AU - Thomson, David J.
AU - Gómez-Caamaño, Antonio
AU - Eriksen, Jesper G.
AU - Thomas, Steve J.
AU - Bates, Amy M.
AU - Overgaard, Jens
AU - Cascallar-Caneda, Luis M.
AU - Duprez, Fréderic
AU - Barnett, Gillian C.
AU - Dorling, Leila
AU - Chua, Melvin L.K.
AU - Vega, Ana
AU - West, Catharine M.L.
AU - Langendijk, Johannes A.
AU - Nicolaj Andreassen, Christian
AU - Alizadeh, Behrooz Z.
AU - On the behalf of the Radiogenomics Consortium
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022/11
Y1 - 2022/11
N2 - 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 × 10-8). In-silico functional analyses identified “3′-5'-exoribonuclease activity” (FDR = 1.6e-10) for dysphagia, “inositol phosphate-mediated signalling” for mucositis (FDR = 2.20e-09), and “drug catabolic process” 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.
AB - 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 × 10-8). In-silico functional analyses identified “3′-5'-exoribonuclease activity” (FDR = 1.6e-10) for dysphagia, “inositol phosphate-mediated signalling” for mucositis (FDR = 2.20e-09), and “drug catabolic process” 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.
KW - Head and neck cancer
KW - Meta-GWAS
KW - Polygenic risk score
KW - Radiation-induced acute toxicity
KW - SNP-based heritability
U2 - 10.1016/j.radonc.2022.09.016
DO - 10.1016/j.radonc.2022.09.016
M3 - Journal article
C2 - 36191651
AN - SCOPUS:85140271946
SN - 0167-8140
VL - 176
SP - 138
EP - 148
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
ER -