Abstract
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 (STAT acute) 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: From393 suggestive SNPs identified in discovery set; 37 were nominally significant (p replication<0.05) in replication set, but none reached genome-wide significance (p combined<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 STAT acute (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% (STAT acute). Positive genetic correlation was rg=0.65 (p=0.048) between dysphagia and STAT acute. PRS s explained limited variation of dysphagia (3%), mucositis (2.5%), and STAT acute (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.
| Original language | English |
|---|---|
| Pages (from-to) | 138-148 |
| Number of pages | 11 |
| Journal | Radiotherapy and Oncology |
| Volume | 176 |
| Early online date | 30 Sept 2022 |
| DOIs | |
| Publication status | Published - 1 Nov 2022 |
Bibliographical note
Funding Information:EN was supported by a scholarship for a Ph.D. from the University of Groningen, Groningen, the Netherlands. TD is funded as an Academic Clinical Fellow by the National Institute for Health Research, UK. DJT is supported by a grant from The Taylor Family Foundation and Cancer Research UK [ C19941/A30286 ]. MLKC is supported by the National Medical Research Council Singapore Clinician Scientist Award ( NMRC/CSA-INV/0027/2018 ), National Research Foundation Proton Competitive Research Program ( NRF-CRP17-2017-05 ), Ministry of Education Tier 3 Academic Research Fund ( MOE2016-T3-1-004 ), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, and the Kua Hong Pak Head and Neck Cancer Research Programme. GCB is supported by Cancer research UK RadNet Cambridge [ C17918/A28870 ]. RADIOGEN research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds ( INT20/00071 , INT15/00070 , INT17/00133 , INT16/00154 ; PI19/01424 ; PI16/00046 ; PI13/02030 ; PI10/00164 ); by AECC grant PRYES211091VEGA and through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B).
Funding Information:
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 National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) 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. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). This study was done using HNC cohorts involved in radiogenomics consortium. Data are available from the corresponding author (Elnaz Naderi) on request. Summary statistics for GWAS results will be made available to download from the GWAS Catalog. EN was supported by a scholarship for a Ph.D. from the University of Groningen, Groningen, the Netherlands. TD is funded as an Academic Clinical Fellow by the National Institute for Health Research, UK. DJT is supported by a grant from The Taylor Family Foundation and Cancer Research UK [C19941/A30286]. MLKC is supported by the National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSA-INV/0027/2018), National Research Foundation Proton Competitive Research Program (NRF-CRP17-2017-05), Ministry of Education Tier 3 Academic Research Fund (MOE2016-T3-1-004), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, and the Kua Hong Pak Head and Neck Cancer Research Programme. GCB is supported by Cancer research UK RadNet Cambridge [C17918/A28870]. RADIOGEN research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT20/00071, INT15/00070, INT17/00133, INT16/00154; PI19/01424; PI16/00046; PI13/02030; PI10/00164); by AECC grant PRYES211091VEGA and through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B). The authors declare no conflicts of interest. No one was paid to write this article by a pharmaceutical company or agency.
Funding Information:
This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) 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. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169).
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