A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer
Abstract Background Most head and neck cancer (HNC) patients receive radiotherapy (RT) and develop toxicities. This genome-wide association study (GWAS) was designed to identify single nucleotide polymorphisms (SNPs) associated with common acute radiation-induced toxicities (RITs) in an HNC cohort....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-11-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-021-03145-1 |
| _version_ | 1818857950428528640 |
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| author | Elnaz Naderi Anne Petra Gerarda Crijns Roel Johannes Henricus Marinus Steenbakkers Johanna Geertruida Maria van den Hoek Hendrika Marike Boezen Behrooz Ziad Alizadeh Johannes Albertus Langendijk |
| author_facet | Elnaz Naderi Anne Petra Gerarda Crijns Roel Johannes Henricus Marinus Steenbakkers Johanna Geertruida Maria van den Hoek Hendrika Marike Boezen Behrooz Ziad Alizadeh Johannes Albertus Langendijk |
| author_sort | Elnaz Naderi |
| collection | DOAJ |
| description | Abstract Background Most head and neck cancer (HNC) patients receive radiotherapy (RT) and develop toxicities. This genome-wide association study (GWAS) was designed to identify single nucleotide polymorphisms (SNPs) associated with common acute radiation-induced toxicities (RITs) in an HNC cohort. Methods A two-stage GWAS was performed in 1279 HNC patients treated with RT and prospectively scored for mucositis, xerostomia, sticky saliva, and dysphagia. The area under the curve (AUC) was used to estimate the average load of toxicity during RT. At the discovery study, multivariate linear regression was used in 957 patients, and the top-ranking SNPs were tested in 322 independent replication cohort. Next, the discovery and the replication studies were meta-analyzed. Results A region on 5q21.3 containing 16 SNPs showed genome-wide (GW) significance association at P-value < 5.0 × 10–8 with patient-rated acute xerostomia in the discovery study. The top signal was rs35542 with an adjusted effect size of 0.17*A (95% CI 0.12 to 0.23; P-value < = 3.78 × 10–9). The genome wide significant SNPs were located within three genes (EFNA5, FBXL17, and FER). In-silico functional analysis showed these genes may be involved in DNA damage response and co-expressed in minor salivary glands. We found 428 suggestive SNPs (P-value < 1.0 × 10–5) for other toxicities, taken to the replication study. Eleven of them showed a nominal association (P-value < 0.05). Conclusions This GWAS suggested novel SNPs for patient-rated acute xerostomia in HNC patients. If validated, these SNPs and their related functional pathways could lead to a predictive assay to identify sensitive patients to radiation, which may eventually allow a more individualized RT treatment. |
| first_indexed | 2024-12-19T08:48:32Z |
| format | Article |
| id | doaj.art-d2b527daec7c40419e2912e942d7b6cd |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-19T08:48:32Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-d2b527daec7c40419e2912e942d7b6cd2022-12-21T20:28:46ZengBMCJournal of Translational Medicine1479-58762021-11-0119111010.1186/s12967-021-03145-1A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancerElnaz Naderi0Anne Petra Gerarda Crijns1Roel Johannes Henricus Marinus Steenbakkers2Johanna Geertruida Maria van den Hoek3Hendrika Marike Boezen4Behrooz Ziad Alizadeh5Johannes Albertus Langendijk6Department of Radiation Oncology, University Medical Center GroningenDepartment of Radiation Oncology, University Medical Center GroningenDepartment of Radiation Oncology, University Medical Center GroningenDepartment of Radiation Oncology, University Medical Center GroningenDepartment of Epidemiology, University Medical Center GroningenDepartment of Epidemiology, University Medical Center GroningenDepartment of Radiation Oncology, University Medical Center GroningenAbstract Background Most head and neck cancer (HNC) patients receive radiotherapy (RT) and develop toxicities. This genome-wide association study (GWAS) was designed to identify single nucleotide polymorphisms (SNPs) associated with common acute radiation-induced toxicities (RITs) in an HNC cohort. Methods A two-stage GWAS was performed in 1279 HNC patients treated with RT and prospectively scored for mucositis, xerostomia, sticky saliva, and dysphagia. The area under the curve (AUC) was used to estimate the average load of toxicity during RT. At the discovery study, multivariate linear regression was used in 957 patients, and the top-ranking SNPs were tested in 322 independent replication cohort. Next, the discovery and the replication studies were meta-analyzed. Results A region on 5q21.3 containing 16 SNPs showed genome-wide (GW) significance association at P-value < 5.0 × 10–8 with patient-rated acute xerostomia in the discovery study. The top signal was rs35542 with an adjusted effect size of 0.17*A (95% CI 0.12 to 0.23; P-value < = 3.78 × 10–9). The genome wide significant SNPs were located within three genes (EFNA5, FBXL17, and FER). In-silico functional analysis showed these genes may be involved in DNA damage response and co-expressed in minor salivary glands. We found 428 suggestive SNPs (P-value < 1.0 × 10–5) for other toxicities, taken to the replication study. Eleven of them showed a nominal association (P-value < 0.05). Conclusions This GWAS suggested novel SNPs for patient-rated acute xerostomia in HNC patients. If validated, these SNPs and their related functional pathways could lead to a predictive assay to identify sensitive patients to radiation, which may eventually allow a more individualized RT treatment.https://doi.org/10.1186/s12967-021-03145-1RadiogenomicsGWASRadiation-induced toxicityHead and neck cancer |
| spellingShingle | Elnaz Naderi Anne Petra Gerarda Crijns Roel Johannes Henricus Marinus Steenbakkers Johanna Geertruida Maria van den Hoek Hendrika Marike Boezen Behrooz Ziad Alizadeh Johannes Albertus Langendijk A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer Journal of Translational Medicine Radiogenomics GWAS Radiation-induced toxicity Head and neck cancer |
| title | A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer |
| title_full | A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer |
| title_fullStr | A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer |
| title_full_unstemmed | A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer |
| title_short | A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer |
| title_sort | two stage genome wide association study of radiation induced acute toxicity in head and neck cancer |
| topic | Radiogenomics GWAS Radiation-induced toxicity Head and neck cancer |
| url | https://doi.org/10.1186/s12967-021-03145-1 |
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