A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

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

doi:10.1186/s12967-021-03145-1

A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	481
Number of pages	10
Journal	Journal of translational medicine
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s12967-021-03145-1
Publication status	Published - 27-Nov-2021

Keywords

Radiogenomics
GWAS
Radiation-induced toxicity
Head and neck cancer
THERAPY
RADIOSENSITIVITY
HERITABILITY
RADIOTHERAPY
BREAST
METAANALYSIS
GENES
XRCC1
ATM

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Additional file 2 of A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer
Naderi, E. (Creator), Crijns, A. P. G. (Creator), Steenbakkers, R. (Contributor), van den Hoek, A. (Contributor), Boezen, H. M. (Creator), Alizadeh, B. Z. (Creator) & Langendijk, J. A. (Creator), figshare, 27-Nov-2021
DOI: 10.6084/m9.figshare.17087902, https://springernature.figshare.com/articles/dataset/Additional_file_2_of_A_two-stage_genome-wide_association_study_of_radiation-induced_acute_toxicity_in_head_and_neck_cancer/17087902
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title = "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.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.",

keywords = "Radiogenomics, GWAS, Radiation-induced toxicity, Head and neck cancer, THERAPY, RADIOSENSITIVITY, HERITABILITY, RADIOTHERAPY, BREAST, METAANALYSIS, GENES, XRCC1, ATM",

author = "Elnaz Naderi and Crijns, {Anne Petra Gerarda} and Steenbakkers, {Roel Johannes Henricus Marinus} and {van den Hoek}, {Johanna Geertruida Maria} and Boezen, {Hendrika Marike} and Alizadeh, {Behrooz Ziad} and Langendijk, {Johannes Albertus}",

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doi = "10.1186/s12967-021-03145-1",

language = "English",

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journal = "Journal of translational medicine",

issn = "1479-5876",

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T1 - A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

AU - Naderi, Elnaz

AU - Crijns, Anne Petra Gerarda

AU - Steenbakkers, Roel Johannes Henricus Marinus

AU - van den Hoek, Johanna Geertruida Maria

AU - Boezen, Hendrika Marike

AU - Alizadeh, Behrooz Ziad

AU - Langendijk, Johannes Albertus

PY - 2021/11/27

Y1 - 2021/11/27

N2 - 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.

AB - 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.

KW - Radiogenomics

KW - GWAS

KW - Radiation-induced toxicity

KW - Head and neck cancer

KW - THERAPY

KW - RADIOSENSITIVITY

KW - HERITABILITY

KW - RADIOTHERAPY

KW - BREAST

KW - METAANALYSIS

KW - GENES

KW - XRCC1

KW - ATM

U2 - 10.1186/s12967-021-03145-1

DO - 10.1186/s12967-021-03145-1

M3 - Article

C2 - 34838041

SN - 1479-5876

VL - 19

JO - Journal of translational medicine

JF - Journal of translational medicine

IS - 1

M1 - 481

ER -

A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

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Additional file 2 of A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer

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