Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.
JNCI Cancer Spectr
; 7(6)2023 Oct 31.
Article
en En
| MEDLINE
| ID: mdl-37862240
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 12â042 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 × 10â8 < P < 1.0 × 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 × 10â7), 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 × 10â6, 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Estudio de Asociación del Genoma Completo
/
Neoplasias
Tipo de estudio:
Systematic_reviews
Límite:
Humans
/
Male
Idioma:
En
Revista:
JNCI Cancer Spectr
Año:
2023
Tipo del documento:
Article
País de afiliación:
Países Bajos