Combining CDKN1A gene expression and genome-wide SNPs in a twin cohort to gain insight into the heritability of individual radiosensitivity

Abstract

Individual variability in response to radiation exposure is recognised and has often been reported as important in treatment planning. Despite many efforts to identify biomarkers allowing the identification of radiation sensitive patients, it is not yet possible to distinguish them with certainty before the beginning of the radiotherapy treatment. A comprehensive analysis of genome-wide single-nucleotide polymorphisms (SNPs) and a transcriptional response to ionising radiation exposure in twins have the potential to identify such an individual. In the present work, we investigated SNP profile and CDKN1A gene expression in blood T lymphocytes from 130 healthy Caucasians with a complex level of individual kinship (unrelated, mono- or dizygotic twins). It was found that genetic variation accounts for 66% (95% CI 37–82%) of CDKN1A transcriptional response to radiation exposure. We developed a novel integrative multi-kinship strategy allowing investigating the role of genome-wide polymorphisms in transcriptomic radiation response, and it revealed that rs205543 ( ETV6 gene), rs2287505 and rs1263612 ( KLF7 gene) are significantly associated with CDKN1A expression level. The functional analysis revealed that rs6974232 ( RPA3 gene), involved in mismatch repair ( p value = 9.68e−04) as well as in RNA repair ( p value = 1.4e−03) might have an important role in that process. Two missense polymorphisms with possible deleterious effect in humans were identified: rs1133833 ( AKIP1 gene) and rs17362588 ( CCDC141 gene). In summary, the data presented here support the validity of this novel integrative data analysis strategy to provide insights into the identification of SNPs potentially influencing radiation sensitivity. Further investigations in radiation response research at the genomic level should be therefore continued to confirm these findings. Electronic supplementary material The online version of this article (10.1007/s10142-019-00658-3) contains supplementary material, which is available to authorized users.

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

“…Unfortunately, the normal tissue around the targeted region is also affected by DNA damage from radiation, and must rely on DNA repair mechanisms for rehabilitation of cellular functions [ 8 ]. A recent twin-study has reported that certain SNPs and their transcriptomic influence are associated with individual radiation sensitivity and a heritability estimate of 66% [ 9 ]. Therefore, it is vital to understand genetics underlying molecular mechanisms involved in adverse effects of radiotherapy and individual genetic variations that may induce radiation sensitivity.…”

“…These studies have identified genetic variations involved in DNA repair pathways to be associated with overall radiotoxicity [ 3 , 10 ]. However, the role of altered gene expression [ 9 ] from aggregated single nucleotide polymorphisms (SNPs) remains elusive in radiotoxicity phenotypes (e.g., proctitis). Regulatory variants are SNPs within coding regions which contribute towards tissue – specific gene expression alterations leading to variations in the phenotypic spectrum.…”

Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

“…However, the role of altered gene expression [9] from aggregated single nucleotide polymorphisms (SNPs) remains elusive in radiotoxicity phenotypes (e.g., proctitis).…”

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

“…Unfortunately, the normal tissue around the targeted region is also affected by DNA damage from radiation, and must rely on DNA repair mechanisms for rehabilitation of cellular functions [8]. A recent twin-study has reported that certain SNPs and their transcriptomic in uence are associated with individual radiation sensitivity and a heritability estimate of 66% [9]. Therefore, it is vital to understand genetics underlying molecular mechanisms involved in adverse effects of radiotherapy and individual genetic variations that may induce radiation sensitivity.…”

“…These studies have identi ed genetic variations involved in DNA repair pathways to be associated with overall radiotoxicity [3,10]. However, the role of altered gene expression [9] from aggregated single nucleotide polymorphisms (SNPs) remains elusive in radiotoxicity phenotypes (e.g., proctitis). Regulatory variants are SNPs within coding regions which contribute towards tissue -speci c gene expression alterations leading to variations in the phenotypic spectrum.…”