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

Abstract

Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and SNP-derived transcriptomic profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2 , and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which ( ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.

Multivariate piecewise linear regression model to predict radiosensitivity using the association with the genome-wide copy number variation

“…Nevertheless, evidence of mechanistic involvement is mounting from studies in radiotherapy patients. A CNV analysis in prostate cancer patients has identified seven genomic regions associated with proctitis following radiotherapy (32). However, there are still limitations in CNV studies mainly related to small sample size, few populations studied, and the potential transitional nature of copy number signatures due to the diversity of mutational processes that give rise to these alterations (33).…”