Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer

Abstract

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10− 8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.

Disparities in prostate cancer incidence and mortality rates: Solvable or not?

“…This drive has led to over 40 genome wide association studies (GWAS) executed over the last decade which have identified approximately 170 common variants to the disease . At the molecular level, these variants can be categorized as hereditary, sporadic or epigenetic, whereby, the latter two can overlap and some noteworthy ones are listed in Table while others are discussed elsewhere …”

“…75 At the molecular level, these variants can be categorized as hereditary, sporadic or epigenetic, whereby, the latter two can overlap and some noteworthy ones are listed in Table 2 while others are discussed elsewhere. [75][76][77][78][79][80][81][82][83] The common thread observed in these studies is that more than 90% of these investigations are conducted in MEA. As a result, significant strides have been made in the design of serum and urine diagnostic biomarkers, whereby some are currently clinically applicable as mentioned earlier and these were recently reviewed in Sharma et al 86 Some include (a) the noncoding RNA, PCA3 that is believed to be overexpressed in 95% of PCa cases in MEA, 76,86 presents in high levels in some men but is unaccompanied by malignancy meanwhile additional studies confirmed an association of this biomarker in Chinese men 87,88…”

Radiogenomics and radiotherapy response modeling

“…This study also found that the top selected SNP, rs264663, was associated with expression of TANC1 mRNA, and it showed a statistical correlation with total biologically effective dose of radiation. A meta-analysis of four GWAS, also in prostate cancer patients, identified two additional loci: SNP rs17599026, which lies in KDM3B , was associated with increased urinary frequency; and rs7720298, which lies in DNAH5 , was associated with decreased urine stream (Kerns et al , 2016). Neither of these genes was previously implicated in cellular radiation response, and they appear to be novel radiosensitivity genes.…”

“…Several studies have highlighted specific epigenetic variants and their impact on late toxicity (Weigel et al , 2016; Weigel et al , 2015). For instance, KDM3B has been shown to have a potential role on histone demethylation and radiosensitivity (Kerns et al , 2016). …”

Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity

“…A fixed-effect meta-analysis was performed using data from four cohorts consisting of 1564 men treated for prostate cancer for which a GWAS was performed in which toxicity was measured at a two-year time point 41 . Two SNPs were identified in this study that met genome wide significance.…”