8-Oxoguanine DNA Glycosylase (OGG1) Cys326 Variant: Increased Risk for Worse Outcome of Patients with Locally Advanced Rectal Cancer after Multimodal Therapy

SIMPLE SUMMARY: In Western countries, the lifetime risk for rectal cancer is around 1.5%. Most patients are diagnosed with locally advanced stages. For these patients, multimodal treatment comprising radiotherapy, chemotherapy, and surgery has become the standard of care. Whereas excellent local control is achieved, still about one out of three dies from this disease. Cytotoxicity of radiochemotherapy substantially involves reactive oxygen species (ROS). In ROS-related genes, we selected eight inherited variants, for which the literature reports functional or medical effects and which occur frequently in the general population. These variants were assessed whether they impact the clinical outcome of patients with rectal cancer. We found that the OGG1 Cys326 variant, which affected 37% of the 287 patients in the sample, was strongly linked with a worse outcome, in particular cancer-specific survival. Screening for this variant may identify a particular risk subgroup of patients who may be considered for more intensified therapy and aftercare. ABSTRACT: Despite excellent loco-regional control by multimodal treatment of locally advanced rectal cancer, a substantial portion of patients succumb to this disease. As many treatment effects are mediated via reactive oxygen species (ROS), we evaluated the effect of single nucleotide polymorphisms (SNPs) in ROS-related genes on clinical outcome. Based on the literature, eight SNPs in seven ROS-related genes were assayed. Eligible patients (n = 287) diagnosed with UICC stage II/III rectal cancer were treated multimodally starting with neoadjuvant radiochemotherapy (N-RCT) according to the clinical trial protocols of CAO/ARO/AIO-94, CAO/ARO/AIO-04, TransValid-A, and TransValid-B. The median follow-up was 64.4 months. The Ser326Cys polymorphism in the human OGG1 gene affected clinical outcome, in particular cancer-specific survival (CSS). This effect was comparable in extent to the ypN status, an already established strong prognosticator for patient outcome. Homozygous and heterozygous carriers of the Cys326 variant (n = 105) encountered a significantly worse CSS (p = 0.0004 according to the log-rank test, p = 0.01 upon multiple testing adjustment). Cox regression elicited a hazard ratio for CSS of 3.64 (95% confidence interval 1.70–7.78) for patients harboring the Cys326 allele. In a multivariable analysis, the effect of Cys326 on CSS was preserved. We propose the genetic polymorphism Ser326Cys as a promising biomarker for outcome in rectal cancer.