Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer.

Hajnalka Laura Pálinkás,Giampaolo Bianchini,Lőrinc Pongor,Ádám Nagy,Balázs Győrffy,Kinga Nagy,Máté Balajti,Beáta G Vértessy,Angéla Békési

doi:10.3390/ijms23020633

Abstract

The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10−3). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.

Highlights

Introduction iationsFollowing DNA damage, healthy human cells activate signaling cascades to prevent cell-cycle progression, as well as to initiate repair mechanisms through DNA damage response
In the case of mutation in any of the DNA repair mechanisms, a significant increase (p < 10−16 ) was observed in the overall mutation burden compared to the wild-type samples (Figure 1B)
We investigated whether a mutation in a DNA repair pathway will result in increased mutation prevalence in another pathway as well

Summary

Introduction

Following DNA damage, healthy human cells activate signaling cascades to prevent cell-cycle progression, as well as to initiate repair mechanisms through DNA damage response. Once the accumulated damage is beyond repair, apoptosis is induced [1]. The main mechanisms of DNA repair include base-excision repair (BER), mismatch repair (MMR), nucleotide-excision repair (NER), homologous recombination (HR), and nonhomologous end joining (NHEJ). NER is utilized after UV radiation-induced injury, where the resulting DNA adducts are recognized, and the damaged, short, single strand is removed and resynthesized by a DNA polymerase using the unharmed strand as the template. BER is involved in repairing non-helix distorting base lesions. These lesions are recognized by DNA glycosylases, which remove damaged and inappropriate bases, forming abasic AP sites, cleaved by AP

Objectives

Methods

Results

Conclusion