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

International Journal of Molecular Sciences

Giampaolo Bianchini¹  Angéla Békési²  Kinga Nagy²  Hajnalka Laura Pálinkás²  Beáta G. Vértessy²  Balázs Győrffy³  Máté Balajti³  Lőrinc Pongor³  Ádám Nagy³ 

[1] Department of Medical Oncology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy;Genome Metabolism Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary;TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary;

关键词: cancer;    DNA repair;    mutation burden;    non-homologous end joining;    survival;    next generation sequencing;   

DOI  :  10.3390/ijms23020633

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown