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Article

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

1
Genome Metabolism Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary
2
Department of Applied Biotechnology and Food Sciences, BME Budapest University of Technology and Economics, Szt Gellért tér 4, H-1111 Budapest, Hungary
3
TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary
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Department of Bioinformatics and 2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, H-1094 Budapest, Hungary
5
Department of Medical Oncology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Paola Ghiorzo
Int. J. Mol. Sci. 2022, 23(2), 633; https://doi.org/10.3390/ijms23020633
Received: 19 October 2021 / Revised: 21 December 2021 / Accepted: 28 December 2021 / Published: 6 January 2022
(This article belongs to the Section Molecular Biology)
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. View Full-Text
Keywords: cancer; DNA repair; mutation burden; non-homologous end joining; survival; next generation sequencing cancer; DNA repair; mutation burden; non-homologous end joining; survival; next generation sequencing
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MDPI and ACS Style

Pálinkás, H.L.; Pongor, L.; Balajti, M.; Nagy, Á.; Nagy, K.; Békési, A.; Bianchini, G.; Vértessy, B.G.; Győrffy, B. Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer. Int. J. Mol. Sci. 2022, 23, 633. https://doi.org/10.3390/ijms23020633

AMA Style

Pálinkás HL, Pongor L, Balajti M, Nagy Á, Nagy K, Békési A, Bianchini G, Vértessy BG, Győrffy B. Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer. International Journal of Molecular Sciences. 2022; 23(2):633. https://doi.org/10.3390/ijms23020633

Chicago/Turabian Style

Pálinkás, Hajnalka Laura, Lőrinc Pongor, Máté Balajti, Ádám Nagy, Kinga Nagy, Angéla Békési, Giampaolo Bianchini, Beáta G. Vértessy, and Balázs Győrffy. 2022. "Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer" International Journal of Molecular Sciences 23, no. 2: 633. https://doi.org/10.3390/ijms23020633

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