1. Lőrinc S. Pongor, 2. Leonardo Marino-Ramirez, David Landsman, 2. Roberto Vera Alvarez, 1,3.Balázs Győrffy
1. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
2. Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
3. MTA TTK Lendulet Cancer Biomarker Research Group, Research Center for Natural Sciences, Budapest, Hungary
Introduction. Mutations in coding regions can have an effect on the RNA and protein sequences of genes, as well as affect their expression levels. Alterations in regions that are recognized by the splicing complexes, or mutations that will lead to a premature stop codon are usually degraded through the nonsense-mediated mRNA decay (NMD), rarely translated to a protein.
Aims. Our aim was to identify mutations that influence the mRNA sequence and expression level of genes in a large cohort of breast cancer patients.
Methods. Exome and RNA sequencing (RNAseq) data from 1,160 breast cancer patients were obtained from the TCGA (The Cancer Genome Atlas) database. Gene expression of normal and tumor samples was calculated using the TPMcalculator. Somatic mutation data was retrieved from VCF files for each patient. Mutations were classified as nonsense-mediated mRNA decay (NMD) causing mutation in cases where the alteration resulted in a premature stop codon, caused a frameshift in the gene, or affected splice-site regions.
Results. Most NMD-causing mutations affected established tumor suppressor genes such as TP53, CDH1, RB1, GATA3, and MLL3, by leading to decreased RNA expression levels in most cases. Certain splice mutations (e.g. TP53) caused intron retention, where the intronic region was highly expressed in the gene. Interestingly, expression of GATA3 or MAP3K1 cancer genes did not decrease in patients harboring NMD-causing mutants.
Conclusions. We focused on the identification of mutations that affect RNA splicing, examining their effect on transcribed RNA sequences, and the level of expression in known cancer genes. NMD causing disruptive mutations principally lead to decreased expression in established tumor suppressor genes, with no effect on the expression of established oncogenes. Out results show that NMD mutations may predominantly help to regulate expression levels of tumor suppressor genes.
Doctoral School: pathological Sciences
Program: Experimental Oncology
Supervisor: Balázs Győrffy
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