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

Pálinkás, Hajnalka Laura; Balajti, Máté; Nagy, Ádám; Nagy, Krisztina; Békési, Angéla; Vértessy, Beáta G.; Győrffy, Balázs

doi:10.3390/ijms23020633

Cited by 2 publications

(1 citation statement)

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“…Based on TCGA, PRKDC had a high mutation rate in several tumors, including UCEC, SKCM, and COAD, while its expression levels varied in different cancers, as was shown in Supplementary Figure 2 ( 35 ). In colorectal cancer, the mutations in PRKDC was deemed to be one of the primary founder mutations, which leads to increased mutation load, as well as increased tumor heterogeneity ( 36 ). In hepatocellular carcinoma, a high mutation frequency (11.5%) was observed in a study cohort, and the matched drugs of DDR-mutant patients were significantly more than those of wild-type patients ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Specific genetic aberrations of parathyroid in Chinese patients with tertiary hyperparathyroidism using whole-exome sequencing

Li,

Sheng,

Zeng

et al. 2023

Front. Endocrinol.

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BackgroundTertiary hyperparathyroidism (THPT) is a peculiar subtype of hyperparathyroidism that usually develops from chronic kidney disease (CKD) and persists even after kidney transplantation. Unlike its precursor, secondary hyperparathyroidism (SHPT), THPT is characterized by uncontrolled high levels of calcium in the blood, which suggests the monoclonal or oligoclonal proliferation of parathyroid cells. However, the molecular abnormalities leading to THPT have not yet been fully understood.MethodsIn this study, we analyzed DNA samples from hyperplastic parathyroid and corresponding blood cells of 11 patients with THPT using whole-exome sequencing (WES). We identified somatic single nucleotide variants (SNV) and insertions or deletions variants (INDEL) and performed driver mutation analysis, KEGG pathway, and GO functional enrichment analysis. To confirm the impact of selected driver mutated genes, we also tested their expression level in these samples using qRT-PCR.ResultsFollowing quality control and mutation filtering, we identified 17,401 mutations, comprising 6690 missense variants, 3078 frameshift variants, 2005 stop-gained variants, and 1630 synonymous variants. Copy number variants (CNV) analysis showed that chromosome 22 copy number deletion was frequently observed in 6 samples. Driver mutation analysis identified 179 statistically significant mutated genes, including recurrent missense mutations on TBX20, ATAD5, ZNF669, and NOX3 genes in 3 different patients. KEGG pathway analysis revealed two enriched pathways: non-homologous end-joining and cell cycle, with a sole gene, PRKDC, involved. GO analysis demonstrated significant enrichment of various cellular components and cytobiological processes associated with four genes, including GO items of positive regulation of developmental growth, protein ubiquitination, and positive regulation of the apoptotic process. Compared to blood samples, THPT samples exhibited lower expression levels of PRKDC, TBX20, ATAD5, and NOX3 genes. THPT samples with exon mutations had relatively lower expression levels of PRKDC, TBX20, and NOX3 genes compared to those without mutations, although the difference was not statistically significant.ConclusionThis study provides a comprehensive landscape of the genetic characteristics of hyperplastic parathyroids in THPT, highlighting the involvement of multiple genes and pathways in the development and progression of this disease. The dominant mutations identified in our study depicted new insights into the pathogenesis and molecular characteristics of THPT.

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Section: Discussionmentioning

confidence: 99%

Specific genetic aberrations of parathyroid in Chinese patients with tertiary hyperparathyroidism using whole-exome sequencing

Li,

Sheng,

Zeng

et al. 2023

Front. Endocrinol.

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The expression and prognostic significance of CCNB1 in colorectal cancer based on TCGA database

Chen

Wang

Tian

et al. 2023

Preprint

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Background Numerous studies have shown that cell cycle-associated protein B1 (Cyclin B1, CCNB1) is overexpressed in many cancers and is involved in cancer cell growth, differentiation, apoptosis, and metastasis. However, the biological functions and molecular mechanisms of CCNB1 in colorectal cancer (CRC) still remain unclear. Methods Herein, the HPA database and the UCSC genomic database were used to analyze the mRNA and protein expression levels of CCNB1 in different tissues of humans or vertebrates. The TIMER database was used to evaluate the expression of CCNB1 in various cancer tissue samples and adjacent normal tissue. R statistical software (version 4.2.1) was employed to analyze the relationship between CCNB1 expression and clinicopathological characteristics in the TCGA database. Kaplan-Meier survival curve and Cox regression were performed to evaluate the prognostic value. Receiver operating characteristic (ROC) curve analysis was applied to assess the diagnostic value of CCNB1. Functional enrichment analysis of CCNB1 and its co-expressed genes was performed to explore the potential molecular mechanisms of CCNB1 in CRC. The correlation of critical cell-cycle regulators and the protein-protein interaction (PPI) network of CCNB1 and CRC was established through the STRING (Search Tool for the Retrieval of Interacting Genes) website and GEPIA database. Results Significant upregulation of CCNB1 was observed in a variety of tumor tissues, with limited tissue specificity and tumor specificity. TCGA database and immunohistochemistry data demonstrated that CCNB1 expression was significantly upregulated in CRC tumor tissues. In addition, CCNB1 expression was correlated with the clinical stage and TNM stage. The progression-free survival (PFS) was considerably improved in the CCNB1 high-expression group. Univariate and multifactorial Cox analysis indicated that CCNB1 could not be used as an independent prognostic factor for patients with CRC. Moreover, we found that genes such as BCAS3, ZBTB4, PTTG1, H2AZ1, LRP1B, KCNJ9, and SCARNA7 could be potential targets for regulating CCNB1. The gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses revealed that CCNB1 was implicated in multiple cancer-related signaling pathways and biological processes. Meanwhile, CCNB1 expression was significantly correlated with the immune infiltrating levels of diverse immune markers. CCNB1 expression was positively correlated with tumor mutation burden and negatively correlated with several immune checkpoint genes. In addition, the efficacy of chemotherapeutic medicines such as 5-Fluorouracil, bexarotene, bleomycin, camptothecin, and cisplatin significantly differed between the high and low CCNB1 expression groups. Conclusion CCNB1 could be a promising biomarker for predicting the diagnosis and prognosis of CRC patients and a potential novel molecular target for tumor immunotherapy.

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

Cited by 2 publications

References 50 publications

Specific genetic aberrations of parathyroid in Chinese patients with tertiary hyperparathyroidism using whole-exome sequencing

Specific genetic aberrations of parathyroid in Chinese patients with tertiary hyperparathyroidism using whole-exome sequencing

The expression and prognostic significance of CCNB1 in colorectal cancer based on TCGA database

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