Biology subjects

van Belzen, I. A. E. M.

Publications and source records attributed to van Belzen, I. A. E. M..

5 recordsLinked to original sources

bioRxiv2026

A single chromosome 3p break initiates clear cell renal cell carcinoma evolution

Clear cell renal cell carcinoma (ccRCC) is initiated by chromosome 3p loss, yet chromosome losses impose a profound fitness burden on normal cells. How renal epithelial cells tolerate this deleterious aneuploidy during early tumorigenesis remains unclear. Analysis of 949 ccRCC genomes reveals two major classes of chromosome 3p alterations: simple deletions and complex rearrangements surrounding a terminal breakpoint - a pattern we term breakpoint-confined chromothripsis. We modeled both alterations in non-transformed human renal proximal tubule epithelial cells by introducing a single DNA double-strand break on chromosome 3p. Despite an initial fitness disadvantage, chromosome 3p loss drives adaptive genomic evolution that recapitulates recurrent ccRCC-associated aneuploidies, including 5q gain and 14q loss. These alterations alleviate the fitness constraints of 3p loss and promote metabolic reprogramming, clonal expansion, and malignant transformation, producing tumors with features of ccRCC. Thus, a single chromosome break initiates the evolutionary trajectory of ccRCC by creating a fitness bottleneck that selects for recurrent aneuploidies.

cancer biology↗

bioRxiv2026

Murine osteosarcoma recapitulates the driver landscape and genomic complexity of osteosarcoma evolution in humans

Osteosarcoma (OS) genomes are characterized by complex genomic rearrangements (CGRs) that drive genomic instability and clonal diversification early in tumor evolution. As a result, OS tumors display high inter-patient variability, which has hindered molecular stratification and targeted therapeutic development. To study genomic complexity in OS and credential a genetically engineered mouse model of the disease (Sp7-Cre Trp53fl Rb1fl), we performed high-depth and multi-region whole genome sequencing (WGS) of 35 tumor samples from 24 mice. Similar to human OS, the murine OS tumors (mOS) had a high number of somatic structural variants (158 per tumor) with low tumor mutational burden of single nucleotide variants (0.87 mutations/MB). CGRs were identified in 63% (15/24) of mOS cases, most frequently affecting chromosome 15 (33%, 8/24 mice) and resulting in Myc amplification in 6 mice, ranging from 5 to 104 copies. Myc amplification was verified with DNA FISH, long-read sequencing and gene expression data, which revealed examples of Myc amplification in both extrachromosomal circular DNA (ecDNA) and in derivative chromosomes generated by CGRs. PTEN loss occurred frequently (59% 12/22 mice), and contributed to osteosarcomagenesis, as demonstrated by tumor initiation with in vivo CRISPR/Cas9-mediated deletion experiments (2 mice). Together, these results demonstrate that a preclinical model of osteosarcoma can generate the genomic heterogeneity and complexity of the human disease, thereby facilitating research into mechanisms of tumor initiation and drivers of progression and relapse.

cancer biology↗

bioRxiv2023

Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors

BackgroundIn pediatric cancer, structural variants (SVs) and copy number alterations can contribute to cancer initiation and progression, and hence aid diagnosis and treatment stratification. The few studies into complex rearrangements have found associations with tumor aggressiveness or poor outcome. Yet, their prevalence and biological relevance across pediatric solid tumors remains unknown. ResultsIn a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy and chromothripsis across five pediatric solid cancer types: neuroblastoma, Ewing sarcoma, Wilms tumor, hepatoblastoma and rhabdomyosarcoma. Complex SVs were identified in 56 tumors (47%) and different classes occurred across multiple cancer types. Recurrently mutated regions tend to be cancer-type specific and overlap with cancer genes, suggesting that selection contributes to shaping the SV landscape. In total, we identified potentially pathogenic complex SVs in 42 tumors that affect cancer driver genes or result in unfavorable chromosomal alterations. Half of which were known drivers, e.g. MYCN amplifications due to ecDNA and EWSR1::FLI1 fusions due to chromoplexy. Recurrent novel candidate complex events include chromoplexy in WT1 in Wilms tumors, focal chromothripsis with 1p loss in hepatoblastomas and complex MDM2 amplifications in rhabdomyosarcomas. ConclusionsComplex SVs are prevalent and pathogenic in pediatric solid tumors. They represent a type of genomic variation which currently remains unexplored. Moreover, carrying complex SVs seems to be associated with adverse clinical events. Our study highlights the potential for complex SVs to be incorporated in risk stratification or exploited for targeted treatments.

cancer biology↗

bioRxiv2021

Systematic discovery of gene fusions in pediatric cancer by integrating RNA-seq and WGS

BackgroundGene fusions are important cancer drivers in pediatric cancer and their accurate detection is essential for diagnosis and treatment. Clinical decision-making requires high confidence and precision of detection. Recent developments show RNA sequencing (RNA-seq) is promising for genome-wide detection of fusion products, but hindered by many false positives that require extensive manual curation and impede discovery of pathogenic fusions. ResultsWe developed Fusion-sq to detect tumor-specific gene fusions by integrating and "fusing" evidence from RNA-seq and whole genome sequencing (WGS) using intron-exon gene structure. In a pediatric pan-cancer cohort of 130 patients, we identified 165 high confidence tumor-specific gene fusions and their underlying structural variants (SVs). This includes all clinically relevant fusions known to be present in this cohort (30 patients). Fusion-sq distinguishes healthy-occurring from tumor-specific fusions, and resolves fusions in amplified regions and copy number unstable genomes. A high gene fusion burden is associated with copy number instability. We identified 27 potentially pathogenic fusions involving oncogenes or tumor-suppressor genes characterised by underlying SVs or expression changes indicative of activating or disruptive effects. ConclusionsOur results indicate how clinically relevant and potentially pathogenic gene fusions can be identified and their functional effects investigated by combining WGS and RNA-seq. Integrating RNA fusion predictions with underlying SVs advances fusion detection beyond extensive manual filtering. Taken together, we developed a method for identifying candidate fusions that is suitable for precision oncology applications. Our method provides multi-omics evidence for assessing the pathogenicity of tumor-specific fusions for future clinical decision making.

genomics↗

bioRxiv2020

PhyRepID: a comparative phylogenomics approach for large-scale quantification of protein repeat evolution

Protein repeats consisting of domains or motifs are involved in key biological processes such as neural development, host-pathogen interactions, and speciation. Expansion and contraction of these repeats can strongly impact protein function as was shown for KNL1 and PRDM9. However, these known cases could only be identified manually and were previously incorrectly reported as conserved in large-scale analyses, because signatures of repeat evolution are difficult to resolve automatically. We developed PhyRepID to compare protein domain repeat evolution and analysed 4939 groups of orthologous proteins (OGs) from 14 vertebrate species. Our main contributions are 1) detecting a wide scope of repeats consisting of Pfam structural domains and motifs, 2) improving sensitivity and precision of repeat unit detection through optimization for the OGs, 3) using phylogenetic analysis to detect evolution within repeat regions. From these phylogenetic signals, we derived a "protein repeat duplication" (PRD) score that quantifies evolution in repeat regions and thereby enables large-scale comparison of protein families. Zinc finger repeats show remarkably fast evolution, comprising 25 of 100 fastest evolving proteins in our dataset, whilst cooperatively-folding domain repeats like beta-propellers are mostly conserved. Motif repeats have a similar PRD score distribution as domain repeats and also show a large diversity in evolutionary rates. A ranking based on the PRD score reflects previous manual observations of both highly conserved (CDC20) and rapidly evolving repeats (KNL1, PRDM9) and proposes novel candidates (e.g. AHNAK, PRX, SPATA31) showing previously undescribed rapid repeat evolution. PhyRepID is available on https://github.com/ivanbelzen/PhyRepID/.

bioinformatics↗