A5023455086- Cancer Genomics and Diagnostics
- Prostate Cancer Treatment and Research
- BRCA gene mutations in cancer
- DNA Repair Mechanisms
- Bladder and Urothelial Cancer Treatments
- Genetic factors in colorectal cancer
- PARP inhibition in cancer therapy
- Cancer-related molecular mechanisms research
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Anomaly Detection Techniques and Applications
- CRISPR and Genetic Engineering
- Ocular Oncology and Treatments
- Urinary and Genital Oncology Studies
- Lung Cancer Treatments and Mutations
- Lung Cancer Research Studies
- RNA modifications and cancer
- Animal Genetics and Reproduction
- Neuroendocrine Tumor Research Advances
- Neuroblastoma Research and Treatments
- Gene expression and cancer classification
- Testicular diseases and treatments
- Genomics and Phylogenetic Studies
- Immune Cell Function and Interaction
- Renal cell carcinoma treatment
Erasmus MC Cancer Institute
2016-2025
Erasmus MC
2016-2025
German Cancer Research Center
2023-2025
Heidelberg University
2023-2025
Erasmus University Rotterdam
2018-2022
Codarts Rotterdam
2020
Maastricht University
2019
Oncode Institute
2019
The Netherlands Cancer Institute
2019
Elisabeth-TweeSteden Ziekenhuis
2019
Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present whole-genome sequencing (WGS) analysis fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on features, define eight distinct clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous...
Abstract Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as grade. To interrogate the evolutionary origins cancer heterogeneity, we analyzed 666 whole genomes. We identified a compendium 223 recurrently mutated driver regions, influencing downstream processes gene expression. validated individual germline variants that predispose tumors to acquire specific...
Current normalization methods for RNA-sequencing data allow either intersample comparison to identify differentially expressed (DE) genes or intrasample the discovery and validation of gene signatures. Most studies on optimization typically use simulated validate methodologies. We describe a new method, GeTMM, which allows both inter- analyses with same normalized set. used actual (i.e. not simulated) RNA-seq from 263 colon cancers (no biological replicates) read count compare GeTMM most...
Although PCR-based techniques have become an essential tool in the field of molecular and genetic research, amplification repetitive DNA sequences is limited.This due to truncated nature amplified sequences, which are also prone errors during polymerase-based amplification.The complex structure can form hairpin loops, promote dissociation polymerase from template, impairing complete amplification, leading formation incomplete fragments that serve as megaprimers.These megaprimers anneal with...
Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This reveals genomic subpopulations aNEN on localization differentiation grade; observe relatively high burdens (TMB) in carcinoma (average 5.45 somatic...
Abstract The Four Core Genotypes (FCG) is a mouse model system used to disentangle the function of sex chromosomes and hormones. We report that copy 3.2 MB region X chromosome has translocated Y Sry- thus increased expression X-linked genes including single-stranded RNA sensor autoimmune disease mediator Tlr7 . This previously-unreported X-Y translocation complicates interpretation studies reliant on C57BL/6J FCG mice.
Abstract Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected be effective beyond carriers, a robust validated test detect HRD tumors lacking. In study, we therefore evaluated functional HR assay exploiting the formation RAD51 foci proliferating cells after ex vivo irradiation fresh breast cancer tissue:...
Abstract In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data metastases 429 CRC patients participating in pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures from CRC, associated with received prior treatments, and metastasis-specific signatures. Compared identify additional...
Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen tumor biopsies from 116 mUC patients who were scheduled palliative systemic treatment within the context trial (NCT01855477 NCT02925234). Hierarchical clustering mutational signatures revealed two major genomic subtypes: GenS1 (67%), which was...
The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss the NURD subunit Deleted Oral Cancer 1 (DOC1) associated with human oral squamous carcinomas (OSCCs). Here, we show restoration DOC1 expression OSCC cells leads to reversal epithelial-mesenchymal transition (EMT). This caused by DOC1-dependent targeting repress transcriptional regulators EMT. recruitment drives extensive epigenetic...
Cell-free circulating tumor DNA (ctDNA) has emerged as a promising biomarker for response evaluation in metastatic castration-resistant prostate cancer (mCRPC). The current study evaluated the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), quick, tumor-agnostic and affordable ctDNA assay that requires small input of DNA, to generate genome-wide (GWA) score mCRPC patients, correlated this matched biopsies. In prospective multicenter study, GWA scores were from blood...
Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic cell. This study determines intratumour heterogeneity to unravel tumour progression initiation until metastasis. In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including precursor neoplasia situ (GCNIS) and metastatic specimens, using whole-genome targeted sequencing. Their evolution was reconstructed....
Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding spliceosome factor SF3B1, and whilst patients with such SF3B1 generally have an intermediate risk on developing metastatic disease, a third these develop early metastasis within 5 years after diagnosis. We therefore investigated whether clinical and/or genetic variables could be indicative short progression-free survival (PFS < 60 months) or long PFS ≥ for SF3B1-mutated (SF3B1mut) UM patients....
Abstract Response to androgen receptor signaling inhibitors (ARSI) varies widely in metastatic castration resistant prostate cancer (mCRPC). To improve treatment guidance, biomarkers are needed. We use whole-genomics (WGS; n = 155) with matching whole-transcriptomics (WTS; 113) from biopsies of ARSI-treated mCRPC patients for unbiased discovery and development machine learning-based prediction models. Tumor mutational burden ( q < 0.001), structural variants 0.05), tandem duplications...
Abstract The Four Core Genotypes (FCG) is a mouse model system heavily used to disentangle the function of sex chromosomes and hormones. We report that copy 3.2 MB region X chromosome has translocated Y Sry- thus increased expression multiple genes including auto-immune master regulator Tlr7 . This previously-unreported X-Y translocation complicates interpretation studies reliant on FCG mice.
Abstract The risk of developing urothelial carcinoma the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract (UTUC) is 22% to 47% 2 years after surgery. Subject debate remains whether UTUC and subsequent UCB are clonally related or represent separate origins. To investigate clonal relationship between both entities, we performed targeted DNA sequencing a panel 41 genes on matched normal tumor tissue 15 primary RNU who later developed 19 UCBs....
EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being its common genomic mutations. There are conflicting reports about prognostic role and it remains unclear whether how differs signaling compared wildtype EGFR.To better understand oncogenic of EGFRvIII, we leveraged 4 large datasets into 1 glioblastoma transcriptome dataset (n = 741) alongside 81 whole-genome samples from 2 datasets.The EGFRvIII/EGFR expression ratios differ strongly...
Abstract Background Fusion genes are typically identified by RNA sequencing (RNA-seq) without elucidating the causal genomic breakpoints. However, non–poly(A)-enriched RNA-seq contains large proportions of intronic reads that also span Results We have developed an algorithm, Dr. Disco, searches for fusion transcripts taking entire reference genome into account as search space. This includes exons but introns, intergenic regions, and sequences do not meet splice junction motifs. Using 1,275...
Metastatic castration-resistant prostate cancer (mCRPC) patients with positive AR-V7 expression in their circulating tumour cells (CTCs) rarely derive benefit from abiraterone and enzalutamide.We performed a prospective, multicenter, single arm phase II clinical trial (CABA-V7) mCRPC previously treated docetaxel androgen deprivation therapy.In this trial, we investigated whether cabazitaxel treatment resulted clinically meaningful PSA response rates CTC-based collected liquid biopsies for...