Edwin Cuppen

• Prof dr
• Research Director at Hartwig Medical Foundation

Background Survival of patients with metastatic castration-resistant prostate cancer (mCRPC) depends on the site of metastatic dissemination. Methods Patients with mCRPC were prospectively included in the CPCT-02 metastatic site biopsy study. We evaluated whole genome sequencing (WGS) of 378 mCRPC metastases to understand the genetic traits that a...

Molecular testing is increasingly relevant for enabling precision medicine for cancer patients. Whole genome sequencing (WGS) provides a tumour-agnostic solution for the growing complexity of DNA-based biomarker detection, with promising results demonstrated in various studies. Here, we present real-world data of 888 patients to demonstrate the cli...

Background Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life. Pathogenic germline variants (PGVs) and its association to late onset glioblastoma remains unclear. This study aimed to investigate the genetic predisposition to adult glioblastoma. Methods We performed an in-depth analysis of w...

While the use of ctDNA-based minimal residual disease (MRD) monitoring is gaining popularity in adult cancers, this approach is not yet widely adopted in pediatric cancers (PCs). We developed a robust and sensitive assay to monitor ctDNA in PCs, which overcomes PC-specific challenges including low tumor mutational burden, paucity of hotspot mutatio...

For glioblastoma patients, the efficacy-targeted therapy is limited to date. Most of the molecular therapies previously studied are lacking efficacy in this population. More trials are needed to study the actual actionability of biomarkers in (recurrent) glioblastoma. This study aimed to assess the current clinical trial landscape to assess the rol...

Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we cu...

Introduction: Longitudinal application of liquid biopsy is commonly used in childhood acute lymphoblastic leukemia to measure minimal residual disease and has emerged as an attractive method for monitoring many adult solid tumours. However, liquid biopsy is not yet widely available across solid paediatric cancers. Here we set out to assess the valu...

Increased use of whole genome sequencing (WGS) in neuro-oncology for diagnostics and research purposes necessitates a renewed conversation about informed consent procedures and governance structures for sharing personal health data. There is currently no consensus on how to obtain informed consent for WGS in this population. In this narrative revie...

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to...

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n=178). An independent validation cohort (n=79) was used to val...

Purpose The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non–small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this diseas...

Purpose Next generation sequencing (NGS) is an important tool used in clinical practice to obtain the required molecular information for accurate diagnostics of high-grade adult-type diffuse glioma (HGG). Since individual centers use either in-house produced or standardized panels, interlaboratory variation could play a role in the practice of HGG...

Purpose Genome sequencing (GS) enables comprehensive molecular analysis of tumours and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pre-test genetic counselling, which is cost-ineffective. Referral for genetic counselling based on tumour variants alone...

Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced RCC was inve...

Metastatic cancer remains an almost inevitably lethal disease1–3. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours and late-stage treated metastatic tumours using a harmonized pan-cancer analysis...

Studies have characterized the immune escape landscape across primary tumors. However, whether late-stage metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. We performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,319 uniformly processed tumor samp...

DNA methylation is important for establishing and maintaining cell identity and for genomic stability. This is achieved by regulating the accessibility of regulatory and transcriptional elements and the compaction of subtelomeric, centromeric, and other inactive genomic regions. Carcinogenesis is accompanied by a global loss in DNA methylation, whi...

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a co...

Deficiency for the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) leads to chromosomal instability and diseases such as cancer. Yet, defective HR also results in vulnerabilities that can be exploited for targeted therapy. Here, we identify such a vulnerability and show that BRCA1-deficient cells are dependent on the lon...

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases an...

Background In ∼3%-5% of patients with metastatic disease, tumor origin remains unknown despite modern imaging techniques and extensive pathology work-up. With long diagnostic delays and limited and ineffective therapy options, the clinical outcome of patients with cancer of unknown primary (CUP) remains poor. Large-scale genome sequencing studies h...

PURPOSE The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transform diagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that is starting to replace the standard of care for oncology molecular testing in health care systems around the world; however, the implementation...

Background Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence...

Genome-wide mutation analyses have revealed that specific anti-cancer drugs are highly mutagenic to cancer cells, but the mutational impact of anti-cancer therapies on normal cells is not known. Here, we examine genome-wide somatic mutation patterns in 42 healthy adult stem cells (ASCs) of the colon or the liver from 14 cancer patients (mean of 3.2...

DNA methylation is important for establishing and maintaining cell identity and for genomic stability. This is achieved by regulating the accessibility of regulatory and transcriptional elements and the compaction of subtelomeric, centromeric, and other inactive genomic regions. Carcinogenesis is accompanied by a global loss in DNA methylation, whi...

Cancers of unknown primary (CUP) origin account for ∼3% of all cancer diagnoses, whereby the tumor tissue of origin (TOO) cannot be determined. Using a uniformly processed dataset encompassing 6756 whole-genome sequenced primary and metastatic tumors, we develop Cancer of Unknown Primary Location Resolver (CUPLR), a random forest TOO classifier tha...

The current increase in number and diversity of targeted anti‐cancer agents poses challenges to the logistics and timeliness of molecular diagnostics (MolDx), resulting in underdiagnosis and treatment. Whole genome sequencing (WGS) may provide a sustainable solution for addressing current as well as future diagnostic challenges. The present study t...

Immune surveillance escape is a hallmark of tumorigenesis1. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types2–4. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed...

Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis...

Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under inv...

Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis...

Bladder cancer has a high recurrence rate and low survival of advanced stage patients. Few genetic drivers of bladder cancer have thus far been identified. We performed in-depth structural variant analysis on whole-genome sequencing data of 206 metastasized urinary tract cancers. In ~ 10% of the patients, we identified recurrent in-frame deletions...

Background: Germline BRCA1/2 mutation status is currently used as predictive biomarker for response to Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated tumors and homologous recombination repair deficient (HRD) tumors with unknown etiology are probably also PARP inhibitor-sensitive...

Precision cancer medicine and tailoring therapies to specific molecular targets are based mainly on driver mutations in protein-coding regions of the genome. Complex computational tools were developed to characterize coding driver mutations in 30+ cancer types. However, genomic and functional characterization of noncoding drivers outside coding reg...

Tumor tissue of origin (TOO) is an important factor for guiding treatment decisions. However, TOO cannot be determined for ~3% of metastatic cancer patients that present in the clinic and are categorized as cancers of unknown primary (CUP). As whole genome sequencing (WGS) of tumors is now transitioning from the research domain to diagnostic practi...

Prostate cancer (PCa) is the most prevalent, non-cutaneous, cancer in men in the Western world. Disease confined to the prostate can be cured, but metastatic disease cannot. PCa metastases are found in bone, lymph-nodes, liver and other visceral organs (visceral), in decreasing order of frequency. After an initial response to androgen receptor dire...

Accurate detection of somatic structural variation (SV) in cancer genomes remains a challenging problem. This is in part due to the lack of high-quality, gold-standard datasets that enable the benchmarking of experimental approaches and bioinformatic analysis pipelines. Here, we performed somatic SV analysis of the paired melanoma and normal lympho...

Background Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced R...

Bladder cancer has a high recurrence rate and low survival of advanced stage patients. Few genetic drivers of bladder cancer have thus far been identified. We performed in-depth structural variant analysis on whole-genome sequencing data of 206 metastasized urinary tract cancers. In ˜10% of the patients, we identified recurrent in-frame deletions o...

The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-g...

Comprehensive analyses of genome-wide mutation profiles has revealed that specific anti-cancer drugs, such as 5-fluorouracil (5-FU), are highly mutagenic to cancer cells and cultured cells. The systemic administration of these chemotherapies presents a potential genotoxic hazard to healthy tissues, however, the true mutational impact on normal cell...

Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1Δ /- mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1Δ...

Complex somatic genomic rearrangements and copy number alterations are hallmarks of nearly all cancers. We have developed an algorithm, LINX, to aid interpretation of structural variant and copy number data derived from short-read, whole-genome sequencing. LINX classifies raw structural variant calls into distinct events and predicts their effect o...

Immune surveillance escape is a hallmark of tumorigenesis. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed a p...

Background The collective of somatic mutations in a genome represents a record of mutational processes that have been operative in a cell. These processes can be investigated by extracting relevant mutational patterns from sequencing data. Results Here, we present the next version of MutationalPatterns, an R/Bioconductor package, which allows in-d...

Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive molecular characterization is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen metastatic tumor biopsies from 116 mUC patients who were scheduled for palliativ...

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that rare cancer patients benefit from approved anti-cancer drugs outside their label similar to common cancers. Patients and methods: In t...

Inflammatory liver disease increases the risk of developing primary liver cancer. The mechanism through which liver disease induces tumorigenesis remains unclear, but is thought to occur via increased mutagenesis. Here, we performed whole-genome sequencing on clonally expanded single liver stem cells cultured as intrahepatic cholangiocyte organoids...

Bladder cancer is a common cancer with a high recurrence rate and with limited progress in treatment and survival of patients with advanced stages of the disease. The tumorigenesis of bladder cancer is still poorly understood, but identification of genetic contributors to its development may provide leads for targeted therapeutic approaches. By an...

Background The collective of somatic mutations in a genome represents a record of mutational processes that have been operative in a cell. These processes can be investigated by extracting relevant mutational patterns from sequencing data. Results Here, we present the next version of MutationalPatterns, an R/Bioconductor package, which allows in-d...

Tumor tissue of origin (TOO) is an important factor for guiding treatment decisions. However, TOO cannot be determined for ~3% of metastatic cancer patients and are categorized as cancers of unknown primary (CUP). As whole genome sequencing (WGS) of tumors is now transitioning from the research domain to diagnostic practice in order to address the...

Tumor tissue of origin (TOO) is an important factor for guiding treatment decisions. However, TOO cannot be determined for ~3% of metastatic cancer patients and are categorized as cancers of unknown primary (CUP). As whole genome sequencing (WGS) of tumors is now transitioning from the research domain to diagnostic practice in order to address the...

Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment cour...

Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq—a protocol that integrates live-cell imaging of tumor organoid outgrowth and w...

Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN...

GRIDSS2 is the first structural variant caller to explicitly report single breakends—breakpoints in which only one side can be unambiguously determined. By treating single breakends as a fundamental genomic rearrangement signal on par with breakpoints, GRIDSS2 can explain 47% of somatic centromere copy number changes using single breakends to non-c...

p>Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options available. To identify novel targets for therapy, large-scale sequencing efforts are needed. The Cancer Genome Atlas (TCGA) initiative substantially improved our knowledge on the genomic and transcriptomic characteristics of primary UC (Robertson et al. Cell...

Whole-genome sequencing either alone or in combination with whole-transcriptome sequencing has started to be used to analyze clinical tumor samples to improve diagnosis, provide risk stratification, and select patient-specific therapies. Compared with current genomic testing strategies, largely focused on small number of genes tested individually o...

Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and w...

We present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories and their genomic localisation and properties. The analysis of 2778 primary and 3824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that all signatures operate dynamically in response to genomic states. Th...

Background Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling. Materials and methods The SENSOR trial was a...

Interrogating the tumor genome in its entirety by whole-genome sequencing (WGS) offers an unprecedented insight into the biology and pathogenesis of cancer, with potential impact on diagnostics, prognostication and therapy selection. WGS is able to detect sequence as well as structural variants and thereby combines central domains of cytogenetics a...

Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected...

TPS4154 Background: Esophageal cancer is the 6th leading cause of mortality worldwide, with an overall 5-year survival rate of 10%. This is in part due to more than 50% of patients presenting with irresectable or metastatic disease. With the introduction of definitive chemoradiation, 3-year survival rates of patients with irresectable tumors have r...

3013 Background: In the next few years numerous drugs will be approved for defined genomic targets, most of these in a tumor agnostic manner. Identifying patients who can benefit from this is critical for the future success of precision medicine, ideally using a single comprehensive test to detect all possible biomarkers. The WIDE study (WGS Implem...

Motivation Integration of viruses into infected host cell DNA can cause DNA damage and disrupt genes. Recent cost reductions and growth of whole genome sequencing has produced a wealth of data in which viral presence and integration detection is possible. While key research and clinically relevant insights can be uncovered, existing software has no...

Whole genome sequencing (WGS) using fresh frozen tissue and matched blood samples from cancer patients is becoming in reach as the most complete genetic tumor test. With a trend towards the availability of small biopsies and the need to screen an increasing number of (complex) biomarkers, the use of a single all-inclusive test is preferred over mul...

Introduction Personalized medicine-based treatments in advanced cancer hold the promise to offer substantial health benefits to genetic subgroups but require efficient biomarker-based patient stratification to match patients to the right treatment and may be expensive. Standard molecular diagnostics is currently very heterogeneous, and tests are of...

Purpose: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole genome sequencing (WGS) based treatment selection is expected to rapidly increase worldwide. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small ce...

Background Molecular characterization of primary urothelial carcinoma (UC) revealed molecular subtypes with different genomic, transcriptomic, and clinicopathological characteristics, which might guide therapeutic decision making. A comprehensive molecular characterization of metastatic UC (mUC), however, is currently lacking in the literature. Bec...

In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups...

The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously devel...

Complex somatic genomic rearrangement and copy number alterations (CNA) are hallmarks of nearly all cancers. Whilst whole genome sequencing (WGS) in principle allows comprehensive profiling of these events, biological and clinical interpretation remains challenging. We have developed LINX, a novel algorithm which allows interpretation of short-read...

Introduction Standard treatment for patients with metastatic urothelial carcinoma (mUC) consists of platinum-based chemotherapy, and recently systemic immunotherapy has become available. Nevertheless, the overall survival of mUC patients remains poor and new therapies are needed. To identify novel targets for therapy, large-scale sequencing efforts...