Group leader: Prof. Roland Kuiper
Childhood cancer predisposition
An estimated 6-10% of the children that are diagnosed with cancer carry a germline mutation in one of the known cancer predisposing genes. Recognition of these syndromes usually occurs on the basis of clinical phenotypes, family history, or tumor types. However, in a significant number of cases an underlying heritable cause of cancer initiation is unknown, or the patient is not recognized as being at risk due to absence of these clinical signs. We aim to identify and characterize novel genetic causes of childhood cancer predisposition, and study its prevalence in the population of children with cancer. We use a patient-parent based sequencing approach to efficiently identify de novo mutations and recessive inheritance. Furthermore, in the Predict study we compare the efficiency of clinically driven recognition of cancer predisposition among children with cancer with standardized sequencing of all childhood cancer predisposition genes.
Furthermore, we characterize the genomics of the tumor samples of these patients to correlate identified germline variants to specific aberrations or pathways of tumor developments. We currently run projects on leukemia and lymphoma predisposition, renal cancer predisposition and DNA repair syndromes. Furthermore, we perform a comprehensive genetic characterization of adolescent and familial urinary bladder cancer patients in order to identify causative germline mutations.
The growing availability of genome-wide profiling and sequencing technologies revolutionizes our understanding of cancer genomes, and provides us with opportunities to better predict risks for cancer development. Single gene mutations have been identified with a major impact on cancer risk and outcome. In the majority of cases, however, the cause of cancer onset and progression is dependent on a more complex interplay between genetic factors, which is more challenging to elucidate. To unravel this interplay of genetic factors, we apply sophisticated analyses of whole genome sequencing and transcriptomics data of both tumor samples and normal inherited DNA, with the ultimate aim to identify novel genes and mechanisms involved in an individual’s risk for cancer development and therapy response.
Renal cancer predisposition
Genetic predisposition is recognized in a substantial subset of children with renal tumors, particularly in patients with well-depicted syndromes, bilateral tumors, or a family history of cancer. For the majority of these cases, however, the genetic cause remains unknown. Furthermore, upfront recognition of enhanced genetic susceptibility in children with renal cancer is still problematic, and its prevalence is currently unknown. In collaboration with the group of prof. dr. Marry van den Heuvel-Eibrink, we investigate the frequency of known and novel genetic causes of renal cancer predisposition in children by whole exome sequencing of patients, parents and, where available, tumors, and structurally document phenotypic characteristics of these patients to optimize genetic counseling and surveillance.
Urinary bladder cancer predisposition
In collaboration with prof. dr. Bart Kiemeney and dr. Sita Vermeulen (Radboud university medical center, Nijmegen, The Netherlands) and deCODE Genetics (Reykjavik, Iceland), we currently perform a large whole genome sequencing study of familial and adolescent (<30 years of age) urinary bladder cancer patients in a patient-parent trio approach, in order to identify novel cancer predisposing genes and mechanisms. Tumor samples will be sequenced where available in order to perform an integrated germline-tumor analysis.
The genetic basis of relapsed acute lymphoblastic leukemia
The overall prognosis of children with B-cell progenitor (BCP) ALL has improved enormously during the last decades, with 5-year event-free survival reaching 90%. Despite these improvements, cure rates for patients that relapse remain poor with survival rates ranging between 20-65% as high treatment intensity is needed to induce a long-term second remission. Furthermore, the adverse effect of this intensified treatment potentially involves higher rates of treatment-related toxicity and late effects. The aim of our group is to unravel the genomic landscape of relapsed BCP ALL to identify novel genes, alterations and mechanisms associated with the occurrence of relapse. We perform whole exome and whole genome sequencing to study the genomic landscape of relapsed ALL. Furthermore, we use deep-sequencing techniques to investigate the role of subclonal mutations. Targeted locus amplification (TLA) is used to identify fusion partners that can be used for minimal residual disease monitoring. In collaboration with the Van Leeuwen group, we study the consequences of genomic alterations in therapy response. Using reverse genetic screens in leukemia cell lines and mouse models, we aim to identify new clues and approaches to circumvent therapy resistance or improve sensitivity of standard treatment in the context of specific genetic alterations.
We focus on subclonal diversity in leukemia and its relevance for therapy response and outcome. The clonal evolution of leukemia is dynamic and strongly influenced by external factors, including therapy. Optimal treatment strategies therefore rely on the ability to constantly monitor not only the clearance of the leukemic cell population as a whole, but also those of minor subclones relative to each other. We invest in technologies that make this monitoring technically possible. I believe that most genetic factors that affect outcome, do so within a certain genomic context. Detection of cooperating events may therefore become of significant value. To be able to detect subclones in their genomic context, I expect that single cell sequencing will become increasingly important.
Technological developments in genomics research have a considerable impact on our current understanding of the genomic architecture of leukemia and will provide enormous opportunities for improved diagnosis, prognosis, and treatment. Research to test whether and how these technologies can be implemented in routine diagnostics in a cost-effective manner is extremely important for the patient. We create and test novel strategies to detect clinically relevant genomic alterations including subclonal mutations and gene fusions, which can be used to adapt the diagnostic pipeline of genetic screening of childhood ALL patients before and during treatment for optimal therapy decision making (targeted therapies).
Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, Ligtenberg MJL, Vos JR, Ten Broeke SW, de Miranda NFCC, Kuiper RA, Kamping EJ, Jansen EAM, Vink-Börger ME, Popp I, Lang A, Spier I, Hüneburg R, James PA, Li N, Staninova M, Lindsay H, Cockburn D, Spasic-Boskovic O, Clendenning M, Sweet K, Capellá G, Sjursen W, Høberg-Vetti H, Jongmans MC, Neveling K, Geurts van Kessel A, Morreau H, Hes FJ, Sijmons RH, Schackert HK, Ruiz-Ponte C, Dymerska D, Lubinski J, Rivera B, Foulkes WD, Tomlinson IP, Valle L, Buchanan DD, Kenwrick S, Adlard J, Dimovski AJ, Campbell IG, Aretz S, Schindler D, van Wezel T, Hoogerbrugge N, Kuiper RP. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. (2019) Cancer Cell. 35:256-266. PubMed PMID: 30753826
Diets IJ, Waanders E, Ligtenberg MJ, van Bladel DAG, Kamping EJ, Hoogerbrugge PM, Hopman S, Olderode-Berends MJ, Gerkes EH, Koolen DA, Marcelis C, Santen GW, van Belzen MJ, Mordaunt D, McGregor L, Thompson E, Kattamis A, Pastorczak A, Mlynarski W, Ilencikova D, van Silfhout AV, Gardeitchik T, de Bont ES, Loeffen J, Wagner A, Mensenkamp AR, Kuiper RP, Hoogerbrugge N, Jongmans MC. High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer. (2018) Clin Cancer Res. 24:1594-1603. PubMed PMID: 29351919.
Drost J, van Boxtel R, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. (2017) Science. 358:234-238. PubMed PMID: 28912133. Waanders E, Scheijen B, Jongmans MC, Venselaar H, van Reijmersdal SV, van Dijk AH, Pastorczak A, Weren RD, van der Schoot CE, van de Vorst M, Sonneveld E, Hoogerbrugge N, van der Velden VH, Gruhn B, Hoogerbrugge PM, van Dongen JJ, Geurts van Kessel A, van Leeuwen FN, Kuiper RP. Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences. (2017) Leukemia. 31:821-828. PubMed PMID: 27733777.
Waanders E, Hebeda KM, Kamping EJ, Groenen PJ, Simons A, Hoischen A, Jongmans MC, Hoogerbrugge PM, van Leeuwen FN, Kuiper RP, Te Loo DM. Independent development of lymphoid and histiocytic malignancies from a shared early precursor. (2016) Leukemia. 30:955-8. PubMed PMID: 26202925
Weren RD, Ligtenberg MJ, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, Hoischen A, Shendure J, Boyle EA, Kamping EJ, Nagtegaal ID, Tops BB, Nagengast FM, Geurts van Kessel A, van Krieken JH, Kuiper RP, Hoogerbrugge N. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. (2015) Nat Genet. 47:668-71. PubMed PMID: 25938944.
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