Kuiper group

Investigators: Jette Bakhuizen (clinical geneticist i.t., researcher), Marjolijn Jongmans (clinical geneticist, lead)

Recognition of cancer predisposition syndromes is important for treatment decisions as well as for risk-based surveillance of the patient and family members. We have assessed the prevalence of cancer predisposition in children (Bakhuizen et al 2023), and we compared extensive phenotype-agnostic germline sequencing on all known childhood CPS genes (n=142) with phenotype-driven genetic testing in a routine clinical setting (Bakhuizen et al., 2024). Phenotype-agnostic germline sequencing had limited added value. Therefore, in the routine diagnostic pipeline, we have chosen to implement routine germline sequencing only for a concise panel of genes that are crucial for establishing the correct tumor diagnosis, informing treatment choices, and determining eligibility for clinical trials.

(Supported by KIKA, project 355)

Investigators: Franziska Oberhammer (PhD student), Freerk van Dijk (bioinformatician)

Up to a third of the children that are diagnosed with Wilms tumor have an underlying germline predisposition (Hol et al, 2023). Recognizing (epi)genetic predisposition in Wilms tumors can be a considerable challenge given the variability in phenotypes, the presence of germline mosaicism, and the existence of undiscovered genes. This project is dedicated to the identification of molecular signatures associated with childhood CPS through the analysis of transcriptome and methylome profiling data derived from a cohort of Wilms tumors. By leveraging these molecular signatures, our objective is to pinpoint individuals with an elevated risk of harboring a (predefined) CPS. Ultimately, our aim is to create a classifier based on transcriptome and methylome somatic signatures, facilitating tumor-based detection of Wilms tumor predisposition.

(Supported by KIKA, project 522)

Investigators: Lianne Suurenbroek (PhD student), Sophie van Peer (PhD student) Michelle Kleisman (bioinformatician)

DNA repair genes associated with cancer susceptibility at adulthood also give rise to childhood CPS when germline pathogenic variants are present in a biallelic state. Examples include the mismatch repair genes (constitutional mismatch repair deficiency), the DNA damage response gene ATM (Ataxia Telangiectasia), and the DNA double strand break repair genes BRCA1, BRCA2, and PALB2 (Fanconi Anemia). Therefore, these genes are included in gene panels of childhood CPS genes, resulting in recurrent findings of heterozygous carriers for which the causal relation with the childhood cancer is uncertain. In this project we use tumor-specific mutational features to establish if, how frequent and in what tumor types heterozygous germline pathogenic variants are causal. Revealing causality is important for counseling and surveillance of the child and its family but, in addition, may also have implications for therapy when the tumor is DNA repair deficient.

(Supported by KIKA, project 484)

Investigators: Lianne Suurenbroek (PhD-student), Dilys Weijers (PhD student)

Germline pathogenic variants in key components of DNA damage response and repair pathways can cause so-called DNA repair disorders with increased risk to develop cancer. Examples are Ataxia telangiectasia, constitutional mismatch repair deficiency (CMMRD), Fanconi anemia, Li-Fraumeni syndrome, Nijmegen Breakage Syndrome, Bloom syndrome, and Xeroderma pigmentosum. We aim to define and characterize the mutational signatures associated with DNA repair defects, with the diagnostic potential to effectively identify genetic predisposition in children with cancer, and predict a risk for resistance or hypersensitivity of treatment with standard and novel DNA damaging chemo- and radiotherapy.

(Supported by KWF, project 12090)

Investigators: Franziska Oberhammer (PhD student), Nienke van Engelen (PhD student)

Comprehensive genomic studies and technological developments have increased the frequency of cancer predisposition syndromes diagnosed in routine pediatric cancer care. Still, we are confronted with families that present with multiple pediatric cancers, in which an underlying germline genetic cause is not found. This results in high levels of uncertainty in these families, since we cannot reveal which family members are at risk. Also, installing efficient surveillance protocols is challenging without a genetic diagnosis.   

In close collaboration with KiTZ Hopp Children’s Cancer Center in Heidelberg (drs. Pajtler, Autry and Hirsch), we aim to find novel genetic causes of pediatric cancers with familial presentation by performing comprehensive genomic and transcriptomic analyses of normal and tumor tissues of multiple cancer patients and/or cancers in each family to find connections between germline variants and recurrent somatic events in the tumors.

(Supported by Ars Donandi: De Hoop Leven fonds and Stichting Tabernaleporis)

Investigators: Emma Kroeze (postdoc), Michelle Kleisman (bioinformatician), Reno Bladergroen (research technician), Jan Loeffen (pediatric oncologist, lead)

T-cell lymphoblastic lymphoma (T-LBL) is a malignancy of immature T-cells in children and young adults. In children, T-LBL accounts for a quarter of the non-Hodgkin lymphomas. During the last decade, several genetic risk factors have been identified, but most did not result in clinically relevant risk groups. We recently discovered gene fusions involving NOTCH1 with at least three different fusion partners (Kroeze et al, 2024). These T-LBL patients with NOTCH1 fusions have a cumulative incidence of relapse of 67% and an overall survival of 10-20%. Since this T-LBL subgroup appears to represent the majority of relapses, upon which salvage rates are extremely poor, this group can be considered very high risk (VHR). Unfortunately, however, methods for effective detection of these NOTCH1 fusions are currently underdeveloped, which hampers urgent follow-up studies. We aim to identify and implement biomarkers that can improve routine detection a clinical setting and to further develop the promising blood biomarker CCL17 (TARC). Furthermore, in close collaboration with the Van Leeuwen lab, we aim to unravel the underlying mechanisms of resistance to standard therapy in NOTCH1 fusion-positive T-LBL, and identify novel potential targets for treatment of this VHR T-LBL subgroup with specific focus on NOTCH1 inhibition.

(Supported by the Princess Máxima Center Foundation)

Investigators: Cedric van der Ham (PhD student), Lianne Suurenbroek (PhD student), Michelle Kleisman (bioinformatician)

In this project we study which mutational processes occur during the development of acute lymphoblastic leukemia. By characterizing the sources of stress and DNA damage that leukemic cells experience we aim to understand the intrinsic and external mutagens shaping the leukemia, including APOBEC mutagenesis in ETV6::RUNX1 positive ALL, UV-associated damage in aneuploid ALL subtypes and thiopurine-associated DNA damage in ALL relapse. At initial diagnosis we aim to identify subgroups of patients who are potentially at higher risk of relapse or more prone to specific chemotherapeutics. Furthermore, analysis of the mutational processes in relapse allows us to better understand the toxic effects of chemotherapy and the role of chemotherapy in clonal selection.

(Supported by KWF, project 12484).

• Molecular footprints of Wilms tumor predisposition: towards implementation of a classifier to recognize hereditary cases (with L. Kester and Van den Heuvel-Eibrink group) – KiKa grant (2025 - 2029)

• Pathogenic germline variants in adult-onset cancer predisposition genes in children with cancer: analyzing causality on a case-by-case basis – KiKa grant (2024 - 2028)

• Tumor-based molecular signatures of childhood cancer predisposition - CoFund Butterfly (2023 - 2027) – News article

• Mechanisms of hypermutation in relapsed acute lymphoblastic leukemia in children and implications for treatment – Dutch Cancer Society (KWF) grant supported by Fight Cancer (2020 - 2024)

• Defining mutational footprints predicting genetic predisposition and therapy sensitivity in cancer – Dutch Cancer Society (KWF) grant (2019 - 2024)

Twinning program KiTZ

Finding novel cancer predisposition genes in unexplained familial presentations of childhood cancer using an integrated germline-tumor approach - with Pajtler, RJ Autry and S. Hirsch (KiTZ) (2024 - 2026)

• van Engelen N, Roest M, van Dijk F, Sonneveld E, Bladergroen R, van Reijmersdal SV, van der Velden VHJ, Hoogeveen PG, Kors WA, Waanders E, Jongmans MCJ, Kuiper RP. A novel germline PAX5 single exon deletion in a pediatric patient with precursor B-cell leukemia. Leukemia. 2023 Sep;37(9):1908-1911. doi: 10.1038/s41375-023-01991-0. Epub 2023 Aug 5. PMID: 37543654; PMCID: PMC10457179.

• Bakhuizen JJ, Hopman SMJ, Bosscha MI, Dommering CJ, van den Heuvel-Eibrink MM, Hol JA, Kester LA, Koudijs MJ, Langenberg KPS, Loeffen JLC, van der Lugt J, Moll AC, van Noesel MM, Smetsers SE, de Vos-Kerkhof E, Merks JHM, Kuiper RP, Jongmans MCJ. Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm. JAMA Netw Open. 2023 Feb 1;6(2):e2254157. doi: 10.1001/jamanetworkopen.2022.54157. PMID: 36735256; PMCID: PMC9898819.

• Hol JA, Kuiper RP, van Dijk F, Waanders E, van Peer SE, Koudijs MJ, Bladergroen R, van Reijmersdal SV, Morgado LM, Bliek J, Lombardi MP, Hopman S, Drost J, de Krijger RR, van den Heuvel-Eibrink MM, Jongmans MCJ. Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization. J Clin Oncol. 2022 Jun 10;40(17):1892-1902. doi: 10.1200/JCO.21.02510. Epub 2022 Mar 1. PMID: 35230882; PMCID: PMC9177240.

• Hol JA, Diets IJ, de Krijger RR, van den Heuvel-Eibrink MM, Jongmans MC, Kuiper RP. TRIM28 variants and Wilms' tumour predisposition. J Pathol. 2021 Jul;254(4):494-504. doi: 10.1002/path.5639. Epub 2021 Mar 15. PMID: 33565090; PMCID: PMC8252630.

• van der Ham CG, Suurenbroek LC, Kleisman MM, Antić Ž, Lelieveld SH, Yeong M, Westera L, Sonneveld E, Hoogerbrugge PM, van der Velden VHJ, van Leeuwen FN, Kuiper RP. Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia. Leukemia. 2024 Nov;38(11):2366-2375. doi: 10.1038/s41375-024-02403-7. Epub 2024 Sep 4. PMID: 39232206

• Bakhuizen JJ, van Dijk F, Koudijs MJ, Bladergroen RS, Bon SBB, Hopman SMJ, Kester LA, Kranendonk MEG, Loeffen JLC, Smetsers SE, Sonneveld E, Tachdjian M, de Vos-Kerkhof E, Goudie C, Merks JHM, Kuiper RP, Jongmans MCJ. Comparison of clinical selection-based genetic testing with phenotype-agnostic extensive germline sequencing to diagnose genetic predisposition in children with cancer: a prospective diagnostic study. Lancet Child Adolesc Health. 2024 Oct;8(10):751-761. doi: 10.1016/S2352-4642(24)00144-5. Epub 2024 Aug 16. PMID: 39159644

• Kroeze E, Kleisman MM, Kester LA, Scheijde-Vermeulen MA, Sonneveld E, Buijs-Gladdines JGC, Hagleitner MM, Meyer-Wentrup FAG, Veening MA, Beishuizen A, Meijerink JPP, Loeffen JLC, Kuiper RP. NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: A high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker. Hemasphere. 2024 Jun 27;8(7):e117. doi: 10.1002/hem3.117. eCollection 2024 Jul. PMID: 38948925