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Tesi, B., Lagerstedt Robinson, K., Abel, F., Díaz de Ståhl, T., Orrsjö, S., Poluha, A., . . . Nordgren, A. (2024). Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors: a nationwide, prospective Swedish study. The Lancet Regional Health: Europe, 39, Article ID 100881.
Open this publication in new window or tab >>Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors: a nationwide, prospective Swedish study
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2024 (English)In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 39, article id 100881Article in journal (Refereed) Published
Abstract [en]

Background

Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.

Methods

gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.

Findings

The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).

Interpretation

Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Childhood cancer predisposition, Whole-genome sequencing, Germline variants, Somatic mutations
National Category
Cancer and Oncology Pediatrics
Identifiers
urn:nbn:se:uu:diva-525280 (URN)10.1016/j.lanepe.2024.100881 (DOI)001234444700001 ()38803632 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Childhood Cancer FoundationStockholm County Council
Note

De fyra sista författarna delar sistaförfattarskapet

Available from: 2024-03-20 Created: 2024-03-20 Last updated: 2024-06-12Bibliographically approved
Holmberg Olausson, K. O., Borgenvik, A., Zhao, M., Giraud, G. & Swartling, F. J. (2024). Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies. Cancers, 16(9), Article ID 1752.
Open this publication in new window or tab >>Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies
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2024 (English)In: Cancers, ISSN 2072-6694, Vol. 16, no 9, article id 1752Article, review/survey (Refereed) Published
Abstract [en]

Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

Place, publisher, year, edition, pages
MDPI, 2024
Keywords
pediatric brain cancer, leptomeningeal spread, SHH, MYC, relapse, metastasis, targeted therapy
National Category
Cancer and Oncology Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-528811 (URN)10.3390/cancers16091752 (DOI)001219774100001 ()38730706 (PubMedID)
Available from: 2024-06-13 Created: 2024-06-13 Last updated: 2024-06-13Bibliographically approved
Krynina, O., Díaz de Ståhl, T., Jylhä, C., Arthur, C., Giraud, G., Nyman, P., . . . Sandvik, U. (2024). The potential of liquid biopsy for detection of the KIAA1549-BRAF fusion in circulating tumor DNA from children with pilocytic astrocytoma. Neuro-Oncology Advances, 6(1), Article ID vdae008.
Open this publication in new window or tab >>The potential of liquid biopsy for detection of the KIAA1549-BRAF fusion in circulating tumor DNA from children with pilocytic astrocytoma
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2024 (English)In: Neuro-Oncology Advances, E-ISSN 2632-2498, Vol. 6, no 1, article id vdae008Article in journal (Refereed) Published
Abstract [en]

Background

Low-grade gliomas (LGGs) represent children’s most prevalent central nervous system tumor, necessitating molecular profiling to diagnose and determine the most suitable treatment. Developing highly sensitive screening techniques for liquid biopsy samples is particularly beneficial, as it enables the early detection and molecular characterization of tumors with minimally invasive samples.

Methods

We examined CSF and plasma samples from patients with pilocytic astrocytoma (PA) using custom multiplexed droplet digital polymerase chain reaction (ddPCR) assays based on whole genome sequencing data. These assays included a screening test to analyze BRAF duplication and a targeted assay for the detection of patient-specific KIAA1549::BRAF fusion junction sequences or single nucleotide variants.

Results

Our findings revealed that 5 out of 13 individual cerebrospinal fluid (CSF) samples tested positive for circulating tumor DNA (ctDNA). Among these cases, 3 exhibited the KIAA1549::BRAF fusion, which was detected through copy number variation (CNV) analysis (n = 1) or a fusion-specific probe (n = 2), while 1 case each displayed the BRAF V600E mutation and the FGFR1 N577K mutation. Additionally, a quantitative analysis of cell-free DNA (cfDNA) concentrations in PA CSF samples showed that most cases had low cfDNA levels, below the limit of detection of our assay (<1.9 ng).

Conclusions

While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
cerebrospinal fluid, cfDNA, ddPCR, KIAA1549::BRAF, pilocytic astrocytoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-524335 (URN)10.1093/noajnl/vdae008 (DOI)001163714900001 ()38371226 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish Childhood Cancer Foundation, KP2021-0017Swedish Childhood Cancer Foundation, TJ2021-0125Swedish Cancer Society, 22 2451Region Stockholm, FoUI-961732Region Stockholm, FoUI-973659
Available from: 2024-03-01 Created: 2024-03-01 Last updated: 2024-03-01Bibliographically approved
Borgenvik, A., Holmberg, K. O., Bolin, S., Zhao, M., Savov, V., Rosén, G., . . . Swartling, F. J. (2022). Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma. Cancer Research, 82(24), 4586-4603
Open this publication in new window or tab >>Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
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2022 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 82, no 24, p. 4586-4603Article in journal (Refereed) Published
Abstract [en]

Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-494638 (URN)10.1158/0008-5472.CAN-22-2108 (DOI)000907019300001 ()36219398 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council, VR-2017-02074EU, Horizon 2020, 640275Swedish Childhood Cancer FoundationSwedish Society of MedicineThe Swedish Brain FoundationÅke Wiberg FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation
Available from: 2023-01-20 Created: 2023-01-20 Last updated: 2023-01-20Bibliographically approved
Jadersten, M., Lilienthal, I., Tsesmetzis, N., Lourda, M., Bengtzen, S., Bohlin, A., . . . Herold, N. (2022). Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial. Journal of Internal Medicine, 292(6), 925-940
Open this publication in new window or tab >>Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
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2022 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 292, no 6, p. 925-940Article in journal (Refereed) Published
Abstract [en]

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission. Conclusion Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study.

Place, publisher, year, edition, pages
John Wiley & SonsWiley, 2022
Keywords
acute myeloid leukaemia, cytarabine, hydroxyurea, precision medicine, SAMHD1, targeted therapy
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-494487 (URN)10.1111/joim.13553 (DOI)000843672900001 ()35934913 (PubMedID)
Funder
Swedish Childhood Cancer Foundation, TJ2018-0128Swedish Childhood Cancer Foundation, PR20190100Swedish Childhood Cancer Foundation, TJ2021-0080Swedish Childhood Cancer Foundation, OA2011-0001Swedish Childhood Cancer Foundation, KP2018-0005Swedish Childhood Cancer Foundation, PR2018-0016Swedish Childhood Cancer Foundation, PR2020-0077Swedish Childhood Cancer Foundation, TJ2019-0072Knut and Alice Wallenberg Foundation, KAW 2015.0291Swedish Foundation for Strategic Research, SSF SB16-0058Swedish Research Council, 2017-06095Swedish Research Council, 2020-01184Swedish Cancer Society, 21 1494 PjSwedish Cancer Society, CAN 2017/517Region Stockholm, 20200246Region Stockholm, K2892-2016
Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2024-01-15Bibliographically approved
Hoffman, L. M., van Zanten, S. E. M., Colditz, N., Baugh, J., Chaney, B., Hoffmann, M., . . . Fouladi, M. (2018). Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. Journal of Clinical Oncology, 36(19), 1963-1972
Open this publication in new window or tab >>Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries
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2018 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 19, p. 1963-1972Article in journal (Refereed) Published
Abstract [en]

Purpose

Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs).

Materials and Methods

Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia.

Results

Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration (P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002).

Conclusion

We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

Place, publisher, year, edition, pages
AMER SOC CLINICAL ONCOLOGY, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-363066 (URN)10.1200/JCO.2017.75.9308 (DOI)000441233400011 ()29746225 (PubMedID)
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-10-18Bibliographically approved
Lobon-Iglesias, M. J., Giraud, G., Castel, D., Philippe, C., Debily, M. A., Briandet, C., . . . Grill, J. (2018). Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?. Journal of Neuro-Oncology, 137(1), 111-118
Open this publication in new window or tab >>Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?
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2018 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 137, no 1, p. 111-118Article in journal (Refereed) Published
Abstract [en]

Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Brainstem glioma, H3K27M mutation, Midline infiltrative glioma, Steroid-independence
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-348978 (URN)10.1007/s11060-017-2702-7 (DOI)000425763900013 ()29198053 (PubMedID)
Funder
Swedish Childhood Cancer Foundation
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-04-26Bibliographically approved
Bolin, S., Borgenvik, A., Savov, V., Holmberg Olausson, K., Zhao, M., Rosén, G., . . . Swartling, F. J. Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence.
Open this publication in new window or tab >>Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence
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(English)In: Article in journal (Refereed) Submitted
Abstract [en]

Tumor recurrence is a slow biological process involving therapy resistance, immune escape, and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified a significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two-thirds of medulloblastoma. To follow relapse at the single-cell level we developed an inducible dual Tet model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells by doxycycline. SOX9 promoted immune es-cape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory, and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.

Keywords
SOX9, medulloblastoma, relapse, recurrence, MYCN, mouse model, pediatric cancer
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-450047 (URN)
Available from: 2021-08-19 Created: 2021-08-19 Last updated: 2021-08-19
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2771-9889

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