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  • 1.
    Borssen, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Cullman, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011Inngår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, nr 12, s. 1144-1151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51 61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

  • 2.
    Borssen, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 6, s. e65373-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

    Design and Methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

    Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

    Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

    Fulltekst (pdf)
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  • 3.
    Borssén, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation as a prognostic marker i acute lymphoblastic leukemia2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Most ALL cases originate from immature B-cells (BCP-ALL) and are characterized by reoccurring structural genetic aberrations. These aberrations hold information of the pathogenesis of ALL and are used for risk stratification in treatment. Despite increased knowledge of genetic aberrations in pediatric T-cell ALL (T-ALL), no reliable molecular genetic markers exist for identifying patients with higher risk of relapse. The lack of molecular prognostic markers is also evident in patients with relapsed ALL. During the last decades, aberrant epigenetic mechanisms including DNA methylation have emerged as important components in cancer development. Telomere maintenance is another important factor in malignant transformation and is crucial for long-term cell survival. Like DNA methylation, telomere length maintenance has also been implicated to reflect outcomes for patients with leukemia.

    In this thesis, the prognostic relevance of DNA methylation and telomere length was investigated in pediatric ALL at diagnosis and relapse. The telomere length (TL) was significantly shorter in diagnostic ALL samples compared to normal bone marrow samples collected at cessation of therapy, reflecting the proliferation associated telomere length shortening. Prognostic relevance of TL was shown in low-risk BCP-ALL patients where longer telomeres at diagnosis were associated with higher risk of relapse.

    Genome-wide methylation characterization by arrays in diagnostic T-ALL samples identified two distinct methylation subgroups denoted CIMP+ (CpG Island Methylator Phenotype high) and CIMP- (low). CIMP- T-ALL patients had significantly worse outcome compared to CIMP+ cases. These results were confirmed in a Nordic cohort treated according to the current NOPHO-ALL2008 protocol.  By combining minimal residual disease (MRD) status at treatment day 29 and CIMP status at diagnosis we could further separate T-ALL patients into risk groups.

    Likewise, the CIMP profile could separate relapsed BCP-ALL patients into risk groups, where the CIMP- cases had a significantly worse outcome compared to CIMP+ cases.  From these data we conclude that DNA methylation subgrouping is a promising prognostic marker in T-ALL, as well as in relapsed BCP-ALL two groups where reliable prognostic markers are currently missing. By elucidating the biology behind the different CIMP profiles, the pathogenesis of ALL will be further understood and may contribute to new treatment strategies.

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  • 4.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, nr 7, s. 1185-1192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

    Fulltekst (pdf)
    fulltext
  • 5.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Nordlund, J
    Haider, Z
    Landfors, M
    Larsson, P
    Forestier, E
    Heyman, M
    Hultdin, M
    Lönnerholm, G
    Syvänen, AC
    Degerman, S
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemiaManuskript (preprint) (Annet vitenskapelig)
  • 6.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordlund, Jessica
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Jónsson, Ólafur Gísli
    Frost, Britt-Marie
    Palle, Josefine
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lönnerholm, Gudmar
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018Inngår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, artikkel-id 31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

    Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

    Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

    Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

    Fulltekst (pdf)
    fulltext
  • 7.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Chranowska, Krystyna H.
    Department of Medical Genetics, Childrens Memorial Health institute, 04-730 Warsaw, Poland.
    Siwicki, Jan Konrad
    Department of Immunology, maria Sklodowska-Curie Memorial Cancer Centre and institute of Oncology, 02-781, Warsaw, Poland.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Senescence bypass and immortalization of T cell cultures are linked to stepwise DNA methylation changesManuskript (preprint) (Annet vitenskapelig)
  • 8.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evelönn, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keith, W. Nicol
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014Inngår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 7, s. 606-615Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

    Fulltekst (pdf)
    fulltext
  • 9.
    Pramanik-Jonsson, Lotta
    et al.
    Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet; Section of Pediatric Hematology, Immunology and HCT, Astrid Lindgren Children's Hospital.
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Section of Pediatric Hematology and Oncology, Child and Adolescent Medical Center, University Hospital of Umeå, Umeå, Sweden.
    Vonlanthen, Sofie
    Department of Clinical Immunology and Transfusion Medicine, Medical Diagnostics Center, Karolinska University Hospital, Stockholm, Sweden.
    Nilsson, Frans
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Section of Pediatric Hematology and Oncology, Child and Adolescent Medical Center, University Hospital of Umeå, Umeå, Sweden.
    Sundin, Mikael
    Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet; Section of Pediatric Hematology, Immunology and HCT, Astrid Lindgren Children's Hospital.
    Severe thrombocytopenia due to bone marrow failure in children with dyskeratosis congenita does not respond to eltrombopag treatment: case series2024Inngår i: Journal of Pediatric Hematology/Oncology, ISSN 1077-4114, E-ISSN 1536-3678, Vol. 46, nr 1, s. 57-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dyskeratosis congenita is a rare inherited disease with classic cutaneous symptoms, sometimes accompanied with more severe extracutaneous manifestations such as bone marrow failure, which can be lethal. Eltrombopag is an orally available thrombopoietin receptor agonist in clinical use for increasing platelet levels in patients with immune thrombocytopenia and aplastic anemia. Here, 3 pediatric patients with dyskeratosis congenita are presented with varying disease severity, in which off-label eltrombopag treatment had no clinical effect on bone marrow failure. This, in addition to the negative results in a previous case report, supports the preclusion of eltrombopag use in dyskeratosis congenita.

  • 10.
    Tesi, Bianca
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden; Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
    Robinson, Kristina Lagerstedt
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden.
    Abel, Frida
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Díaz de Ståhl, Teresita
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
    Orrsjö, Sara
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Poluha, Anna
    Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hellberg, Maria
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Region Skåne, Lund, Sweden.
    Wessman, Sandra
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
    Samuelsson, Sofie
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Region Skåne, Lund, Sweden.
    Frisk, Tony
    Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Vogt, Hartmut
    Crown Princess Victoria Children's Hospital, Division of Children's and Women's Health, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Henning, Karin
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Sabel, Magnus
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden; Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ek, Torben
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden; Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Pal, Niklas
    Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Nyman, Per
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
    Giraud, Geraldine
    Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Pediatric Oncology, Uppsala University Children's Hospital, Uppsala, Sweden; Department of Women's and Children's Health, Uppsala University, Sweden.
    Wille, Joakim
    Childhood Cancer Center, Skåne University Hospital, Lund, Sweden.
    Pronk, Cornelis Jan
    Childhood Cancer Center, Skåne University Hospital, Lund, Sweden; Division of Molecular Hematology/Wallenberg Center for Molecular Medicine, Lund University, Sweden.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Borssén, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Fili, Maria
    Division of Eye and Vision, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St. Erik Eye Hospital, Stockholm, Sweden.
    Stålhammar, Gustav
    Division of Eye and Vision, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; St. Erik Eye Hospital, Stockholm, Sweden.
    Herold, Nikolas
    Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Tettamanti, Giorgio
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Maya-Gonzalez, Carolina
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Arvidsson, Linda
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Region Skåne, Lund, Sweden.
    Rosén, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ekholm, Katja
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden.
    Kuchinskaya, Ekaterina
    Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
    Hallbeck, Anna-Lotta
    Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Nordling, Margareta
    Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Palmebäck, Pia
    Department of Clinical Genetics, Linköping University Hospital, Linköping, Sweden.
    Kogner, Per
    Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Smoler, Gunilla Kanter
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lähteenmäki, Päivi
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Fransson, Susanne
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Martinsson, Tommy
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Shamik, Alia
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
    Mertens, Fredrik
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Region Skåne, Lund, Sweden.
    Rosenquist, Richard
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden; Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Wirta, Valtteri
    Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; Science for Life Laboratory, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institutet of Technology, Stockholm, Sweden.
    Tham, Emma
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden.
    Grillner, Pernilla
    Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Sandgren, Johanna
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
    Ljungman, Gustaf
    Pediatric Oncology, Uppsala University Children's Hospital, Uppsala, Sweden; Department of Women's and Children's Health, Uppsala University, Sweden.
    Gisselsson, David
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Region Skåne, Lund, Sweden.
    Taylan, Fulya
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden.
    Nordgren, Ann
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors: a nationwide, prospective Swedish study2024Inngår i: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 39, artikkel-id 100881Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.

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