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1. Genetic counselling legislation and practice in cancer in EU Member States

Author

McCrary, J. Matt, Van Valckenborgh, Els, Poirel, Hélène A., de Putter, Robin, van Rooij, Jeroen, Horgan, Denis, Dierks, Marie Luise, Antonova, Olga, Brunet, Joan, Chirita-Emandi, Adela, Colas, Chrystelle, Dalmas, Miriam, Ehrencrona, Hans, Grima, Claire, Janavičius, Ramūnas, Klink, Barbara, Koczok, Katalin, Krajc, Mateja, Lace, Baiba, Leitsalu, Liis, Mistrik, Martin, Paneque, Milena, Primorac, Dragan, Roetzer, Katharina M., Ronez, Joelle, Slámová, Lucie, Spanou, Elena, Stamatopoulos, Kostas, Stoklosa, Tomasz, Strang-Karlsson, Sonja, Szakszon, Katalin, Szczałuba, Krzysztof, Turner, Jacqueline, van Dooren, Marieke F., van Zelst-Stams, Wendy A.G., Vassallo, Loredana Maria, Wadt, Karin A.W., Žigman, Tamara, Ripperger, Tim, Genuardi, Maurizio, Van den Bulcke, Marc, Bergmann, Anke Katharina, McCrary, J. Matt, Van Valckenborgh, Els, Poirel, Hélène A., de Putter, Robin, van Rooij, Jeroen, Horgan, Denis, Dierks, Marie Luise, Antonova, Olga, Brunet, Joan, Chirita-Emandi, Adela, Colas, Chrystelle, Dalmas, Miriam, Ehrencrona, Hans, Grima, Claire, Janavičius, Ramūnas, Klink, Barbara, Koczok, Katalin, Krajc, Mateja, Lace, Baiba, Leitsalu, Liis, Mistrik, Martin, Paneque, Milena, Primorac, Dragan, Roetzer, Katharina M., Ronez, Joelle, Slámová, Lucie, Spanou, Elena, Stamatopoulos, Kostas, Stoklosa, Tomasz, Strang-Karlsson, Sonja, Szakszon, Katalin, Szczałuba, Krzysztof, Turner, Jacqueline, van Dooren, Marieke F., van Zelst-Stams, Wendy A.G., Vassallo, Loredana Maria, Wadt, Karin A.W., Žigman, Tamara, Ripperger, Tim, Genuardi, Maurizio, Van den Bulcke, Marc, and Bergmann, Anke Katharina

Abstract

Background: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. Methods: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. Results: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the ‘who, what, when and where’ of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the ‘most important change’ which would improve practice. Conclusions: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.

Published
2024

2. European standard clinical practice - Key issues for the medical care of individuals with familial leukemia

Author

Förster, A, Davenport, C, Duployez, N, Erlacher, M, Ferster, A, Fitzgibbon, J, Göhring, G, Hasle, H, Jongmans, M, Kolenova, A, Kronnie, G, Lammens, T, Mecucci, C, Mlynarski, W, Niemeyer, C, Sole, F, Szczepanski, T, Waanders, E, Biondi, A, Wlodarski, M, Schlegelberger, B, Ripperger, T, Förster, Alisa, Davenport, Claudia, Duployez, Nicolas, Erlacher, Miriam, Ferster, Alina, Fitzgibbon, Jude, Göhring, Gudrun, Hasle, Henrik, Jongmans, Marjolijn C, Kolenova, Alexandra, Kronnie, Geertruijte, Lammens, Tim, Mecucci, Cristina, Mlynarski, Wojciech, Niemeyer, Charlotte M, Sole, Francesc, Szczepanski, Tomasz, Waanders, Esmé, Biondi, Andrea, Wlodarski, Marcin, Schlegelberger, Brigitte, Ripperger, Tim, Förster, A, Davenport, C, Duployez, N, Erlacher, M, Ferster, A, Fitzgibbon, J, Göhring, G, Hasle, H, Jongmans, M, Kolenova, A, Kronnie, G, Lammens, T, Mecucci, C, Mlynarski, W, Niemeyer, C, Sole, F, Szczepanski, T, Waanders, E, Biondi, A, Wlodarski, M, Schlegelberger, B, Ripperger, T, Förster, Alisa, Davenport, Claudia, Duployez, Nicolas, Erlacher, Miriam, Ferster, Alina, Fitzgibbon, Jude, Göhring, Gudrun, Hasle, Henrik, Jongmans, Marjolijn C, Kolenova, Alexandra, Kronnie, Geertruijte, Lammens, Tim, Mecucci, Cristina, Mlynarski, Wojciech, Niemeyer, Charlotte M, Sole, Francesc, Szczepanski, Tomasz, Waanders, Esmé, Biondi, Andrea, Wlodarski, Marcin, Schlegelberger, Brigitte, and Ripperger, Tim

Abstract

Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical

Published
2023

3. Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer

Author

Rhiem, Kerstin, Zachariae, Silke, Waha, Anke, Grill, Sabine, Hester, Anna, Golatta, Michael; https://orcid.org/0000-0002-2605-0060, van Mackelenbergh, Marion, Fehm, Tanja, Schlaiß, Tanja, Ripperger, Tim; https://orcid.org/0000-0001-6470-8612, Ledig, Susanne, Meisel, Cornelia, Speiser, Dorothee; https://orcid.org/0000-0002-6447-629X, Veselinovic, Kristina, Schröder, Christopher, Witzel, Isabell; https://orcid.org/0000-0002-8734-4521, Gallwas, Julia, Weber, Bernhard H F; https://orcid.org/0000-0002-8808-7723, Solbach, Christine; https://orcid.org/0000-0001-8284-3199, Aktas, Bariyhe, Hahnen, Eric, Engel, Christoph; https://orcid.org/0000-0002-7247-282X, Schmutzler, Rita, Rhiem, Kerstin, Zachariae, Silke, Waha, Anke, Grill, Sabine, Hester, Anna, Golatta, Michael; https://orcid.org/0000-0002-2605-0060, van Mackelenbergh, Marion, Fehm, Tanja, Schlaiß, Tanja, Ripperger, Tim; https://orcid.org/0000-0001-6470-8612, Ledig, Susanne, Meisel, Cornelia, Speiser, Dorothee; https://orcid.org/0000-0002-6447-629X, Veselinovic, Kristina, Schröder, Christopher, Witzel, Isabell; https://orcid.org/0000-0002-8734-4521, Gallwas, Julia, Weber, Bernhard H F; https://orcid.org/0000-0002-8808-7723, Solbach, Christine; https://orcid.org/0000-0001-8284-3199, Aktas, Bariyhe, Hahnen, Eric, Engel, Christoph; https://orcid.org/0000-0002-7247-282X, and Schmutzler, Rita

Abstract

Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis. Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19–78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression. Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21–1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years. Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.

Published
2023

4. Validation and clinical application of transactivation assays for RUNX1 variant classification

Author

Decker, Melanie, Agarwal, Anupriya, Benneche, Andreas, Churpek, Jane, Duployez, Nicolas, Duvall, Adam, Ernst, Martijn P.T., Forster, Alisa, Høberg-Vetti, Hildegunn, Hofmann, Inga, Nash, Michelle, Raaijmakers, Marc H.G.P., Tvedt, Tor H.A., Vlachos, Adrianna, Schlegelberger, Brigitte, Illig, Thomas, Ripperger, Tim, Decker, Melanie, Agarwal, Anupriya, Benneche, Andreas, Churpek, Jane, Duployez, Nicolas, Duvall, Adam, Ernst, Martijn P.T., Forster, Alisa, Høberg-Vetti, Hildegunn, Hofmann, Inga, Nash, Michelle, Raaijmakers, Marc H.G.P., Tvedt, Tor H.A., Vlachos, Adrianna, Schlegelberger, Brigitte, Illig, Thomas, and Ripperger, Tim

Abstract

Familial platelet disorder with associated myeloid malignancies (RUNX1-familial platelet disorder [RUNX1-FPD]) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies Variant Curation Expert Panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of 2 other variants. We demonstrated functionality of 4 VUS, but reclassification to (likely) benign was challenging and suggested the need for reevaluating current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of 7 families. Our data confirmed RUNX1-FPD suspicion in 3 families with RUNX1-FPD-specific family history, whereas for 3 variants identified in RUNX1-FPD-nonspecific families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.

Published
2022

5. Genetic testing and surveillance in infantile myofibromatosis : a report from the SIOPE Host Genome Working Group

Author

Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., Demoulin, Jean-Baptiste, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., and Demoulin, Jean-Baptiste

Abstract

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked toPDGFRBgermline variants. SomaticPDGFRBvariants were also detected in solitary and multifocal IM lesions.PDGFRBvariants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRBgermline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Published
2021
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6. Genetic testing and surveillance in infantile myofibromatosis : a report from the SIOPE Host Genome Working Group

Author

Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., Demoulin, Jean-Baptiste, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., and Demoulin, Jean-Baptiste

Abstract

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked toPDGFRBgermline variants. SomaticPDGFRBvariants were also detected in solitary and multifocal IM lesions.PDGFRBvariants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRBgermline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Published
2021
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7. Genetic testing and surveillance in infantile myofibromatosis : a report from the SIOPE Host Genome Working Group

Author

Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., Demoulin, Jean-Baptiste, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., and Demoulin, Jean-Baptiste

Abstract

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked toPDGFRBgermline variants. SomaticPDGFRBvariants were also detected in solitary and multifocal IM lesions.PDGFRBvariants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRBgermline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Published
2021
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8. Genetic testing and surveillance in infantile myofibromatosis : a report from the SIOPE Host Genome Working Group

Author

Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., Demoulin, Jean-Baptiste, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., and Demoulin, Jean-Baptiste

Abstract

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked toPDGFRBgermline variants. SomaticPDGFRBvariants were also detected in solitary and multifocal IM lesions.PDGFRBvariants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRBgermline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Published
2021
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9. Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies

Author

Decker, Melanie, Lammens, Tim, Ferster, Alina, Erlacher, Miriam, Yoshimi-Noellke, A. (Ayami), Niemeyer, Charlotte M., Ernst, Martijn, Raaijmakers, Marc, Duployez, Nicolas, Flaum, Andreas, Steinemann, Doris, Schlegelberger, Brigitte, Illig, Thomas, Ripperger, Tim, Decker, Melanie, Lammens, Tim, Ferster, Alina, Erlacher, Miriam, Yoshimi-Noellke, A. (Ayami), Niemeyer, Charlotte M., Ernst, Martijn, Raaijmakers, Marc, Duployez, Nicolas, Flaum, Andreas, Steinemann, Doris, Schlegelberger, Brigitte, Illig, Thomas, and Ripperger, Tim

Published
2021

10. Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li–Fraumeni syndrome

Author

Winter, Greta, Kirschner-Schwabe, Renate, Groeneveld-Krentz, Stefanie, Escherich, Gabriele, Möricke, Anja, von Stackelberg, Arend, Stanulla, Martin, Bailey, Simon, Richter, Lisa, Steinemann, Doris, Ripperger, Tim, Escudero, Adela, Farah, Roula, Lohi, Olli, Wadt, Karin, Jongmans, Marjolijn, van Engelen, Nienke, Eckert, Cornelia, Kratz, Christian Peter, Winter, Greta, Kirschner-Schwabe, Renate, Groeneveld-Krentz, Stefanie, Escherich, Gabriele, Möricke, Anja, von Stackelberg, Arend, Stanulla, Martin, Bailey, Simon, Richter, Lisa, Steinemann, Doris, Ripperger, Tim, Escudero, Adela, Farah, Roula, Lohi, Olli, Wadt, Karin, Jongmans, Marjolijn, van Engelen, Nienke, Eckert, Cornelia, and Kratz, Christian Peter

Published
2021

11. Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li–Fraumeni syndrome

Author

Winter, Greta, Kirschner-Schwabe, Renate, Groeneveld-Krentz, Stefanie, Escherich, Gabriele, Möricke, Anja, von Stackelberg, Arend, Stanulla, Martin, Bailey, Simon, Richter, Lisa, Steinemann, Doris, Ripperger, Tim, Escudero, Adela, Farah, Roula, Lohi, Olli, Wadt, Karin, Jongmans, Marjolijn, van Engelen, Nienke, Eckert, Cornelia, Kratz, Christian Peter, Winter, Greta, Kirschner-Schwabe, Renate, Groeneveld-Krentz, Stefanie, Escherich, Gabriele, Möricke, Anja, von Stackelberg, Arend, Stanulla, Martin, Bailey, Simon, Richter, Lisa, Steinemann, Doris, Ripperger, Tim, Escudero, Adela, Farah, Roula, Lohi, Olli, Wadt, Karin, Jongmans, Marjolijn, van Engelen, Nienke, Eckert, Cornelia, and Kratz, Christian Peter

Published
2021

12. Genetic testing and surveillance in infantile myofibromatosis : a report from the SIOPE Host Genome Working Group

Author

Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., Demoulin, Jean-Baptiste, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R., Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P., and Demoulin, Jean-Baptiste

Abstract

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked toPDGFRBgermline variants. SomaticPDGFRBvariants were also detected in solitary and multifocal IM lesions.PDGFRBvariants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRBgermline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Published
2021
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13. Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies

Author

Decker, Melanie, Lammens, Tim, Ferster, Alina, Erlacher, Miriam, Yoshimi, Ayami, Niemeyer, Charlotte Marie, Ernst, Martijn M.P.T., Raaijmakers, Marc M.H.G.P., Duployez, Nicolas, Flaum, Andreas, Steinemann, Doris, Schlegelberger, Brigitte, Illig, Thomas, Ripperger, Tim, Decker, Melanie, Lammens, Tim, Ferster, Alina, Erlacher, Miriam, Yoshimi, Ayami, Niemeyer, Charlotte Marie, Ernst, Martijn M.P.T., Raaijmakers, Marc M.H.G.P., Duployez, Nicolas, Flaum, Andreas, Steinemann, Doris, Schlegelberger, Brigitte, Illig, Thomas, and Ripperger, Tim

Abstract

SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021

14. Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group

Author

Hettmer, Simone; https://orcid.org/0000-0003-1709-4448, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R, Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P, Demoulin, Jean-Baptiste, Hettmer, Simone; https://orcid.org/0000-0003-1709-4448, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R, Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P, and Demoulin, Jean-Baptiste

Abstract

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Published
2021

15. Clinical and genetic characteristics of children with acute lymphoblastic leukemia and Li–Fraumeni syndrome

Author

Genetica, Genetica Klinische Genetica, Child Health, Cancer, Winter, Greta, Kirschner-Schwabe, Renate, Groeneveld-Krentz, Stefanie, Escherich, Gabriele, Möricke, Anja, von Stackelberg, Arend, Stanulla, Martin, Bailey, Simon, Richter, Lisa, Steinemann, Doris, Ripperger, Tim, Escudero, Adela, Farah, Roula, Lohi, Olli, Wadt, Karin, Jongmans, Marjolijn, van Engelen, Nienke, Eckert, Cornelia, Kratz, Christian Peter, Genetica, Genetica Klinische Genetica, Child Health, Cancer, Winter, Greta, Kirschner-Schwabe, Renate, Groeneveld-Krentz, Stefanie, Escherich, Gabriele, Möricke, Anja, von Stackelberg, Arend, Stanulla, Martin, Bailey, Simon, Richter, Lisa, Steinemann, Doris, Ripperger, Tim, Escudero, Adela, Farah, Roula, Lohi, Olli, Wadt, Karin, Jongmans, Marjolijn, van Engelen, Nienke, Eckert, Cornelia, and Kratz, Christian Peter

Published
2021

16. Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group

Author

Genetica, Genetica Klinische Genetica, Child Health, Cancer, Pathologie Pathologen staf, Pathologie Algemene Pat.zorg, Haematologie patientenzorg, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R, Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P, Demoulin, Jean-Baptiste, Genetica, Genetica Klinische Genetica, Child Health, Cancer, Pathologie Pathologen staf, Pathologie Algemene Pat.zorg, Haematologie patientenzorg, Hettmer, Simone, Dachy, Guillaume, Seitz, Guido, Agaimy, Abbas, Duncan, Catriona, Jongmans, Marjolijn, Hirsch, Steffen, Kventsel, Iris, Kordes, Uwe, de Krijger, Ronald R, Metzler, Markus, Michaeli, Orli, Nemes, Karolina, Poluha, Anna, Ripperger, Tim, Russo, Alexandra, Smetsers, Stephanie, Sparber-Sauer, Monika, Stutz, Eveline, Bourdeaut, Franck, Kratz, Christian P, and Demoulin, Jean-Baptiste

Published
2021

17. High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers

Author

Gonzalez-Acosta, Maribel, Marin, Fatima, Puliafito, Benjamin, Bonifaci, Nuria, Fernandez, Anna, Navarro, Matilde, Salvador, Hector, Balaguer, Francesc, Iglesias, Silvia, Velasco, Angela, Garces, Elia Grau, Moreno, Victor, Gonzalez-Granado, Luis Ignacio, Guerra-Garcia, Pilar, Ayala, Rosa, Florkin, Benoit, Kratz, Christian, Ripperger, Tim, Rosenbaum, Thorsten, Januszkiewicz-Lewandowska, Danuta, Azizi, Amedeo A., Ragab, Iman, Nathrath, Michaela, Pander, Hans-Juergen, Lobitz, Stephan, Suerink, Manon, Dahan, Karin, Imschweiler, Thomas, Demirsoy, Ugur, Brunet, Joan, Lazaro, Conxi, Rueda, Daniel, Wimmer, Katharina, Capella, Gabriel, Pineda, Marta, Gonzalez-Acosta, Maribel, Marin, Fatima, Puliafito, Benjamin, Bonifaci, Nuria, Fernandez, Anna, Navarro, Matilde, Salvador, Hector, Balaguer, Francesc, Iglesias, Silvia, Velasco, Angela, Garces, Elia Grau, Moreno, Victor, Gonzalez-Granado, Luis Ignacio, Guerra-Garcia, Pilar, Ayala, Rosa, Florkin, Benoit, Kratz, Christian, Ripperger, Tim, Rosenbaum, Thorsten, Januszkiewicz-Lewandowska, Danuta, Azizi, Amedeo A., Ragab, Iman, Nathrath, Michaela, Pander, Hans-Juergen, Lobitz, Stephan, Suerink, Manon, Dahan, Karin, Imschweiler, Thomas, Demirsoy, Ugur, Brunet, Joan, Lazaro, Conxi, Rueda, Daniel, Wimmer, Katharina, Capella, Gabriel, and Pineda, Marta

Abstract

Introduction Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. Materials and methods Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. Results The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). Conclusions The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

Published
2020

18. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

Author

Rio-Machin, Ana, Vulliamy, Tom, Hug, Nele, Walne, Amanda, Tawana, Kiran, Cardoso, Shirleny, Ellison, Alicia, Pontikos, Nikolas, Wang, Jun, Tummala, Hemanth, Al Seraihi, Ahad Fahad H., Alnajar, Jenna, Bewicke-Copley, Findlay, Armes, Hannah, Barnett, Michael, Bloor, Adrian, Bödör, Csaba, Bowen, David, Fenaux, Pierre, Green, Andrew, Hallahan, Andrew, Hjorth-Hansen, Henrik, Hossain, Upal, Killick, Sally, Lawson, Sarah, Layton, Mark, Male, Alison M., Marsh, Judith, Mehta, Priyanka, Mous, Rogier, Nomdedeu, Josep, Owen, Carolyn, Pavlu, Jiri, Payne, Elspeth M., Protheroe, Rachel E., Preudhomme, Claude, Pujol-Moix, Nuria, Renneville, Aline, Russell, Nigel, Saggar, Anand, Sciuccati, Gabriela, Taussig, David, Toze, Cynthia L., Uyttebroeck, Anne, Vandenberghe, Peter, Schlegelberger, Brigitte, Ripperger, Tim, Steinemann, Doris, Wu, John, Mason, Joanne, Page, Paula, Akiki, Susanna, Reay, Kim, Cavenagh, Jamie D., Plagnol, Vincent, Caceres, Javier F., Fitzgibbon, Jude, Dokal, Inderjeet, Universitat Autònoma de Barcelona, Rio-Machin, Ana, Vulliamy, Tom, Hug, Nele, Walne, Amanda, Tawana, Kiran, Cardoso, Shirleny, Ellison, Alicia, Pontikos, Nikolas, Wang, Jun, Tummala, Hemanth, Al Seraihi, Ahad Fahad H., Alnajar, Jenna, Bewicke-Copley, Findlay, Armes, Hannah, Barnett, Michael, Bloor, Adrian, Bödör, Csaba, Bowen, David, Fenaux, Pierre, Green, Andrew, Hallahan, Andrew, Hjorth-Hansen, Henrik, Hossain, Upal, Killick, Sally, Lawson, Sarah, Layton, Mark, Male, Alison M., Marsh, Judith, Mehta, Priyanka, Mous, Rogier, Nomdedeu, Josep, Owen, Carolyn, Pavlu, Jiri, Payne, Elspeth M., Protheroe, Rachel E., Preudhomme, Claude, Pujol-Moix, Nuria, Renneville, Aline, Russell, Nigel, Saggar, Anand, Sciuccati, Gabriela, Taussig, David, Toze, Cynthia L., Uyttebroeck, Anne, Vandenberghe, Peter, Schlegelberger, Brigitte, Ripperger, Tim, Steinemann, Doris, Wu, John, Mason, Joanne, Page, Paula, Akiki, Susanna, Reay, Kim, Cavenagh, Jamie D., Plagnol, Vincent, Caceres, Javier F., Fitzgibbon, Jude, Dokal, Inderjeet, and Universitat Autònoma de Barcelona

Abstract

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management. Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions.

Published
2020

19. High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers

Author

Gonzalez-Acosta, Maribel, Marin, Fatima, Puliafito, Benjamin, Bonifaci, Nuria, Fernandez, Anna, Navarro, Matilde, Salvador, Hector, Balaguer, Francesc, Iglesias, Silvia, Velasco, Angela, Garces, Elia Grau, Moreno, Victor, Gonzalez-Granado, Luis Ignacio, Guerra-Garcia, Pilar, Ayala, Rosa, Florkin, Benoit, Kratz, Christian, Ripperger, Tim, Rosenbaum, Thorsten, Januszkiewicz-Lewandowska, Danuta, Azizi, Amedeo A., Ragab, Iman, Nathrath, Michaela, Pander, Hans-Juergen, Lobitz, Stephan, Suerink, Manon, Dahan, Karin, Imschweiler, Thomas, Demirsoy, Ugur, Brunet, Joan, Lazaro, Conxi, Rueda, Daniel, Wimmer, Katharina, Capella, Gabriel, Pineda, Marta, Gonzalez-Acosta, Maribel, Marin, Fatima, Puliafito, Benjamin, Bonifaci, Nuria, Fernandez, Anna, Navarro, Matilde, Salvador, Hector, Balaguer, Francesc, Iglesias, Silvia, Velasco, Angela, Garces, Elia Grau, Moreno, Victor, Gonzalez-Granado, Luis Ignacio, Guerra-Garcia, Pilar, Ayala, Rosa, Florkin, Benoit, Kratz, Christian, Ripperger, Tim, Rosenbaum, Thorsten, Januszkiewicz-Lewandowska, Danuta, Azizi, Amedeo A., Ragab, Iman, Nathrath, Michaela, Pander, Hans-Juergen, Lobitz, Stephan, Suerink, Manon, Dahan, Karin, Imschweiler, Thomas, Demirsoy, Ugur, Brunet, Joan, Lazaro, Conxi, Rueda, Daniel, Wimmer, Katharina, Capella, Gabriel, and Pineda, Marta

Abstract

Introduction Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. Materials and methods Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. Results The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). Conclusions The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

Published
2020

20. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1 : consensus guidelines for testing a child without malignancy

Author

Suerink, Manon, Ripperger, Tim, Messiaen, Ludwine, Menko, Fred H, Bourdeaut, Franck, Colas, Chrystelle, Jongmans, Marjolijn, Goldberg, Yael, Nielsen, Maartje, Muleris, Martine, van Kouwen, Mariëtte, Slavc, Irene, Kratz, Christian, Vasen, Hans F, Brugiѐres, Laurence, Legius, Eric, Wimmer, Katharina, Suerink, Manon, Ripperger, Tim, Messiaen, Ludwine, Menko, Fred H, Bourdeaut, Franck, Colas, Chrystelle, Jongmans, Marjolijn, Goldberg, Yael, Nielsen, Maartje, Muleris, Martine, van Kouwen, Mariëtte, Slavc, Irene, Kratz, Christian, Vasen, Hans F, Brugiѐres, Laurence, Legius, Eric, and Wimmer, Katharina

Published
2019

21. An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

Author

Suerink, Manon, Rodríguez-Girondo, Mar, van der Klift, Heleen M., Colas, Chrystelle, Brugieres, Laurence, Lavoine, Noémie, Jongmans, Marjolijn, Munar, Gabriel Capellá, Evans, D. Gareth, Farrell, Michael P., Genuardi, Maurizio, Goldberg, Yael, Gomez-Garcia, Encarna, Heinimann, Karl, Hoell, Jessica I., Aretz, Stefan, Jasperson, Kory W., Kedar, Inbal, Modi, Mitul B., Nikolaev, Sergey, van Os, Theo A.M., Ripperger, Tim, Rueda, Daniel, Senter, Leigha, Sjursen, Wenche, Sunde, Lone, Therkildsen, Christina, Tibiletti, Maria G., Trainer, Alison H., Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Wimmer, Katharina, Zimmermann, Stefanie Y., Vasen, Hans F., van Asperen, Christi J., Houwing-Duistermaat, Jeanine J., ten Broeke, Sanne W., Nielsen, Maartje, Suerink, Manon, Rodríguez-Girondo, Mar, van der Klift, Heleen M., Colas, Chrystelle, Brugieres, Laurence, Lavoine, Noémie, Jongmans, Marjolijn, Munar, Gabriel Capellá, Evans, D. Gareth, Farrell, Michael P., Genuardi, Maurizio, Goldberg, Yael, Gomez-Garcia, Encarna, Heinimann, Karl, Hoell, Jessica I., Aretz, Stefan, Jasperson, Kory W., Kedar, Inbal, Modi, Mitul B., Nikolaev, Sergey, van Os, Theo A.M., Ripperger, Tim, Rueda, Daniel, Senter, Leigha, Sjursen, Wenche, Sunde, Lone, Therkildsen, Christina, Tibiletti, Maria G., Trainer, Alison H., Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Wimmer, Katharina, Zimmermann, Stefanie Y., Vasen, Hans F., van Asperen, Christi J., Houwing-Duistermaat, Jeanine J., ten Broeke, Sanne W., and Nielsen, Maartje

Published
2019

22. An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

Author

Suerink, Manon, Rodríguez-Girondo, Mar, van der Klift, Heleen M., Colas, Chrystelle, Brugieres, Laurence, Lavoine, Noémie, Jongmans, Marjolijn, Munar, Gabriel Capellá, Evans, D. Gareth, Farrell, Michael P., Genuardi, Maurizio, Goldberg, Yael, Gomez-Garcia, Encarna, Heinimann, Karl, Hoell, Jessica I., Aretz, Stefan, Jasperson, Kory W., Kedar, Inbal, Modi, Mitul B., Nikolaev, Sergey, van Os, Theo A.M., Ripperger, Tim, Rueda, Daniel, Senter, Leigha, Sjursen, Wenche, Sunde, Lone, Therkildsen, Christina, Tibiletti, Maria G., Trainer, Alison H., Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Wimmer, Katharina, Zimmermann, Stefanie Y., Vasen, Hans F., van Asperen, Christi J., Houwing-Duistermaat, Jeanine J., ten Broeke, Sanne W., Nielsen, Maartje, Suerink, Manon, Rodríguez-Girondo, Mar, van der Klift, Heleen M., Colas, Chrystelle, Brugieres, Laurence, Lavoine, Noémie, Jongmans, Marjolijn, Munar, Gabriel Capellá, Evans, D. Gareth, Farrell, Michael P., Genuardi, Maurizio, Goldberg, Yael, Gomez-Garcia, Encarna, Heinimann, Karl, Hoell, Jessica I., Aretz, Stefan, Jasperson, Kory W., Kedar, Inbal, Modi, Mitul B., Nikolaev, Sergey, van Os, Theo A.M., Ripperger, Tim, Rueda, Daniel, Senter, Leigha, Sjursen, Wenche, Sunde, Lone, Therkildsen, Christina, Tibiletti, Maria G., Trainer, Alison H., Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Wimmer, Katharina, Zimmermann, Stefanie Y., Vasen, Hans F., van Asperen, Christi J., Houwing-Duistermaat, Jeanine J., ten Broeke, Sanne W., and Nielsen, Maartje

Published
2019

23. An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

Author

Genetica Klinische Genetica, Cancer, UMC Utrecht, Biostatistiek Onderzoek, JC onderzoeksprogramma Methodologie, Suerink, Manon, Rodríguez-Girondo, Mar, van der Klift, Heleen M., Colas, Chrystelle, Brugieres, Laurence, Lavoine, Noémie, Jongmans, Marjolijn, Munar, Gabriel Capellá, Evans, D. Gareth, Farrell, Michael P., Genuardi, Maurizio, Goldberg, Yael, Gomez-Garcia, Encarna, Heinimann, Karl, Hoell, Jessica I., Aretz, Stefan, Jasperson, Kory W., Kedar, Inbal, Modi, Mitul B., Nikolaev, Sergey, van Os, Theo A.M., Ripperger, Tim, Rueda, Daniel, Senter, Leigha, Sjursen, Wenche, Sunde, Lone, Therkildsen, Christina, Tibiletti, Maria G., Trainer, Alison H., Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Wimmer, Katharina, Zimmermann, Stefanie Y., Vasen, Hans F., van Asperen, Christi J., Houwing-Duistermaat, Jeanine J., ten Broeke, Sanne W., Nielsen, Maartje, Genetica Klinische Genetica, Cancer, UMC Utrecht, Biostatistiek Onderzoek, JC onderzoeksprogramma Methodologie, Suerink, Manon, Rodríguez-Girondo, Mar, van der Klift, Heleen M., Colas, Chrystelle, Brugieres, Laurence, Lavoine, Noémie, Jongmans, Marjolijn, Munar, Gabriel Capellá, Evans, D. Gareth, Farrell, Michael P., Genuardi, Maurizio, Goldberg, Yael, Gomez-Garcia, Encarna, Heinimann, Karl, Hoell, Jessica I., Aretz, Stefan, Jasperson, Kory W., Kedar, Inbal, Modi, Mitul B., Nikolaev, Sergey, van Os, Theo A.M., Ripperger, Tim, Rueda, Daniel, Senter, Leigha, Sjursen, Wenche, Sunde, Lone, Therkildsen, Christina, Tibiletti, Maria G., Trainer, Alison H., Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Wimmer, Katharina, Zimmermann, Stefanie Y., Vasen, Hans F., van Asperen, Christi J., Houwing-Duistermaat, Jeanine J., ten Broeke, Sanne W., and Nielsen, Maartje

Published
2019

24. A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes

Author

Gallon, Richard, Muehlegger, Barbara, Wenzel, Soeren-Sebastian, Sheth, Harsh, Hayes, Christine, Aretz, Stefan, Dahan, Karin, Foulkes, William, Kratz, Christian P., Ripperger, Tim, Azizi, Amedeo A., Feldman, Hagit Baris, Chong, Anne-Laure, Demirsoy, Ugur, Florkin, Benoit, Imschweiler, Thomas, Januszkiewicz-Lewandowska, Danuta, Lobitz, Stephan, Nathrath, Michaela, Pander, Hans-Juergen, Perez-Alonso, Vanesa, Perne, Claudia, Ragab, Iman, Rosenbaum, Thorsten, Rueda, Daniel, Seidel, Markus G., Suerink, Manon, Taeubner, Julia, Zimmermann, Stefanie-Yvonne, Zschocke, Johannes, Borthwick, Gillian M., Burn, John, Jackson, Michael S., Santibanez-Koref, Mauro, Wimmer, Katharina, Gallon, Richard, Muehlegger, Barbara, Wenzel, Soeren-Sebastian, Sheth, Harsh, Hayes, Christine, Aretz, Stefan, Dahan, Karin, Foulkes, William, Kratz, Christian P., Ripperger, Tim, Azizi, Amedeo A., Feldman, Hagit Baris, Chong, Anne-Laure, Demirsoy, Ugur, Florkin, Benoit, Imschweiler, Thomas, Januszkiewicz-Lewandowska, Danuta, Lobitz, Stephan, Nathrath, Michaela, Pander, Hans-Juergen, Perez-Alonso, Vanesa, Perne, Claudia, Ragab, Iman, Rosenbaum, Thorsten, Rueda, Daniel, Seidel, Markus G., Suerink, Manon, Taeubner, Julia, Zimmermann, Stefanie-Yvonne, Zschocke, Johannes, Borthwick, Gillian M., Burn, John, Jackson, Michael S., Santibanez-Koref, Mauro, and Wimmer, Katharina

Abstract

Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low-frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically-confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at-risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.

Published
2019

25. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology

Author

Ripperger, Tim, Bielack, Stefan S., Borkhardt, Arndt, Brecht, Ines B., Burkhardt, Birgit, Calaminus, Gabriele, Debatin, Klaus-Michael, Deubzer, Hedwig, Dirksen, Uta, Eckert, Cornelia, Eggert, Angelika, Erlacher, Miriam, Fleischhack, Gudrun, Fruehwald, Michael C., Gnekow, Astrid, Goehring, Gudrun, Graf, Norbert, Hanenberg, Helmut, Hauer, Julia, Hero, Barbara, Hettmer, Simone, von Hoff, Katja, Horstmann, Martin, Hoyer, Juliane, Illig, Thomas, Kaatsch, Peter, Kappler, Roland, Kerl, Kornelius, Klingebiel, Thomas, Kontny, Udo, Kordes, Uwe, Koerholz, Dieter, Koscielniak, Ewa, Kramm, Christof M., Kuhlen, Michaela, Kulozik, Andreas E., Lamottke, Britta, Leuschner, Ivo, Lohmann, Dietmar R., Meinhardt, Andrea, Metzler, Markus, Meyer, Lder H., Moser, Olga, Nathrath, Michaela, Niemeyer, Charlotte M., Nustede, Rainer, Pajtler, Kristian W., Paret, Claudia, Rasche, Mareike, Reinhardt, Dirk, Riess, Olaf, Russo, Alexandra, Rutkowski, Stefan, Schlegelberger, Brigitte, Schneider, Dominik, Schneppenheim, Reinhard, Schrappe, Martin, Schroeder, Christopher, von Schweinitz, Dietrich, Simon, Thorsten, Sparber-Sauer, Monika, Spix, Claudia, Stanulla, Martin, Steinemann, Doris, Strahm, Brigitte, Temming, Petra, Thomay, Kathrin, von Bueren, Andre O., Vorwerk, Peter, Witt, Olaf, Wlodarski, Marcin, Woessmann, Willy, Zenker, Martin, Zimmermann, Stefanie, Pfister, Stefan M., Kratz, Christian P., Ripperger, Tim, Bielack, Stefan S., Borkhardt, Arndt, Brecht, Ines B., Burkhardt, Birgit, Calaminus, Gabriele, Debatin, Klaus-Michael, Deubzer, Hedwig, Dirksen, Uta, Eckert, Cornelia, Eggert, Angelika, Erlacher, Miriam, Fleischhack, Gudrun, Fruehwald, Michael C., Gnekow, Astrid, Goehring, Gudrun, Graf, Norbert, Hanenberg, Helmut, Hauer, Julia, Hero, Barbara, Hettmer, Simone, von Hoff, Katja, Horstmann, Martin, Hoyer, Juliane, Illig, Thomas, Kaatsch, Peter, Kappler, Roland, Kerl, Kornelius, Klingebiel, Thomas, Kontny, Udo, Kordes, Uwe, Koerholz, Dieter, Koscielniak, Ewa, Kramm, Christof M., Kuhlen, Michaela, Kulozik, Andreas E., Lamottke, Britta, Leuschner, Ivo, Lohmann, Dietmar R., Meinhardt, Andrea, Metzler, Markus, Meyer, Lder H., Moser, Olga, Nathrath, Michaela, Niemeyer, Charlotte M., Nustede, Rainer, Pajtler, Kristian W., Paret, Claudia, Rasche, Mareike, Reinhardt, Dirk, Riess, Olaf, Russo, Alexandra, Rutkowski, Stefan, Schlegelberger, Brigitte, Schneider, Dominik, Schneppenheim, Reinhard, Schrappe, Martin, Schroeder, Christopher, von Schweinitz, Dietrich, Simon, Thorsten, Sparber-Sauer, Monika, Spix, Claudia, Stanulla, Martin, Steinemann, Doris, Strahm, Brigitte, Temming, Petra, Thomay, Kathrin, von Bueren, Andre O., Vorwerk, Peter, Witt, Olaf, Wlodarski, Marcin, Woessmann, Willy, Zenker, Martin, Zimmermann, Stefanie, Pfister, Stefan M., and Kratz, Christian P.

Abstract

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

Published
2017

26. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology

Author

Ripperger, Tim, Bielack, Stefan S., Borkhardt, Arndt, Brecht, Ines B., Burkhardt, Birgit, Calaminus, Gabriele, Debatin, Klaus-Michael, Deubzer, Hedwig, Dirksen, Uta, Eckert, Cornelia, Eggert, Angelika, Erlacher, Miriam, Fleischhack, Gudrun, Fruehwald, Michael C., Gnekow, Astrid, Goehring, Gudrun, Graf, Norbert, Hanenberg, Helmut, Hauer, Julia, Hero, Barbara, Hettmer, Simone, von Hoff, Katja, Horstmann, Martin, Hoyer, Juliane, Illig, Thomas, Kaatsch, Peter, Kappler, Roland, Kerl, Kornelius, Klingebiel, Thomas, Kontny, Udo, Kordes, Uwe, Koerholz, Dieter, Koscielniak, Ewa, Kramm, Christof M., Kuhlen, Michaela, Kulozik, Andreas E., Lamottke, Britta, Leuschner, Ivo, Lohmann, Dietmar R., Meinhardt, Andrea, Metzler, Markus, Meyer, Lder H., Moser, Olga, Nathrath, Michaela, Niemeyer, Charlotte M., Nustede, Rainer, Pajtler, Kristian W., Paret, Claudia, Rasche, Mareike, Reinhardt, Dirk, Riess, Olaf, Russo, Alexandra, Rutkowski, Stefan, Schlegelberger, Brigitte, Schneider, Dominik, Schneppenheim, Reinhard, Schrappe, Martin, Schroeder, Christopher, von Schweinitz, Dietrich, Simon, Thorsten, Sparber-Sauer, Monika, Spix, Claudia, Stanulla, Martin, Steinemann, Doris, Strahm, Brigitte, Temming, Petra, Thomay, Kathrin, von Bueren, Andre O., Vorwerk, Peter, Witt, Olaf, Wlodarski, Marcin, Woessmann, Willy, Zenker, Martin, Zimmermann, Stefanie, Pfister, Stefan M., Kratz, Christian P., Ripperger, Tim, Bielack, Stefan S., Borkhardt, Arndt, Brecht, Ines B., Burkhardt, Birgit, Calaminus, Gabriele, Debatin, Klaus-Michael, Deubzer, Hedwig, Dirksen, Uta, Eckert, Cornelia, Eggert, Angelika, Erlacher, Miriam, Fleischhack, Gudrun, Fruehwald, Michael C., Gnekow, Astrid, Goehring, Gudrun, Graf, Norbert, Hanenberg, Helmut, Hauer, Julia, Hero, Barbara, Hettmer, Simone, von Hoff, Katja, Horstmann, Martin, Hoyer, Juliane, Illig, Thomas, Kaatsch, Peter, Kappler, Roland, Kerl, Kornelius, Klingebiel, Thomas, Kontny, Udo, Kordes, Uwe, Koerholz, Dieter, Koscielniak, Ewa, Kramm, Christof M., Kuhlen, Michaela, Kulozik, Andreas E., Lamottke, Britta, Leuschner, Ivo, Lohmann, Dietmar R., Meinhardt, Andrea, Metzler, Markus, Meyer, Lder H., Moser, Olga, Nathrath, Michaela, Niemeyer, Charlotte M., Nustede, Rainer, Pajtler, Kristian W., Paret, Claudia, Rasche, Mareike, Reinhardt, Dirk, Riess, Olaf, Russo, Alexandra, Rutkowski, Stefan, Schlegelberger, Brigitte, Schneider, Dominik, Schneppenheim, Reinhard, Schrappe, Martin, Schroeder, Christopher, von Schweinitz, Dietrich, Simon, Thorsten, Sparber-Sauer, Monika, Spix, Claudia, Stanulla, Martin, Steinemann, Doris, Strahm, Brigitte, Temming, Petra, Thomay, Kathrin, von Bueren, Andre O., Vorwerk, Peter, Witt, Olaf, Wlodarski, Marcin, Woessmann, Willy, Zenker, Martin, Zimmermann, Stefanie, Pfister, Stefan M., and Kratz, Christian P.

Abstract

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

Published
2017

27. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms

Author

Tesi, Bianca, Davidsson, Josef, Voss, Matthias, Rahikkala, Elisa, Holmes, Tim D., Chiang, Samuel C. C., Komulainen-Ebrahim, Jonna, Gorcenco, Sorina, Rundberg Nilsson, Alexandra, Ripperger, Tim, Kokkonen, Hannaleena, Bryder, David, Fioretos, Thoas, Henter, Jan-Inge, Mottonen, Merja, Niinimaki, Riitta, Nilsson, Lars, Pronk, Cornelis Jan, Puschmann, Andreas, Qian, Hong, Uusimaa, Johanna, Moilanen, Jukka, Tedgard, Ulf, Cammenga, Jörg, Bryceson, Yenan T., Tesi, Bianca, Davidsson, Josef, Voss, Matthias, Rahikkala, Elisa, Holmes, Tim D., Chiang, Samuel C. C., Komulainen-Ebrahim, Jonna, Gorcenco, Sorina, Rundberg Nilsson, Alexandra, Ripperger, Tim, Kokkonen, Hannaleena, Bryder, David, Fioretos, Thoas, Henter, Jan-Inge, Mottonen, Merja, Niinimaki, Riitta, Nilsson, Lars, Pronk, Cornelis Jan, Puschmann, Andreas, Qian, Hong, Uusimaa, Johanna, Moilanen, Jukka, Tedgard, Ulf, Cammenga, Jörg, and Bryceson, Yenan T.

Abstract

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cis SAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 1 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-alpha or IFN-gamma induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with 27/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis., Funding Agencies|European Research Council (ERC) under the European Union [311335]; Swedish Research Council; Norwegian Research Council; Swedish Foundation for Strategic Research; Wallenberg Foundation; Swedish Cancer Foundation; Swedish Childhood Cancer Foundation; Stockholm County Council; Karolinska Institutet Center for Innovative Medicine; Hemato-Linne; Cancerfonden; Barncancerfonden; Board of Postgraduate Studies at Karolinska Institute; Swedish Society for Medical Research; Skane University Hospital; Wenner-Gren Foundation; EMBO (ALTF); European Commision [LTFCOFUND] [GA-2013-609409]; Histiocytosis Association; Swedish Society for Medicine; Swedish National Infrastructure for Computing (SNIC) through the Uppsala Multidisciplinary Center for Advanced Computational Science [SNIC b2012204]

Published
2017
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