Research on Rare Diseases in Germany - Cancer Predisposition Syndrome Registry

Background: Cancer predisposition syndromes (CPS) are rare diseases that are associated with an increased risk of cancer due to genetic alterations. At least 8 % of all cases of childhood cancer are attributable to CPS. The CPS registry was launched in 2017 to learn more about CPS and to improve the care to those afflicted by these diseases. Methods: This is an internationally networked registry with associated accompanying studies that investigate cancer risks and spectra, the possibilities of cancer prevention, early detection and therapy. Results: For several of these syndromes, new insights into the cancer risks and cancer types as well as factors modifying cancer risk have been gained. In addition, experimental, psycho-oncological, preclinical and clinical studies were initiated. Conclusions: The CPS registry is an example of how progress can be made within a short period of time to the benefit of individuals with rare diseases through systematic data collection and research

Forschung zu Seltenen Erkrankungen in Deutschland - Das Krebsprädispositionssyndrom-Register

Hintergrund: Krebsprädispositionssyndrome (KPS) sind seltene Erkrankungen, die auf Grund von genetischen Veränderungen mit einem erhöhten Krebsrisiko einhergehen. Mindestens 8 % aller Krebserkrankungen im Kindesalter sind auf ein KPS zurückzuführen [1, 2]. 2017 wurde das KPS-Register eröffnet, um mehr über KPS zu lernen und um die Betreuung Betroffener zu verbessern. Methode: Es handelt sich um ein international vernetztes Register sowie daran angegliederte Begleitstudien, die die Krebsrisiken und -spektren, die Möglichkeiten der Krebsprävention und -früherkennung sowie der -therapie untersuchen. Ergebnisse: Für mehrere KPS wurden neue Erkenntnisse zu Krebsrisiken und Krebsarten sowie zu Faktoren, die das Krebsrisiko modifizieren, erworben. Zudem wurden experimentelle, psychoonkologische sowie präklinische und klinische Studien ins Leben gerufen. Schlussfolgerungen: Das KPS-Register ist ein Beispiel dafür, wie für Menschen mit Seltenen Erkrankungen innerhalb kurzer Zeit durch systematische Datensammlung und Forschung Fortschritte erzielt werden können

Impact of somatic mutations on the outcome of children and adolescents with therapy-related myelodysplastic syndrome

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Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children

Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome. Germline SAMD9 and SAMD9L mutations (SAMD9/9L(mut)) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9L(mut) accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L(mut) cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9L(mut) clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L(mut) suppressed HEK293 cell growth, and mutations expressed in CD34(+) cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L(mut) patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 +/- cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9L(mut)). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L(mut) MDS and exemplify the exceptional plasticity of hematopoiesis in children

Genotype and phenotype spectrum of NRAS germline variants

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots