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Background Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria. Methods To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants. Results We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM ). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A /p14 ARF , and RUNX1 ). Conclusions Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.

Most malignant diseases develop sporadically. However, a significant proportion of cancers are based on genetic predispositions. In this case, cancer develops as a result of causal germline variants. In general, the associated diseases are called genetic tumor risk syndromes or cancer predisposition syndromes. Recognition of these syndromes is in the interest of those affected, as well as of their relatives, as this may have influence on immediate therapy or aftercare. In the course, risk-adapted surveillance or risk-reducing operations may be indicated.BACKGROUNDMost malignant diseases develop sporadically. However, a significant proportion of cancers are based on genetic predispositions. In this case, cancer develops as a result of causal germline variants. In general, the associated diseases are called genetic tumor risk syndromes or cancer predisposition syndromes. Recognition of these syndromes is in the interest of those affected, as well as of their relatives, as this may have influence on immediate therapy or aftercare. In the course, risk-adapted surveillance or risk-reducing operations may be indicated.Taking into account four signs (i.e., past medical history, characteristic tumors or suspicious age of onset, somatic alterations of the tumors, and family history), radiologists can contribute to the identification of patients with cancer predisposition. Besides appraisal of screening images, the expertise of radiologists is especially needed to develop and reevaluate risk-adapted surveillance programs.CLINICAL IMPACTTaking into account four signs (i.e., past medical history, characteristic tumors or suspicious age of onset, somatic alterations of the tumors, and family history), radiologists can contribute to the identification of patients with cancer predisposition. Besides appraisal of screening images, the expertise of radiologists is especially needed to develop and reevaluate risk-adapted surveillance programs.

RUNX1-familial platelet disorder with associated myeloid malignancy (RUNX1-FPDMM) is caused by heterozygous germline variants of . With the broader application of next-generation sequencing (NGS)-based gene panel analysis in individuals presenting with benign hematologic abnormalities such as thrombocytopenia, pathogenic variants were more frequently identified, independent of a hematologic malignancy. This study aimed to describe the clinical and genetic characteristics of individuals with pathogenic germline variants, with a particular focus on platelet function and diagnostic challenges. We retrospectively analyzed 10 individuals from 6 families with genetically confirmed RUNX1-FPDMM. Platelet counts and function were evaluated using light transmission aggregometry (LTA) and flow cytometry (FC). For genetic analysis, NGS-based panel sequencing for inherited platelet disorders, Sanger sequencing, karyotyping, fluorescence hybridization (FISH), and microarray analysis were performed. Platelet counts ranged between 40 and 208 G/L. In all six tested individuals, LTA revealed impaired aggregation in response to collagen, adenosine diphosphate (ADP), and epinephrine. FC analysis identified a pronounced granule secretion defect in three of the eight tested individuals. Disease-causing variants included whole-gene or intragenic deletions, one missense, two not previously reported non-sense variants, and a mosaic loss most probably due to the loss of a derivative chromosome 21. One patient has developed acute myeloid leukemia (AML), and another was diagnosed with RUNX1-FPDMM due to thrombocytopenia onset following T-lymphoblastic lymphoma. RUNX1-FPDMM is a challenging disease due to its associated increased risk for hematologic malignancies, mainly myelodysplastic syndrome (MDS) or AML. Genetic diagnosis in individuals with thrombocytopenia or functional platelet defects of unknown origin is crucial to offer structured surveillance and patient education. Increased risk of bleeding due to qualitative platelet function defects, particularly granule secretion abnormalities, must be considered when managing patients, especially prior to invasive procedures.

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4+ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27+ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

Zusammenfassung Hintergrund Krebserkrankungen treten meist sporadisch auf. Einem signifikanten Anteil der Erkrankungen liegt allerdings eine genetische Disposition zugrunde. Krebserkrankungen entstehen hier auf Basis einer ursächlichen konstitutionellen genetischen Veränderung. In diesem Fall spricht man im Allgemeinen von genetischen Tumorrisikosyndromen oder Krebsdispositionssyndromen. Die Erkennung dieser Syndrome liegt im Interesse der Betroffenen, aber auch ihrer Angehörigen, da dies möglicherweise Einfluss auf die unmittelbare Therapie bzw. Nachsorge hat. Im Verlauf können dann je nach Erkrankung risikoadaptierte Früherkennungsuntersuchungen oder auch risikoreduzierende Operationen indiziert sein. Klinische Bedeutung Unter Berücksichtigung von vier Indizien (Eigenanamnese, typische Tumoren und/oder Erkrankungsalter, somatische Charakteristika der Tumore und Familienanamnese) kann auch innerhalb der Radiologie ein Beitrag zur Identifikation Betroffener geleistet werden. Darüber hinaus ist die Fachexpertise der Radiologen im Kontext der Früherkennung gefragt. In diesem Bereich geht es neben der Befundung von Früherkennungsuntersuchungen insbesondere um die Entwicklung und fortlaufende Reevaluation risikoadaptierter Früherkennungsprogramme.

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.

Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.

Pathogenic germline variants affecting RUNX1 are associated with qualitative and/or quantitative platelet defects, and predispose to hematologic malignancies. The latter manifests in approximately 44% of carriers and can occur from early childhood to late adulthood. In addition to the predisposing RUNX1 germline variant, the acquisition of somatic genetic alterations is presumed to drive leukemic transformation in an inflammatory bone marrow niche. The spectrum of somatic mutations occurs heterogeneously between individuals, even within families, and there is no clear genotype–phenotype correlation. In this review, we summarize previously published patients harboring (likely) pathogenic RUNX1 germline alterations in whom somatic alterations were additionally analyzed. We provide an overview of their phenotypes and the most frequent somatic genetic alterations. Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.