Christian P Kratz’s research while affiliated with Hannover Medical School and other places

Background Recent large-scale sequencing studies reveal that up to 18% of children with cancer harbor pathogenic variants (PV) in known cancer predisposing genes (CPG). However, many patients exhibit features of an underlying predisposition but lack CPG PV. This observation suggests the presence of unidentified cancer predisposing variants and/or genes. To address this gap, we interrogated genes implicated in DNA damage repair (DDR) as a source of novel cancer predisposing signals that could account for this missing heritability. Methods We examined germline data from 5,993 childhood cancer cases and 14,477 adult non-cancer controls for damaging variants among 189 DDR genes. Damaging variants were defined as rare (allele frequency <0·05% in the gnomAD v2.1 non-cancer subset), nonsense, frameshift, canonical splice site, and missense with REVEL scores >0·7. Enrichment of damaging variants was determined using logistic and firth regression models. Putative novel CPG were replicated using data from 1,494 additional childhood cancer cases in three independent cohorts. Findings Pan-cancer analyses revealed enrichment of germline TP53 variants (false discovery rate [FDR] logistic =0·0066, FDR Firth =0·0064). Cancer-specific analyses demonstrated significant associations for TP53 in adrenocortical carcinoma (37%, FDR logistic <0·0001, FDR Firth =0) and high-grade glioma (2·4%, FDR logistic =0·0022, FDR Firth =0·1082), as well as BARD1 in neuroblastoma (1·2%, FDR logistic =0·0341, FDR Firth =0·2682). Three novel gene-tumor associations were identified, including POLL in Ewing sarcoma (1·7%, FDR logistic =0·0319, FDR Firth =0·3101), SMC5 in medulloblastoma (1·6%, FDR logistic =0·0005, FDR Firth =0·0499) and SMARCAL1 in osteosarcoma (2·6%, FDR logistic =0·0250, FDR Firth =0·2180). Among these new putative CPG, enrichment of SMARCAL1 PV in osteosarcoma was replicated across all three additional pediatric cancer cohorts (2·5%, P Fisher <0·0001). All osteosarcoma tumors (n=3) with whole genome sequencing data available exhibited deletion of the wild-type SMARCAL1 allele. Interpretation We report a catalogue of germline SMARCAL1 variants in pediatric osteosarcoma and demonstrate potential molecular effects in tumor formation through the presence of second somatic SMARCAL1 hits. The contribution of germline POLL and SMC5 variants in Ewing sarcoma and medulloblastoma, respectively, warrants further investigation. Our study highlights the power of unbiased genomic investigations to uncover novel CPG, providing insights into tumor biology and creating opportunities for therapeutic intervention, surveillance, and prevention. Funding Funding was provided by the American Lebanese Syrian Associated Charities and US National Institutes of Health, German Cancer Research Center, German Cancer Consortium. Research in context Evidence before this study We performed a PubMed search using the terms “childhood cancer” OR “pediatric cancer” AND “germline mutation” OR “germline variant” AND “predisposition gene” AND “sequencing” AND “DNA damage repair” OR “DNA damage response” between Jan 1, 2020, and April 1, 2025, to investigate the spectrum of genes mutated in the germline of children with cancer. Genes participating in DNA damage repair (DDR) are often mutated in childhood tumors, highlighting the integral role of defective DNA repair in tumor formation. Further, pathogenic variants (PV) in DDR genes underlie several highly penetrant cancer predisposition syndromes and are implicated in the increased risk of treatment-related subsequent malignant neoplasms among adult survivors of childhood cancer. To the best of our knowledge, a comprehensive assessment of DDR genes across children with primary cancers has not yet been performed. Added value of this study The use of a robust case-control design, stringent germline variant filtering criteria, and integration of tumor data provided a rigorous framework with which to identify novel associations between germline PV in DDR genes and childhood cancers, including POLL in Ewing sarcoma, SMC5 in medulloblastoma, and SMARCAL1 in osteosarcoma. Among these, enrichment of SMARCAL1 PV in osteosarcoma was replicated across three additional pediatric cancer cohorts with loss-of-heterozygosity at the SMARCAL1 locus observed in all osteosarcoma tumors with whole genome sequencing available. Altogether, these findings provide compelling evidence linking SMARCAL1 germline variation with pediatric osteosarcoma. Implications of all the available evidence Identifying SMARCAL1 as a novel osteosarcoma predisposing gene has significant biological and clinical implications. This information provides new insights into the pathogenesis of osteosarcoma, an aggressive and often fatal childhood cancer, and may enable development of more effective therapies. Incorporating germline genetic testing for SMARCAL1 into clinical practice could inform the institution of novel surveillance strategies to detect incipient osteosarcoma tumors at the earliest and most curable stages, thereby improving outcomes for affected children and families. Future research should focus on inheritance patterns, penetrance, and therapeutic vulnerabilities of SMARCAL1 -deficient tumors, including their potential sensitivity to agents that inhibit DNA damage repair.

Recent studies indicate up to 20% of sarcomas may be associated with predisposition genes, and this number will probably increase as genetic testing becomes more available. Evidence on the management of patients with sarcoma and genetic predisposition remains, however, scarce. This review compiles available research on genetic predisposition syndromes associated with sarcoma and sarcoma treatment within such syndromes, addressing key gaps in knowledge. We explore the current evidence on how genetic predisposition may influence treatment decisions and clinical management, focusing on surgery, radiotherapy, systemic treatment, and surveillance. Evidence-based recommendations are currently not available for most syndromes, and we have therefore included pragmatic advice for clinicians. Unanswered questions and unmet needs are also identified, underscoring the importance of multidisciplinary input from specialists such as geneticists, radiologists, surgeons and oncologists. The review stresses the need for future research to improve clinical outcomes for patients with sarcoma and genetic predisposition. Funding No funding has been provided for this work.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition condition characterized by a high lifetime risk for a wide spectrum of malignancies associated with germline pathogenic/likely pathogenic (P/LP) variants in the TP53 tumor suppressor gene. Secondary malignant neoplasms are particularly common. Early cancer detection through surveillance enables early intervention and leads to improved clinical outcomes with reduced tumor-related mortality and treatment-related morbidity. Since the 2017 publication of LFS tumor surveillance guidelines from the inaugural AACR Childhood Cancer Predisposition Workshop, understanding the genotype:phenotype relationships in LFS have evolved, and adaptations of the guidelines have been implemented in institutions worldwide. The “Toronto Protocol” remains the current standard for life-long surveillance; however, as outlined in this Perspective, modifications should be considered as to the use of certain modalities to target organs in an age-dependent manner. The Working Group’s recommendations have also been extended to include a more detailed outline for surveillance in the adult TP53 P/LP variant carrier population based on the recognition that early education of both practitioners and patients on what to expect after the transition from childhood/adolescence to young adulthood is important in preparing them for changes in surveillance strategies. In this perspective, we provide an up-to-date clinical overview of LFS, and present our updated consensus tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.

Schwannomatoses (SWN) are distinct cancer predisposition syndromes caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas and less commonly ependymoma. SMARCB1-related SWN is a familial SWN-syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN-syndromes.

Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients’ families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.

Li-Fraumeni syndrome is a cancer predisposition syndrome caused by pathogenic TP53 germline variants and associated with a high lifelong cancer risk. We analysed the German LFS registry that contains data on 304 individuals. Cancer phenotypes were correlated with variants grouped according to their ability to transactivate target genes in a yeast assay using a traditional (non-functional, partially-functional) and a novel (clusters A, B, C) classification of variants into different groups. Partially-functional and cluster B or C variants were enriched in patients not meeting clinical testing criteria. Time to first malignancy was longer in carriers of partially-functional variants (Hazard Ratio [HR] = 0.38; 95% CI, 0.22 to 0.66). Variants grouped within clusters B (HR = 0.45; 95% CI, 0.28 to 0.71) or C (HR = 0.34; 95% CI, 0.19 to 0.62) were associated with later cancer onset than NULL variants. These findings can be used to risk-stratify patients and inform care.

Although cancer is rare in children and adolescents, it remains a leading cause of death within this age range, and genetic predisposition is the main known risk factor. Since the discovery of retinoblastoma-predisposing RB1 pathogenic germline variants in 1985, several additional high-penetrance cancer predisposition genes (CPGs) have been identified. Although few clinically recognizable genetic conditions display moderate cancer phenotypes, burden testing has revealed low-to-moderate penetrance CPGs. In addition to germline pathogenic variants in CPGs, postzygotic somatic mosaic CPG pathogenic variants acquired during embryonic development are increasingly recognized as factors that predispose children and adolescents to malignancies. Genome-wide association studies of various childhood and adolescent cancer types have identified some common low-risk cancer susceptibility alleles. Although the clinical utility of polygenic risk scores is currently limited in children and adolescents, polygenic risk scores developed for adults can predict subsequent cancer risks in childhood and adolescent cancer survivors. In this Review, I describe our current knowledge of genetic predisposition to childhood and adolescent cancers. Survival rates in children and adolescents with cancer and CPGs are often poor, necessitating better integration of genomic testing into clinical care to improve cancer prevention, surveillance and therapies.

RAS/MAPK signaling is one of the most critical in mammalian biology. Given this, hyperactivation of the RAS/MAPK pathway, via somatic mutation or germline pathogenic variants, is a frequent event in cancer and causative for RASopathies, respectively. Somatic mutations in one of the three isoforms of RAS, or downstream effector genes, are present in roughly one-third of all human cancers. Pancreatic cancer, a highly lethal cancer, is molecularly characterized by the presence of KRAS p.G12D in over 90% of all tumors and is known to initiate tumor development. A high percentage of melanomas are characterized by the presence of BRAF p.V600E, which also represents a successful therapeutic target. In contrast, pathogenic germline variants in RAS/MAPK genes underlie the RASopathies, where increased cancer risk has been observed in some, but not all, syndromes. In Costello syndrome, arising from germline HRAS pathogenic variants, cancer risk is observed in approximately 17% of individuals by age 20 years. However, in Legius syndrome, arising from SPRED1 variants, cancer risk is comparable to that of the general population. Understanding the intersections of RAS/MAPK somatic and germline variation may reveal novel strategies to inform clinical care in both RAS-related cancer and the RASopathies.

Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to an individually variable spectrum of cancers caused by pathogenic TP53 germline variants. We used a clustering method to assign TP53 missense variants to classes based on their functional activities in experimental assays assessing biological p53 functions. Correlations with LFS phenotypes were analyzed using the public germline TP53 mutation database and validated in three LFS clinical cohorts. Class A carriers recapitulated all phenotypic traits of fully penetrant LFS, whereas class B carriers showed a slightly less penetrant form dominated by specific cancers, consistent with the notion that these classes identify variants with distinct functional properties. Class C displayed a lower lifetime cancer risk associated with attenuated LFS features, consistent with the notion that these variants have hypomorphic features. Class D carriers showed low lifetime cancer risks inconsistent with LFS definitions. This classification of TP53 variants provides insights into structural/functional features causing pathogenicity.