Experiences of pediatric cancer patients (age 12-18 years) with extensive germline sequencing for cancer predisposition: a qualitative study.

This study explored the experiences and needs of adolescents, ranging from 12 to 18 years old, who have recently been diagnosed with cancer and participated in a nationwide germline genetic sequencing study within the context of pediatric oncology. The 21 adolescents in this qualitative interview study viewed genetic sequencing as an integral part of their cancer journey. They often characterized germline sequencing as "good-to-know" without specifying immediate utility. While the adolescents comprehended the significance of germline genetic sequencing, they were less focused on its potential long-term implications. Adolescents expressed a strong desire to be actively engaged in decisions related to genetics. They advocated for a participatory role in genetic decision-making from a young age onwards. They recommended that re-consent should be sought before re-analysis of their genetic data is performed and believe that patients should have the opportunity to provide (re-)consent once they reach adulthood. Moreover, the adolescents emphasized the importance of developing counseling materials that are not only concise but also visually attractive. In conclusion, this study underscores the positive perception that adolescents diagnosed with cancer hold regarding germline genetic sequencing. They articulate a strong interest in being actively involved in genetic decision-making. To address these articulated needs and preferences, we recommend the development of visually engaging counseling materials. These materials should effectively convey both the immediate and long-term implications of genetic sequencing, enabling adolescents with cancer to make informed decisions about genetic sequencing.

Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations.

Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non-LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non-LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR-deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non-LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS.

No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation.

BACKGROUND: Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis. METHODS: In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples. RESULTS: Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28). CONCLUSIONS: Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not. LEVEL OF EVIDENCE: Level IV.

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.

Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm.

Importance: To improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking. Objective: To describe a national children's cancer center's experience in diagnosing CPSs before introducing routine next-generation sequencing. Design, Setting, and Participants: This retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022. Exposures: As part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing. Main Outcomes and Measures: Detected cancer predisposition syndromes. Results: A total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role. Conclusions and Relevance: In this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.

The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes.

Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'.

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.

Parents' experiences with large-scale sequencing for genetic predisposition in pediatric renal cancer: A qualitative study.

OBJECTIVE: In pediatric oncology, large-scale genetic sequencing contributes to the identification of cancer predisposition, which can facilitate surveillance and family counseling. Our qualitative study explores families' motives, knowledge, and views regarding germline genetic sequencing to improve future counseling and support. METHODS: Semi-structured interviews were conducted with parents of children with renal tumors participating in a national center, germline sequencing study. An inductive thematic analysis approach was used. Twenty nine parents participated, 17 mothers and 12 fathers. The median age of the affected children was 4 years. RESULTS: Parents were generally positive about sequencing and reported a combination of individual and altruistic motives to participate. Some families counseled about sequencing shortly after cancer diagnosis felt overwhelmed. Many parents had difficulties distinguishing between panel and exome-wide analysis. Families in which no predisposition was identified felt reassured. Most families did not experience distress after a predisposition was disclosed, although sometimes stress following disclosure of a predisposition added to pre-existing (cancer-related) stress. CONCLUSIONS: Even though families reported positive experiences with germline genetic sequencing to detect cancer predisposition, timing of consent for sequencing as well as parents' understanding of genetic concepts can be further improved.

Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization.

PURPOSE: Wilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors. PATIENTS AND METHODS: All children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered. RESULTS: A total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1-related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes (BRCA2, PMS2, CHEK2, and MUTYH) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation. CONCLUSION: (Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist.

Characteristics and outcome of children with renal tumors in the Netherlands: The first five-year's experience of national centralization.

Around 6% of all childhood malignancies represent renal tumors, of which a majority includes Wilms tumor (WT). Although survival rates have improved over the last decades, specific patients are still at risk for adverse outcome. In the Netherlands, since 2015, pediatric oncology care for renal tumors has been centralized in the Princess Máxima Center for Pediatric Oncology. Here, we describe experiences of the first 5 years of centralized care and explore whether this influences the epidemiological landscape by comparing data with the Netherlands Cancer Registry (NCR). We identified all patients <19 years with a renal mass diagnosed between 01-01-2015 and 31-12-2019 in the Princess Máxima Center. Epidemiology, characteristics and management were analyzed. We identified 164 patients (including 1 patient who refused consent for registration), in our center with a suspicion of a renal tumor. The remaining 163 cases included WT (n = 118)/cystic partially differentiated nephroblastoma (n = 2)/nephrogenic rests only (n = 6) and non-WT (n = 37). In this period, the NCR included 138 children, 1 17-year-old patient was not referred to the Princess Máxima Center. Central radiology review (before starting treatment) was performed in 121/163 patients, and central pathology review in 148/152 patients that underwent surgery. Treatment stratification, according to SIOP/EpSSG protocols was pursued based on multidisciplinary consensus. Preoperative chemotherapy was administered in 133 patients, whereas 19 patients underwent upfront surgery. Surgery was performed in 152 patients, and from 133 biomaterial was stored. Centralization of care for children with renal tumors led to referral of all but 1 new renal tumor cases in the Netherlands, and leads to referral of very rare subtypes not registered in the NCR, that benefit from high quality diagnostics and multidisciplinary decision making. National centralization of care led to enhanced development of molecular diagnostics and other innovation-based treatments for the future.

High Prevalence of Constitutional Mismatch Repair Deficiency in a Pediatric T-cell Lymphoblastic Lymphoma Cohort.

This study describes the clinical characteristics of a complete Dutch T-cell lymphoblastic lymphoma (T-LBL) cohort, including second primary malignancies and comorbidities. We show that over 10% of patients in this complete T-LBL cohort have been diagnosed with a cancer predisposition syndrome (CPS), consisting almost exclusively of constitutional mismatch repair deficiency (CMMRD). The clinical characteristics of sporadic T-LBL patients were compared with T-LBL patients that have been diagnosed with CMMRD. This shows that disease presentation is comparable but that disease localization in CMMRD patients might be more localized. The percentage of CPS seems reliable considering the completeness of the cohort of Dutch T-LBL patients and might even be an underestimation (possibility of undiagnosed CPS patients in cohort). As the frequency of an underlying predisposition syndrome among T-LBL patients may be underestimated at present, we advocate for screening all pediatric T-LBL patients for the presence of germline mutations in mismatch repair genes.

Bilateral Renal Tumors in Children: The First 5 Years' Experience of National Centralization in The Netherlands and a Narrative Review of the Literature.

Survival of unilateral Wilms tumors (WTs) is exceeding 90%, whereas bilateral WTs have an inferior outcome. We evaluated all Dutch patients with bilateral kidney tumors, treated in the first five years of national centralization and reviewed relevant literature. We identified 24 patients in our center (2015-2020), 23 patients had WT/nephroblastomatosis and one renal cell carcinoma. Patients were treated according to SIOP-RTSG protocols. Chemotherapy response was observed in 26/34 WTs. Nephroblastomatosis lesions were stable (n = 7) or showed response (n = 18). Nephron-sparing surgery was performed in 11/22 patients undergoing surgery (n = 2 kidneys positive margins). Local stage in 20 patients with ≥1 WT revealed stage I (n = 7), II (n = 4) and III (n = 9). Histology was intermediate risk in 15 patients and high risk in 5. Three patients developed a WT in a treated nephroblastomatosis lesion. Two of 24 patients died following toxicity and renal failure, i.e., respectively dialysis-related invasive fungal infection and septic shock. Genetic predisposition was confirmed in 18/24 patients. Our literature review revealed that knowledge is scarce on bilateral renal tumor patients with metastases and that radiotherapy seems important for local stage III patients. Bilateral renal tumors are a therapeutic challenge. We describe management and outcome in a national expert center and summarized available literature, serving as baseline for further improvement of care.

Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome.

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.

Wilms tumour surveillance in at-risk children: Literature review and recommendations from the SIOP-Europe Host Genome Working Group and SIOP Renal Tumour Study Group.

Since previous consensus-based Wilms tumour (WT) surveillance guidelines were published, novel genes and syndromes associated with WT risk have been identified, and diagnostic molecular tests for previously known syndromes have improved. In view of this, the International Society of Pediatric Oncology (SIOP)-Europe Host Genome Working Group and SIOP Renal Tumour Study Group hereby present updated WT surveillance guidelines after an extensive literature review and international consensus meetings. These guidelines are for use by clinical geneticists, pediatricians, pediatric oncologists and radiologists involved in the care of children at risk of WT. Additionally, we emphasise the need to register all patients with a cancer predisposition syndrome in national or international databases, to enable the development of better tumour risk estimates and tumour surveillance programs in the future.

Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group.

DICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging because uncertainty exists about the clinical efficacy of surveillance, and appraisal of potential benefits and harms vary. In addition, there is increasing evidence that germline DICER1 pathogenic variants are associated with lower penetrance for cancer than previously assumed. To address these issues and to harmonize DICER1 syndrome surveillance programs within Europe, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) and Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom reviewed current surveillance strategies and evaluated additional relevant literature. Consensus was achieved for a new surveillance protocol and information leaflet that informs patients about potential symptoms of DICER1-associated tumors. The surveillance protocol comprises a minimum program and an extended version for consideration. The key recommendations of the minimum program are: annual clinical examination from birth to age 20 years, six-monthly chest X-ray and renal ultrasound from birth to age 6 years, and thyroid ultrasound every 3 years from age 8 to age 40 years. The surveillance program for consideration comprises additional surveillance procedures, and recommendations for DICER1 pathogenic variant carriers outside the ages of the surveillance interval. Patients have to be supported in choosing the surveillance program that best meets their needs. Prospective evaluation of the efficacy and patient perspectives of proposed surveillance recommendations is required to expand the evidence base for DICER1 surveillance protocols.

Clinical and Molecular Characteristics and Outcome of Cystic Partially Differentiated Nephroblastoma and Cystic Nephroma: A Narrative Review of the Literature.

In children presenting with a predominantly cystic renal tumor, the most likely diagnoses include cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN). Both entities are rare and limited information on the clinical and molecular characteristics, treatment, and outcome is available since large cohort studies are lacking. We performed an extensive literature review, in which we identified 113 CPDN and 167 CN. The median age at presentation for CPDN and CN was 12 months (range: 3 weeks-4 years) and 16 months (prenatal diagnosis-16 years), respectively. No patients presented with metastatic disease. Bilateral disease occurred in both entities. Surgery was the main treatment for both. Two/113 CPDN patients and 26/167 CN patients had previous, concomitant, or subsequent other tumors. Unlike CPDN, CN was strongly associated with somatic (n = 27/29) and germline (n = 12/12) DICER1-mutations. Four CPDN patients and one CN patient relapsed. Death was reported in six/103 patients with CPDN and six/118 CN patients, none directly due to disease. In conclusion, children with CPDN and CN are young, do not present with metastases, and have an excellent outcome. Awareness of concomitant or subsequent tumors and genetic testing is important. International registration of cystic renal tumor cohorts is required to enable a better understanding of clinical and genetic characteristics.

Clinical, Pathology, Genetic, and Molecular Features of Colorectal Tumors in Adolescents and Adults 25 Years or Younger.

BACKGROUND & AIMS: Colorectal cancers (CRCs) are rare in adolescents and adults ages 25 years or younger. We analyzed clinical, pathology, and molecular features of colorectal tumors from adolescents and young adults in an effort to improve genetic counseling, surveillance, and, ultimately, treatment and outcomes. METHODS: We analyzed clinical data and molecular and genetic features of colorectal tumor tissues from 139 adolescents or young adults (age, ≤25 y; median age, 23 y; 58% male), collected from 2000 through 2017; tumor tissues and clinical data were obtained from the nationwide network and registry of histopathology and cytopathology and The Netherlands Cancer Registry, respectively. DNA samples from tumors were analyzed for microsatellite instability, mutations in 56 genes, and genome-wide somatic copy number aberrations. RESULTS: Mucinous and/or signet ring cell components were observed in 33% of tumor samples. A genetic tumor risk syndrome was confirmed for 39% of cases. Factors associated with shorter survival time included younger age at diagnosis, signet ring cell carcinoma, the absence of a genetic tumor risk syndrome, and diagnosis at an advanced stage of disease. Compared with colorectal tumors from patients ages 60 years or older in the Cancer Genome Atlas, higher proportions of tumors from adolescents or young adults were microsatellite stable with nearly diploid genomes, or contained somatic mutations in TP53 and POLE, whereas lower proportions contained mutations in APC. CONCLUSIONS: We found clinical, molecular, and genetic features of CRCs in adolescents or young adults to differ from those of patients older than age 60 years. In 39% of patients a genetic tumor risk syndrome was identified. These findings provide insight into the pathogenesis of CRC in young patients and suggest new strategies for clinical management. Performing genetic and molecular analyses for every individual diagnosed with CRC at age 25 years or younger would aid in this optimization.