Germline genomic findings in children and young adults with melanocytic tumors.

In this retrospective study, we examined the prevalence and spectrum of germline variants in selected cancer predisposition genes in 38 children and young adults with melanocytic lesions at St. Jude Children's Research Hospital. Diagnoses included malignant melanoma (n = 16; 42%), spitzoid melanoma (n = 16; 42%), uveal melanoma (n = 5; 13%), and malignant melanoma arising in a giant congenital melanocytic nevus (n = 1; 3%). Six patients (15.8%) harbored pathogenic germline variants: one with bi-allelic PMS2 variants, one with a heterozygous 17q21.31 deletion, and one each with a pathogenic variant in TP53, BRIP1, ATM, or AXIN2. Overall, 15.8% of patients harbored a cancer-predisposing genetic variant.

Genomes for Nurses: Understanding and Overcoming Barriers to Nurses Utilizing Genomics.

Background: Genomic testing is an increasingly important technology within pediatric oncology that aids in cancer diagnosis, provides prognostic information, identifies therapeutic targets, and reveals underlying cancer predisposition. However, nurses lack basic knowledge of genomics and have limited self-assurance in using genomic information in their daily practice. This single-institution project was carried out at an academic pediatric cancer hospital in the United States with the aim to explore the barriers to achieving genomics literacy for pediatric oncology nurses. Method: This project assessed barriers to genomic education and preferences for receiving genomics education among pediatric oncology nurses, nurse practitioners, and physician assistants. An electronic survey with demographic questions and 15 genetics-focused questions was developed. The final survey instrument consisted of nine sections and was pilot-tested prior to administration. Data were analyzed using a ranking strategy, and five focus groups were conducted to capture more-nuanced information. The focus group sessions lasted 40 min to 1 hour and were recorded and transcribed. Results: Over 50% of respondents were uncomfortable with or felt unprepared to answer questions from patients and/or family members about genomics. This unease ranked as the top barrier to using genomic information in clinical practice. Discussion: These results reveal that most nurses require additional education to facilitate an understanding of genomics. This project lays the foundation to guide the development of a pediatric cancer genomics curriculum, which will enable the incorporation of genomics into nursing practice.

Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop.

Genetic predisposition to neuroblastoma (NB) is relatively rare. Only 1% to 2% of patients have a family history of NB, 3% to 4% of cases present with bilateral or multifocal primary tumors, and occasional patients have syndromes that are associated with increased NB risk. Previously, a germline pathogenic variant (GPV) in PHOX2B was associated with Hirschsprung disease and congenital central hypoventilation syndrome. Recently, certain GPVs were shown to be responsible for congenital central hypoventilation syndrome and NB predisposition. Also, several groups determined that activating GPVs in ALK accounted for a substantial number of familial NB. Finally, there are additional genes and cancer predisposition syndromes in which NB occurs with greater frequency or that have been associated with NB based on genome-wide association studies. We review the evidence for all these genes and whether there is sufficient evidence to warrant surveillance. We review recommended surveillance for hereditary patients with NB, including minor updates to surveillance recommendations that were published previously in 2017.

C5aR plus MEK inhibition durably targets the tumor milieu and reveals tumor cell phagocytosis.

Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of NF1 and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment.

Performance of Tumor Surveillance for Children With Cancer Predisposition.

Importance: Pediatric oncology patients are increasingly recognized as having an underlying cancer predisposition syndrome (CPS). Surveillance is often recommended to detect new tumors at their earliest and most curable stages. Data on the effectiveness and outcomes of surveillance for children with CPS are limited. Objective: To evaluate the performance of surveillance across a wide spectrum of CPSs. Design, Setting, and Participants: This cohort study reviewed surveillance outcomes for children and young adults from birth to age 23 years with a clinical and/or molecular CPS diagnosis from January 1, 2009, through September 31, 2021. Patients were monitored using standard surveillance regimens for their corresponding CPS at a specialty pediatric oncology center. Patients with hereditary retinoblastoma and bone marrow failure syndromes were excluded. Data were analyzed between August 1, 2021, and December 6, 2023. Exposure: Cancer predisposition syndrome. Main Outcomes and Measures: Outcomes of surveillance were reviewed to evaluate the incidence, spectrum, and clinical course of newly detected tumors. Surveillance modalities were classified for accuracy and assessed for common strengths and weaknesses. Results: A total of 274 children and young adults (mean age, 8 years [range, birth to 23 years]; 144 female [52.6%]) with 35 different CPSs were included, with a median follow-up of 3 years (range, 1 month to 12 years). During the study period, 35 asymptomatic tumors were detected in 27 patients through surveillance (9.9% of the cohort), while 5 symptomatic tumors were detected in 5 patients (1.8% of the cohort) outside of surveillance, 2 of whom also had tumors detected through surveillance. Ten of the 35 tumors (28.6%) were identified on first surveillance imaging. Malignant solid and brain tumors identified through surveillance were more often localized (20 of 24 [83.3%]) than similar tumors detected before CPS diagnosis (71 of 125 [56.8%]; P < .001). Of the 24 tumors identified through surveillance and surgically resected, 17 (70.8%) had completely negative margins. When analyzed across all imaging modalities, the sensitivity (96.4%), specificity (99.6%), positive predictive value (94.3%), and negative predictive value (99.6%) of surveillance were high, with few false-positive (6 [0.4%]) or false-negative (5 [0.3%]) findings. Conclusions and Relevance: These findings suggest that standardized surveillance enables early detection of new tumors across a wide spectrum of CPSs, allowing for complete surgical resection and successful treatment in the majority of patients.

Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment.

To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor-like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.

Collaboration to Promote Research and Improve Clinical Care in the Evolving Field of Childhood Cancer Predisposition.

Germline pathogenic variants in cancer susceptibility genes are identified in up to 18% of all children with cancer. Because pediatric cancer predisposition syndromes (CPS) themselves are rare and underrecognized, there are limited data to guide the diagnosis and management of affected children and at-risk relatives. Furthermore, the care of affected children requires distinct considerations given the early onset of cancers, lifelong risks of additional cancers, and potential late effects of therapy. Herein, we discuss efforts to leverage existing infrastructure, organize experts, and develop a new consortium to optimize care and advance research for children with CPS. A 2016 workshop organized by the American Association for Cancer Research united many experts in childhood cancer predisposition and resulted in publication of multiple consensus guidelines for tumor surveillance. More recently, several of these authors established the Consortium for Childhood Cancer Predisposition (C3P), a multi-institutional collaboration that provides a structure for systematic research in cancer predisposition, screening, and prevention in children. The Consortium intends to work with other cooperative groups to merge longitudinal data from children with CPS throughout the continuum of the cancer risk period, as well as cancer treatment and survivorship care, to optimize overall outcomes.

WNT5A inhibition alters the malignant peripheral nerve sheath tumor microenvironment and enhances tumor growth.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that cause significant mortality in adults with neurofibromatosis type 1. We compared gene expression of growth factors in normal human nerves to MPNST and normal human Schwann cells to MPNST cell lines. We identified WNT5A as the most significantly upregulated ligand-coding gene and verified its protein expression in MPNST cell lines and tumors. In many contexts WNT5A acts as an oncogene. However, inhibiting WNT5A expression using shRNA did not alter MPNST cell proliferation, invasion, migration, or survival in vitro. Rather, shWNT5A-treated MPNST cells upregulated mRNAs associated with the remodeling of extracellular matrix and with immune cell communication. In addition, these cells secreted increased amounts of the proinflammatory cytokines CXCL1, CCL2, IL6, CXCL8, and ICAM1. Versus controls, shWNT5A-expressing MPNST cells formed larger tumors in vivo. Grafted tumors contained elevated macrophage/stromal cells, larger and more numerous blood vessels, and increased levels of Mmp9, Cxcl13, Lipocalin-1, and Ccl12. In some MPNST settings, these effects were mimicked by targeting the WNT5A receptor ROR2. These data suggest that the non-canonical Wnt ligand WNT5A inhibits MPNST tumor formation by modulating the MPNST microenvironment, so that blocking WNT5A accelerates tumor growth in vivo.

Cdkn2a Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST.

Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST. SIGNIFICANCE: New mouse models recapitulate the stepwise progression of NF1 tumors and will be useful to define effective treatments that halt tumor growth and tumor progression in NF1.

Genetic predisposition to cancer: Surveillance and intervention.

Cancer is one of the leading causes of early mortality for children and adolescents. Identifiable genetic cancer predisposition conditions account for a growing proportion of pediatric and adolescent cancer, likely due to increasing knowledge about various predisposition conditions, more widespread cancer genetic counseling, and available diagnostics. Greater awareness, data-driven surgical intervention and clinical surveillance can help facilitate cancer prevention and early detection at cancer stages more amenable to cure. An extensive literature review of published studies and expert opinion with consensus guidelines are reviewed. Specific syndromes where genetics, imaging and surgical intervention are utilized to benefit affected patients and families are presented. In many tumor predisposition syndromes, the underlying genetic diagnosis is made concurrently, or after, malignancy is identified. Improved recognition of underlying predispositions, along with appropriate surgical interventions and imaging surveillance should lead to increased patient survival.