Update on surveillance guidelines in emerging Wilms tumor predisposition syndromes.

Wilms tumors are commonly associated with predisposition syndromes. Many of these syndromes are associated with specific phenotypic features and are discussed in the related paper from the AACR Pediatric Cancer Working Group. Guidelines for surveillance in this population were published in 2017 but since then several studies have identified new genes with recurrent pathogenic variants associated with increased risk for Wilms tumor development. In general, variants in these genes are less likely to be associated with other phenotypic features. Recently, members of the AACR Pediatric Cancer Working Group met to update surveillance guidelines for patients with a predisposition to Wilms tumors with a review of recently published evidence and risk estimates. Risk estimates for Wilms tumor for the more recently described genes are discussed here along with suggested surveillance guidelines for these populations. Several other emerging clinical scenarios associated with Wilms tumor predisposition are also discussed including patients with family histories of Wilms tumor and no identified causative gene, patients with bilateral tumors, and patients with somatic mosaicism for chromosome 11p15.5 alterations. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on emerging evidence and harmonize updated surveillance recommendations in the North American and Australian context for patients with emerging forms of Wilms tumor predisposition.

Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study.

PURPOSE: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population. PATIENTS AND METHODS: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood. RESULTS: Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (P = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (P < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (P = .6171). CONCLUSION: Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.

Update on surveillance for Wilms tumor and hepatoblastoma in Beckwith-Wiedemann Syndrome and other predisposition syndromes.

Wilms tumors are commonly associated with predisposition syndromes many, but not all, of which include overgrowth. Several of these syndromes also include a risk of other embryonal malignancies - particularly hepatoblastoma. Guidelines for surveillance in this population were published in 2017 and recently members of the AACR Pediatric Cancer Working Group met to update those guidelines with a review of more recently published evidence and risk estimates. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines and harmonize updated surveillance recommendations in the North American and Australian context for patients with overgrowth syndromes and other syndromes associated with Wilms tumor predisposition.

Pediatric Cancer Screening in Hereditary Gastrointestinal Cancer Risk Syndromes: An Update from the AACR Childhood Cancer Predisposition Working Group.

Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of a syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017. These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.

Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.

Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

Disparate Rates of Germline Variants in Cancer Predisposition Genes in African American/Black Compared With Non-Hispanic White Individuals Between 2015 and 2022.

PURPOSE: African American/Black (AA/B) individuals are under-represented in genomic databases and thus less likely to receive definitive information from germline genetic testing (GGT) than non-Hispanic White (NHW) individuals. With nearly 500,000 AA/B and NHW individuals having undergone multigene panel testing (MGPT) for hereditary cancer risk at a single commercial laboratory, to our knowledge, we present the largest study to date investigating cancer GGT results in AA/B and NHW individuals. METHODS: MGPT results from a retrospective cohort of AA/B (n = 48,684) and NHW (n = 444,831) patients were evaluated. Frequencies of pathogenic germline variants (PGVs) and variants of uncertain significance (VUS) were compared between AA/B and NHW individuals. Changes in frequency of VUS over time were determined. Pearson's chi-squared test was used to compare categorical variables among groups. All significance tests were two-tailed, and P < .05 was considered statistically significant. RESULTS: Between 2015 and 2022, rates of VUS decreased 2.3-fold in AA/B and 1.8-fold in NHW individuals; however, frequencies of VUS and PGV remained significantly higher (46% v 32%; P < .0001) and lower (9% v 13%; P < .0001) in AA/B compared with NHW individuals. Rates of VUS in ATM, BRCA1, BRCA2, PALB2, and PMS2 were significantly higher in AA/B compared with NHW individuals, whereas rates of PGV in BRCA1, BRCA2, and PALB2 were higher in AA/B compared with NHW individuals (P < .001). CONCLUSION: Despite reductions in VUS frequencies over time, disparities in definitive GGT results persist. Increasing inclusion of AA/B populations in both testing and research will further increase knowledge of genetic variants across these racial groups.

Correction: Childhood cancer survival in the highly vulnerable population of South Texas: A cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0278354.].

Families' experiences accessing care after genomic sequencing in the pediatric cancer context: "It's just been a big juggle".

Access to genomic sequencing (GS) and resulting recommendations have not been well described in pediatric oncology. GS results may provide a cancer predisposition syndrome (CPS) diagnosis that warrants screening and specialist visits beyond cancer treatment, including testing or surveillance for family members. The Texas KidsCanSeq (KCS) Study evaluated implementation of GS in a diverse pediatric oncology population. We conducted semi-structured interviews (n = 20) to explore experiences of KCS patients' families around learning about a CPS diagnosis and following up on recommended care. We used qualitative content analysis to develop themes and subthemes across families' descriptions of their experiences accessing care and to understand which factors presented barriers and/or facilitators. We found participants had difficulty differentiating which follow-up care recommendations were made for their child's current cancer treatment versus the CPS. In families' access to follow-up care for CPS, organizational factors were crucial: travel time and distance were common hardships, while coordination of care to streamline multiple appointments with different providers helped facilitate CPS care. Financial factors also impacted families' access to CPS-related follow-up care: having financial assistance and insurance were facilitators for families, while costs and lack of insurance posed as barriers for patients who lost coverage during transitions from pediatric to adult care, and for adult family members who had no coverage. Factors related to beliefs and perceptions, specifically perceiving the risk as less salient to them and feeling overwhelmed with the patient's cancer care, presented barriers to follow-up care primarily for family members. Regarding social factors, competing life priorities made it difficult for families to access follow-up care, though having community support alleviated these barriers. We suggest interventions to improve coordination of cancer treatment and CPS-related care and adherence to surveillance protocols for families as children age, such as care navigators and integrating longitudinal genetic counseling into hereditary cancer centers.

Comprehensive characterization of patient-derived xenograft models of pediatric leukemia.

Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poorer overall outcome. Of 117 primary leukemia samples obtained, successful engraftment and serial passage in mice were achieved in 82 samples (70%). Hispanic patient samples engrafted at a rate (51/73, 70%) that was similar to non-Hispanic patient samples (31/45, 70%). With a new algorithm to remove mouse contamination in multi-omics datasets including methylation data, we found PDX models faithfully reflected somatic mutations, copy-number alterations, RNA expression, gene fusions, whole-genome methylation patterns, and immunophenotypes found in primary tumor (PT) samples in the first 50 reported here. This cohort of characterized PDX childhood leukemias represents a valuable resource in that germline DNA sequencing has allowed the unambiguous determination of somatic mutations in both PT and PDX.

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer.

Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.

Circulating tumor DNA sequencing of pediatric solid and brain tumor patients: An institutional feasibility study.

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.

Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma.

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153Δ and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153Δ unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRASG12D-driven ERMS-model.

Childhood cancer survival in the highly vulnerable population of South Texas: A cohort study.

This study examines childhood cancer survival rates and prognostic factors related to survival in the majority Hispanic population of South Texas. The population-based cohort study used Texas Cancer Registry data (1995-2017) to examine survival and prognostic factors. Cox proportional hazard models and Kaplan-Meier survival curves were used for survival analyses. The 5-year relative survival rate for 7,999 South Texas cancer patients diagnosed at 0-19 years was 80.3% for all races/ethnicities. Hispanic patients had statistically significant lower 5-year relative survival rates than non-Hispanic White (NHW) patients for male and female together diagnosed at age≥5 years. When comparing survival among Hispanic and NHW patients for the most common cancer, acute lymphocytic leukemia (ALL), the difference was most significant in the 15-19 years age range, with 47.7% Hispanic patients surviving at 5 years compared to 78.4% of NHW counterparts. The multivariable-adjusted analysis showed that males had statistically significant 13% increased mortality risk than females [hazard ratio (HR): 1.13, 95% confidence interval (CI):1.01-1.26] for all cancer types. Comparing to patients diagnosed at ages 1-4 years, patients diagnosed at age < 1 year (HR: 1.69, 95% CI: 1.36-2.09), at 10-14 year (HR: 1.42, 95% CI: 1.20-1.68), or at 15-19 years (HR: 1.40, 95% CI: 1.20-1.64) had significant increased mortality risk. Comparing to NHW patients, Hispanic patients showed 38% significantly increased mortality risk for all cancer types, 66% for ALL, and 52% for brain cancer. South Texas Hispanic patients had lower 5-year relative survival than NHW patients especially for ALL. Male gender, diagnosis at age<1 year or 10-19 years were also associated with decreased childhood cancer survival. Despite advances in treatment, Hispanic patients lag significantly behind NHW patients. Further cohort studies in South Texas are warranted to identify additional factors affecting survival and to develop interventional strategies.

Disparities in Cancer Genetic Testing and Variants of Uncertain Significance in the Hispanic Population of South Texas.

PURPOSE: Racial and ethnic disparities have included a lack of access to both genetic testing and research, resulting in poor understanding of the genomic architecture in under-represented populations. The South Texas population is primarily of Hispanic background and has been largely devoid of genetic services. We extended access to this underserved population and uncovered genetic variants previously not observed, emphasizing the need to continually improve both genomic databases and clarification of variant significance to provide meaningful patient counseling. METHODS: This study consisted of a retrospective cohort review of patients seen through a cancer genetics education and service program across 24 counties in South Texas. In total, 1,595 individuals were identified as appropriate for cancer genetic counseling and 1,377 completed genetic testing. RESULTS: Eighty percent of those receiving genetic counseling self-identified as Hispanic, 16% as non-Hispanic White (NHW), 3% as African American, and 1% as other race/ethnicity. Of reported variants, 18.8% were pathogenic and 13.7% were reported as a variant of uncertain significance (VUS). VUS was reported in 17.2% of the Hispanic individuals compared with 9% NHW (P = .005). CONCLUSION: Individuals of Hispanic ethnicity were significantly more likely to harbor a VUS compared with NHW. The extended reach into our regional communities revealed a gap in the ability to accurately interpret genomic variation with implications for advising patients on screening, prevention, and management strategies. A higher percentage of VUS also emphasizes the challenge of continued follow-up amid existing barriers that led to disparities in access. As understanding of the variants develops, hopefully gaps in knowledge of the genomic landscape will be lessened with increased clarity to provide accurate cancer risk assessment and recommendations for implementing prevention initiatives.

Prevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups.

BACKGROUND: Germline studies in testicular cancer have focused on unselected populations but so far have not led to recommendations for testicular cancer screening. OBJECTIVE: Herein, we hypothesized that men with testicular cancer and an additional risk factor for hereditary cancer predisposition carry a higher rate of pathogenic variants than men with testicular cancer without another risk factor. METHODS AND RESULTS: 187 patients with a personal history of testicular cancer underwent germline testing via Invitae. Patients were divided into low-risk and high-risk patients. Low-risk patients (n=83) had testicular cancer as their only primary malignancy without a family history of testicular cancer. High-risk patients (n=104) had additional primary malignancies and/or a family history of testicular cancer. 23.1% of patients harbored pathogenic germline variants with 19.6% carrying actionable variants. Among low-risk patients, 13.5% carried pathogenic variants versus 29.9% in the high-risk cohort. Of patients with a family history of non-testicular cancers and a personal history of additional primary malignancies, 32% harbored pathogenic variants. CONCLUSION: High-risk patients are twice as likely to harbor pathogenic variants compared to low-risk patients. Importantly, patients with a family history of cancer and other primary malignancies represent a subset of patients that may benefit from genetic evaluation.

Bloom syndrome in a Mexican American family with rhabdomyosarcoma: evidence of a Mexican founder mutation.

Bloom syndrome is a rare autosomal recessive disorder with less than 300 cases reported in the literature. Bloom syndrome is characterized by chromosome instability, physical stigmata, growth deficiency, immunodeficiency, and a predisposition to cancer, most commonly leukemias, although solid tumors are reported as well. Bloom syndrome occurs in multiple ethnic groups with a higher incidence in persons of Ashkenazi Jewish origin. Few patients of Hispanic ethnicity have been reported. We report here a Mexican American family with a BLM pathogenic variant, c.2506_2507delAG, previously reported in a single patient from Mexico. In this family of four siblings, three have phenotypic features of Bloom syndrome, and BLM gene mutation was homozygous in these affected individuals. Our proband developed a rhabdomyosarcoma. Analysis of surrounding markers in the germline DNA revealed a common haplotype, suggesting a previously unrecognized founder mutation in the Hispanic population of Mexican origin.

Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia.

PURPOSE: Treatment-related pancreatitis (TRP) is a serious complication occurring in children with acute lymphoblastic leukemia (ALL). Those affected are at high risk for severe organ toxicity and treatment delays that can impact outcomes. TRP is associated with asparaginase, a standard therapeutic agent in childhood ALL. Native American ancestry, older age, high-risk leukemia, and increased use of asparaginase are linked to pancreatitis risk. However, dedicated genetic studies evaluating pancreatitis in childhood ALL include few Hispanics. Thus, the genetic basis for higher risk of pancreatitis among Hispanic children with ALL remains unknown. METHODS: Cases of children with ALL treated in from 1994 through 2013 were reviewed and identified 14, all Hispanic, who developed pancreatitis related to asparaginase therapy. Forty-six controls consisting of Hispanic children treated on the same regimens without pancreatitis were selected for comparison. Total DNA isolated from whole blood was used for targeted DNA sequencing of 23 selected genes, including genes associated with pancreatitis without ALL and genes involved in asparagine metabolism. RESULTS: Non-synonymous polymorphisms and frameshift deletions were detected in 15 genes. Most children with TRP had variants in ABAT, ASNS, and CFTR. Notably, children with TRP harbored many more CFTR variants (71.4%) compared with controls (39.1%). Among these, V470M (rs213950) was most frequent (OR 4.27, p = 0.025). CONCLUSIONS: This is the first study of genetic factors in treatment-related pancreatitis in Hispanic children with ALL. Identifying correlative variants in ethnically vulnerable populations may improve screening to identify which patients with ALL are at greatest risk for pancreatitis.

The Impact of COVID-19 on Cancer Screening: Challenges and Opportunities.

Cancer is a leading cause of death in the United States and across the globe. Cancer screening is an effective preventive measure that can reduce cancer incidence and mortality. While cancer screening is integral to cancer control and prevention, due to the COVID-19 outbreak many screenings have either been canceled or postponed, leaving a vast number of patients without access to recommended health care services. This disruption to cancer screening services may have a significant impact on patients, health care practitioners, and health systems. In this paper, we aim to offer a comprehensive view of the impact of COVID-19 on cancer screening. We present the challenges COVID-19 has exerted on patients, health care practitioners, and health systems as well as potential opportunities that could help address these challenges.

Highly aggressive thoracic desmoid tumors in adolescent siblings with fatal outcomes in an FAP kindred: a need for increased vigilance and intervention in at-risk AYAs.

Desmoid tumors are a manifestation of familial adenomatous polyposis (FAP), associated with mutation of the APC gene. Although considered benign tumors, desmoids can be aggressive and cause considerable morbidity. Known risk factors for desmoid tumor growth include location of mutations within the APC gene, family history of desmoid tumors, previous surgery, female gender, and pregnancy. Desmoids occur at diverse sites, commonly within the abdomen or at sites of previous surgery; thoracic desmoids are relatively uncommon. Reported here is a highly desmoid tumor-prone FAP family with a truncating mutation in the APC gene at codon 1550 (c.4648G>T) in which female siblings developed remarkably similar thoracic desmoids with highly aggressive tumor behavior during the onset of puberty, throughout adolescence, and in one sibling during and following pregnancy. Both siblings had a fatal outcome. This case underscores the potential for aggressive behavior of desmoids during adolescence and the need for close vigilance during the adolescent and young adult (AYA) age range in desmoid-prone FAP kindreds.