Retinoblastoma: present scenario and future challenges

Paired tumor-germline sequencing can identify somatic variants for targeted therapy and germline pathogenic variants (GPVs) causative of hereditary cancer/tumor predisposition syndromes. It is unknown how patients/families in pediatric oncology use information about an identified GPV. We assessed recall of germline results and actions taken on the basis of findings. We completed phone surveys with patients (and/or their parent) with GPVs identified via a single academic medical center's paired tumor-germline sequencing study. Seven hundred forty pediatric (aged 0-25 years) oncology patients were enrolled in this sequencing study between May 2012 and August 2021. Ninety-six participants (13.0%) had at least one GPV identified and were therefore eligible for this survey. The parent/guardian (for patients younger than 18 years or deceased patients) or patients themselves (if 18 years or older) were contacted. Survey topics included germline result recall, experience with genetic counseling, changes to patient's cancer treatment/screening, sharing of results with family members, and lifestyle changes. Fifty-three surveys (response rate, 55.2%) were completed between October 2021 and June 2022. Thirty-seven (69.8%) respondents correctly recalled the identified GPV. Discussing results with a genetic counselor (P = .0001), having a GPV related to the cancer/tumor diagnosis (P = .002), and non-Hispanic White race/ethnicity (P = .02) were associated with accurate recall. Twenty-five respondents (47.2%) reported a change in the child's cancer treatment and/or screening recommendations, 17 respondents (32.1%) made a lifestyle change on the basis of the results, and 44 respondents (83.0%) shared results with at least one family member. While most respondents remembered that a GPV was identified in the patient, some did not recall having a GPV found, and others recalled germline findings incorrectly. Future work may determine patient/family preferences for timing/method of result return to optimize patient recall and use of germline results.

Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA?

Absence of Mutation in the p53 and the Retinoblastoma Susceptibility Genes in Primary Cervical Carcinomas

Multigene panels are commercially available for the evaluation of prostate cancer (PCA) predisposition, which necessitates tailored genetic counseling (GC) for men. Here we describe emerging results of Genetic Evaluation of Men, prospective multigene testing study in PCA to inform personalized genetic counseling, with emerging implications for referrals, cancer screening, and precision therapy. Eligibility criteria for men affected by or at high risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Detailed demographic, clinical, and FH data were obtained from participants and medical records. Multigene testing was conducted after GC. Mutation rates were summarized by eligibility criteria and compared across FH data. The 95% CI of mutation prevalence was constructed by using Poisson distribution. Of 200 men enrolled, 62.5% had PCA. Eleven (5.5%; 95% CI, 3.0% to 9.9%) had mutations; 63.6% of mutations were in DNA repair genes. FH of breast cancer was significantly associated with mutation status (P = .004), and FH that met criteria for hereditary breast and ovarian cancer syndrome was significantly associated with PCA (odds ratio, 2.33; 95% CI, 1.05 to 5.18). Variants of uncertain significance were reported in 70 men (35.0%). Among mutation carriers, 45.5% had personal/FH concordant with the gene. A tailored GC model was developed based on emerging findings. Multigene testing for PCA identifies mutations mostly in DNA repair genes, with implications for precision therapy. The study highlights the importance of comprehensive genetic evaluation for PCA beyond metastatic disease, including early-stage disease with strong FH. Detailed FH is important for referrals of men for genetic evaluation. The results inform precision GC and cancer screening for men and their male and female blood relatives.

Purpose: While cancer risk is increased among children with chromosomal birth defects, less is known about associations between specific non-chromosomal structural birth defects and specific childhood cancers. To investigate these, we established a population-based retrospective cohort of >10 million children by pooling statewide registry data from four U.S. states (Texas, Michigan, North Carolina, and Arkansas) for the period 1992-2013. Methods: Individual level data from birth certificates, birth defects registries, and cancer registries were linked in each state; demographic and diagnostic variables were harmonized; and the data were pooled for the overall analysis. We used Cox proportional hazards models to evaluate associations between 60 birth defects and 31 childhood cancers when there were five or more comorbid cases. A hazard ratio (HR) and 95% confidence interval (CI) was calculated for each birth defect-childhood cancer (BD-CC) pairwise combination, adjusted for maternal age, infant sex, and state. The false discovery rate (FDR) was computed via the Benjamini-Hochberg procedure to account for multiple comparisons. Results: We identified 517,548 children with non-chromosomal structural birth defects and 14,774 children with cancer. The risk of any cancer was increased among children with any non-chromosomal structural defect compared to children without any birth defect (HR=2.6, 95% CI 2.4-2.7). Of 2,511 potential BD-CC combinations, we tested 606 where there were ≥5 comorbid cases and identified 496 BD-CC associations with significantly elevated HRs at a 5% FDR. No significant inverse associations were identified for any BD-CC combination. Notably, hepatoblastoma, astrocytoma, ependymoma, and extracranial germ cell tumors were each strongly associated with several birth defects. For example, the risk of hepatoblastoma was increased among children with atrial septal defects (HR=12.5, 95% CI 7.9-19.7) and craniosynostosis (HR=15.4, 95% CI 7.6-31.3). Astrocytoma and ependymoma were associated with central nervous system (CNS) defects (HR=6.7, 95% CI 4.6-9.8 and HR=7.4, 95%CI 3.5-15.7, respectively). Elevated risk of extracranial germ cell tumors was observed among children with CNS defects (HR=22.5, 95% CI 10.9-46.4) and obstructive genitourinary defects (HR=32.4, 95% CI 16.2-64.6). Conclusions: By pooling registry data across four U.S. states, we were able to evaluate specific BD-CC patterns and report several novel associations. Our findings suggest that children with non-chromosomal birth defects have a significantly elevated risk of several childhood cancers. These findings may inform research into the etiologies of childhood cancer, as well as new cancer surveillance protocols for children with non-chromosomal birth defects. This work was supported by the Cancer Prevention Research Institute of Texas. Citation Format: Jeremy M. Schraw, Tania A. Desrosiers, Wendy N. Nembhard, Glenn Copeland, Robert E. Meyer, Austin L. Brown, Tiffany M. Chambers, Heather E. Danysh, Saumya Sisoudiya, Chunqiao Luo, Amir Mian, Michael E. Scheurer, Sharon E. Plon, Philip J. Lupo. A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-161.

The scope and emphasis of a public health program are necessarily influenced by the changing characteristics of the population it serves. The rate of population growth affects long-range planning of community health and medical facilities. Alterations in age composition, internal migration of racial or industrial groups, changes in population density and urban-rural movement require current adaptation of the health program to solve the new problems thus created. Among the various characteristics of recent population trends, aging of the population is one of the most fundamental in its bearing on national health. The social and economic effects of an aging population have long been recognized. Dr. Louis I. Dublin appraised the problem of old age in some detail in 1926, when the provision of economic security for the aged was the dominant theme of contemporary discussion.1 The passage of the Social Security Act in 1935 represented the fruits of the efforts of this early period. Adjustment of national policy with respect to the health problems associated with aging of the population has been slower in development. Under the terms of the Social Security Act, a limited expansion of activities designed to promote the health of older adults—control of cancer and pneumonia, and industrial hygiene services—has been made possible in the cooperating States. However, the Act makes no provision for the solution of such fundamental problems as invalidity insurance and medical care of the aged. During the past five years, the health aspects of old age have received increasing attention in the discussions of public health administrators. It therefore seems appropriate to resurvey this general problem, and to consider, in particular, the nature of future trends in mortality, morbidity, and the receipt of medical care which may be expected solely as a result of changing age structure of the population.

Who should be treating adolescents and young adults with acute lymphoblastic leukaemia?

Introduction:The recent advancement and implementation of high throughput genomic profiling technologies in the clinical setting has advanced identification of underlying germline cancer predisposition variants in the pediatric population.Several studies now indicate that approximately 10-15% of pediatric cancers arise due to an underlying pediatric cancer predisposition syndrome (CPS).Methods: Clinical genomic tumor profiling for 927 pediatric patients was performed between August 2019-September 2024 using the Oncomine Childhood Cancer Research Assay, which targets 86 genes for hotspot DNA analysis, 44 genes for full-coding DNA analysis, 28 genes for amplifications, and RNA analysis for 91 genes involved in known fusions.The age range at time of tumor profiling was <1 month to 32 years (mean= 10 years).Indications for testing included hematologic malignancies (37%), central nervous system tumors (37%), solid tumors (25%), and germ cell tumors (<1%).Retrospective analysis was performed to identify Tier I and Tier II variants reported at a variant allele frequency concerning for being germline, prompting recommendation for genetic counseling and germline testing.Laboratory records and patient electronic medical records were reviewed to determine if follow up testing was pursued.Results: Of the 927 pediatric patients who underwent tumor profiling, 3.9% (n=36) had a clinical diagnosis or prior germline testing consistent with a known CPS.The clinical diagnoses included neurofibromatosis type 1 (NF1), 50% (n=18); transient abnormal myelopoiesis or myeloid leukemia associated with trisomy 21, 19.4% (n=7); neurofibromatosis type 2 (NF2), 8.3% (n=3); Li-Fraumeni syndrome (TP53), 8.3% (n=3); essential thrombocythemia (JAK2), 2.8% (n=1); retinoblastoma (RB1), 2.8% (n=1); rhabdoid tumor predisposition syndrome (SMARCB1), 2.8% (n=1); and tuberous sclerosis type 1 and 2 (TSC1, TSC2), 2.8% (n=1 for each gene).An additional 9.2% (86/933) of patients had molecular findings prompting recommendation for genetic counseling and germline testing.Of these patients, 45.3% (n=39) had no documentation of follow up testing.For the remaining 47 patients, 76.6% (n=36) had follow up testing which did not identify a germline pathogenic variant, while 23.4% (n=11) of patients had follow up testing which identified a germline pathogenic variant consistent with a CPS.Three patients presenting with cystic nephroma (n=1) and Sertoli-Leydig cell tumor (n=2) were identified to have DICER1 pathogenic variants; 2 patients with anaplastic medulloblastoma (n=1) and choroid plexus carcinoma (n=1) had germline TP53 variants; 2 unrelated patients with large B-cell lymphoma had germline SH2D1A variants; 1 patient with dysembryoplastic neuroepithelial tumor had a germline PTPN11 variant; 1 patient with schwannoma had a germline LZTR1 variant; 1 patient with metastatic hepatoblastoma had a germline ASXL1 variant; 1 patient with glioblastoma had a tumor profile suggestive of constitutional mismatch repair deficiency (CMMRD), which was confirmed by identification of a germline homozygous MLH1 variant.Conclusion: This study demonstrates the utility of genomic tumor profiling to uncover cancer predisposition syndromes in a pediatric cancer cohort.Overall, 3.9% of patients (n=36) who underwent tumor profiling had a potential germline finding consistent with the patient's clinical diagnosis or a priori germline testing.An additional 9.2% of patients had molecular findings concerning for a potential underlying CPS, in which 11 had a subsequent confirmed germline finding.The cumulative diagnostic yield for identifying a CPS was 5.1% (n=47/927).The diagnostic yield may be lower than reported frequencies in pediatric cancer cohorts due to the targeted nature of the panel employed, and thus, incomplete coverage of all known CPS genes.In addition, 39 patients had a molecular finding suspicious for a germline cancer predisposition, but no documentation of follow up testing being performed.This highlights the importance of genetic counseling following somatic testing to facilitate germline testing when appropriate, allowing for informed decision making, appropriate surveillance, and at-risk familial testing when desired.

DNA Repair in Prostate Cancer: Biology and Clinical Implications

PURPOSENeurotrophic tyrosine receptor kinase (NTRK) fusions have been described asoncogenic drivers in a variety of tumors. However, little is known about theoverall frequency of NTRK fusion in unselected pediatric tumors. Here, weassessed the frequency, fusion partners, and clinical course in pediatricpatients with NTRK fusion–positive tumors.PATIENTS AND METHODSWe studied 1,347 consecutive pediatric tumors from 1,217 patients whounderwent tumor genomic profiling using custom-designed DNA and RNAnext-generation sequencing panels. NTRK fusions identified were orthogonallyconfirmed.RESULTS AND DISCUSSIONNTRK fusions were identified in 29 tumors from 27 patients with a positiveyield of 2.22% for all patients and 3.08% for solid tumors. AlthoughNTRK2 fusions were found exclusively in CNS tumors andNTRK1 fusions were highly enriched in papillary thyroidcarcinomas, NTRK3 fusions were identified in all tumorcategories. The most canonical fusion was ETV6-NTRK3observed in 10 patients with diverse types of tumors. Several novel NTRKfusions were observed in rare tumor types, includingKCTD16-NTRK1 in ganglioglioma andIRF2BP2-NTRK3 in papillary thyroid carcinomas. Thedetection of an NTRK fusion confirmed the morphologic diagnosis includingfive cases where the final tumor diagnosis was largely based on thediscovery of an NTRK fusion. In one patient, the diagnosis was changedbecause of the identification of an ETV6-NTRK3 fusion. Onepatient with infantile fibrosarcoma was treated with larotrectinib andachieved complete pathologic remission.CONCLUSIONNTRK fusions are more frequently seen in pediatric tumors than in adulttumors and involve a broader panel of fusion partners and a wider range oftumors than previously recognized. These results highlight the importance ofscreening for NTRK fusions as part of the tumor genomic profiling forpatients with pediatric cancer.

Introduction: Oncogenic fusions involving the neurotrophic receptor tyrosine kinase genes, NTRK1, NTRK2, or NTRK3 are detected in both adult and pediatric cancers, including in 1% of a broad range of common cancer types such as lung, colorectal, and breast, 25% of thyroid and gastrointestinal stromal tumors, and &amp;gt;90% of several rare tumor types, such as congenital infantile fibrosarcoma (1). Fusions arise by intra- or extrachromosomal rearrangement, fusing the NTRK kinase domain to a 5’ upstream gene partner, leading to constitutive kinase activation, thereby driving oncogenesis. This seems to occur primarily via activation of PI3K, MAPK and/or PLCg signaling, however our understanding of NTRK fusion biology is limited by a scarcity of disease models (1). Aim: The aim of this project is to generate additional preclinical models to further our understanding of NTRK fusion-driven oncogenesis and response to treatment. Methods and Results: We identified a novel SGK3-NTRK3 fusion in a patient, with breast cancer and brain metastases, treated at our center. We generated cellular models in HEK293 (human embryonic kidney cell line) and MCF7 (breast adenocarcinoma cell line) by transfecting with a plasmid encoding the fusion construct, with and without a CMV promoter, and demonstrated that the fusion induces AKT activation. To employ more physiologically relevant models, we additionally generated the fusion in these cell lines by CRISPR-gene editing, utilizing sgRNAs that induce double stranded breaks in the relevant genomic loci for this specific fusion. A genetically engineered mouse model of the fusion was further developed in a C57BL/6J background by intracranial injection of an adeno-associated viral construct (GFP/Cre) with sgRNAs targeting SGK3, NTRK3, and TP53. Tumors developed in 50% of the mice within four months, suggesting that this novel fusion acts as an oncogenic driver. Fluorescence In Situ Hybridization to further validate and localize the fusion, gene expression analysis to further characterize the fusion’s biological impact, and viability assays to assess its sensitivity to NTRK inhibition are underway. Conclusions: These findings suggest that the SGK3-NTRK3 fusion is a strong oncogenic driver in a glioma setting, and we are currently extending these investigations to a breast cancer setting. Through the integration of these novel models, our research seeks to advance our understanding of NTRK fusion-driven cancer biology and to improve therapeutic strategies for these cancers.

Omenn syndrome is a rare autosomal recessive hereditary severe combined immunodeficiency. The purpose of this study was to understand clinical characteristics and genetic mutation type of Omenn syndrome and to improve the recognition of Omenn syndrome among pediatric clinicians. One suspected case of severe combined immunodeficiency was found to have pneumonia repeatedly, intractable diarrhea, poor antibiotic treatment effect, lymphadenopathy, hepatosplenomegaly and erythroderma. The patient was diagnosed as having Omenn syndrome by RT-PCR, and the expression of RAG1/RAG2 and gene analysis of RAG1/RAG2 were performed. The classification of lymphocyte was CD3(+) cells (35.3%), CD19(+) cells (0.4%), CD16(+) cells (57.6%). After stimulation with phytohemagglutinin (PHA), lymphocyte proliferation of the child was extremely low. Genetic studies showed RAG1 homozygous deletion mutation (2302 del T). He had detectable activated T-lymphocytes with low circulating B-lymphocytes and no evidence of maternal T-cell engrafment as indicated by the short tandem repeat (STR) analysis. Omenn syndrome is a severe combined immunodeficiency disease caused by mutations in the RAG1/RAG2 gene. The disease has been reported rarely in China. The clinical manifestations of the disease is early postnatal repeated infections and erythroderma. Mutation analysis of RAG1/RAG2 gene may help to confirm the diagnosis and may be useful in early immune reconstitution and genetic counseling.

Forty-two adult males--10 with Klinefelter's syndrome (karyotype XXY), 17 with normal sex chromosome karyotype (XY) but with physical signs of hypogonadism, and 15 presumed to be normal both chromosomally and hormonally--completed tests of Verbal and Nonverbal ability. It was predicted: a) that the XXY group would perform more poorly than the other two groups on tests of Verbal ability, and b) that the XY, hypogonadal group would perform more poorly than the others on tests of Non-verbal ability. The first hypothesis was supported. However, in spite of measurable verbal deficits, the XXY men (whose parents were more highly educated than those of the other two groups) did not appear to be underachievers. Rather, they were, in general, as well educated, as likely to be employed, and of socioeconomic status equivalent to that of the other men in the study. These findings are discussed briefly in terms of implications for early childhood education and genetic counselling. The second hypothesis was not supported: this is attributed to presumed heterogeneity of etiology of hypogonadism in the XY, hypogonadal group.

To determine the rate of sudden infant death syndrome (SIDS) in very low birthweight children (VLBW) relative to children with low (LBW) and normal birthweights. Cohort study of consecutive live births in Victoria, 1993-1997 inclusive. All sudden unexpected deaths in early childhood over this five-year period; all deaths from SIDS (defined as a sudden unexpected death without a definite pathological explanation); and the proportion of SIDS in live births in three birthweight subgroups (VLBW, 500-1499 g; LBW, 1500-2499 g; and normal birthweight, > 2499 g). There were 316,028 live births (with known birthweight) in Victoria over the five-year period; 224 (0.71 per 1000 live births) died unexpectedly. In 10 of these deaths there was a definite pathological explanation, giving a rate of SIDS of 0.68 per 1000 live births. The rate of SIDS in VLBW children was 2.52 per 1000 live births, lower than the rate reported before the 1990s. The rate of SIDS in VLBW children was not significantly different from the rate in LBW children of 1.98 per 1000 live births (difference per 1000 live births, 0.53; 95% CI, -1.45 to 2.52), but was significantly higher than the rate in normal birthweight children of 0.59 per 1000 live births (difference per 1000 live births, 1.93; 95% CI, 0.06-3.79). The rate of SIDS in VLBW children has fallen in the 1990s, along with the overall fall in the rate of SIDS, but remains higher than that in normal birthweight children.

Emergency IVF versus ovarian tissue cryopreservation: decision making in fertility preservation for female cancer patients