Clinical updates and surveillance recommendations for DNA replication-repair deficiency syndromes in children and young adults.

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2 or MLH1 genes, and/ or in the polymerase-proofreading genes, POLE and POLD1. RRD predisposition syndromes [constitutional MMR deficiency (CMMRD), Lynch, polymerase-proofreading associated polyposis (PPAP)] share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with CMMRD, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations, helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/ genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and PPAP syndromes harbouring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations regarding genetic counselling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance, develop prevention strategies, and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.

Early death from childhood cancer: First medical record-level analysis reveals insights on diagnostic timing and cause of death.

BACKGROUND: Approximately 7.5% of pediatric cancer deaths occur in the first 30 days post diagnosis, termed early death (ED). Previous database-level analyses identified increased ED in Black/Hispanic patients, infants, late adolescents, those in poverty, and with specific diagnoses. Socioeconomic and clinical risk factors have never been assessed at the medical record level and are poorly understood. METHODS: We completed a retrospective case-control study of oncology patients diagnosed from 1995 to 2016 at Children's Hospital Colorado. The ED group (n = 45) was compared to a non-early death (NED) group surviving >31 days, randomly selected from the same cohort (n = 44). Medical records and death certificates were manually reviewed for sociodemographic and clinical information to identify risk factors for ED. RESULTS: We identified increased ED risk in central nervous system (CNS) tumors and, specifically, high-grade glioma and atypical teratoid/rhabdoid tumor. There was prolonged time from symptom onset to seeking care in the ED group (29.4 vs. 9.8 days) with similar time courses to diagnosis thereafter. Cause of death was most commonly from tumor progression in brain/CNS tumors and infection in hematologic malignancies. CONCLUSIONS: In this first medical record-level analysis of ED, we identified socioeconomic and clinical risk factors. ED was associated with longer time from first symptoms to presentation, suggesting that delayed presentation may be an addressable risk factor. Many individual patient-level risk factors, including socioeconomic measures and barriers to care, were unable to be assessed through record review, highlighting the need for a prospective study to understand and address childhood cancer ED.

Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.

PURPOSE: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10-12), immunohistochemistry (86%, P = 4.6 × 10-3), or tumor mutational burden (80%, P = 9.1 × 10-4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD (P = 2.2 × 10-5). CONCLUSION: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Incorporating genetic counseling into the evaluation of pediatric bone marrow failure.

The timely identification of germline genetic causes of pediatric bone marrow failure (BMF) impacts medical screening practices, family counseling, therapeutic decision-making, and risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). At diagnosis, treatment decisions need to be made quickly to mitigate risks associated with profound cytopenias. As genetic testing options are rapidly evolving, an efficient multi-disciplinary approach and algorithm, including early involvement of a genetics team, is needed to expedite diagnosis and therapeutic decision-making. This process aids in the identification of appropriate candidates for molecular genetic testing. We present our single center experience reviewing the implementation of genetic counseling and a diagnostic and therapeutic algorithm used to guide genetic evaluation of pediatric BMF. Disease-specific next-generation sequencing (NGS) panels were most often pursued in patients who presented with a clinical phenotype consistent with a known inherited BMF syndrome and when trying to reduce incidental or uninformative results. Broader BMF NGS panels were most often utilized when unable to narrow the suspected etiology to a single disorder. Whole exome sequencing helped with optimizing treatment decision-making in higher risk children with BMF who required expedited hematopoietic stem cell transplantation. The experience has led to improvements to our process for evaluating patients with BMF.

Pediatric Head and Neck Tumors Associated with Li-Fraumeni Syndrome.

INTRODUCTION: Cancer predisposition syndromes are germline pathogenic variants in genes that greatly raise the risk of developing neoplastic diseases. One of the most well-known is Li-Fraumeni syndrome (LFS), which is due to pathogenic variants in the TP53 gene. Children with LFS have higher risks for multiple malignancies before adulthood, often with rare and aggressive subtypes. OBJECTIVE: To examine head and neck manifestations of LFS in children treated at a tertiary children's hospital over a 20-year period. METHODS: A retrospective review of LFS children with neoplastic disease presenting in traditional Otolaryngologic head and neck subsites from 2000 to 2019, with patient charts reviewed for relevant clinical, imaging, and operative data. RESULTS: Of the 40 LFS patients initially identified, 27 neoplastic tumors were identified in 20 children within this cohort (20 primary, 7 second primary). Head and neck subsites aside from the brain or orbit were involved in 22% (6/27) of these tumors, representing 20% (4/20) of primary tumors and 29% (2/7) of second primary tumors. Both second primaries within the head and neck were within the radiation fields of the first primary tumor. The mean ages at primary and second primary diagnosis were 4.6 years (SD 3.5) and 12 years (SD 1.4), respectively. The male/female ratio was 1:6 among all patients with head and neck tumors. All 6 head and neck tumors were sarcomas. Rhabdomyosarcoma (N = 3, 50%) was the most common pathology, and the other 3 demonstrated rare tumor pathological subtypes (synovial cell sarcoma, pleomorphic myxoid liposarcoma, mandibular osteosarcoma). The neck was the most common subsite (75%) within this group for primary tumor presentation. CONCLUSION: This study identifies a high potential for head and neck involvement in children with LFS, which has not been previously described in the literature. Otolaryngological care should be included in a multidisciplinary care team surveilling these patients.

A novel, germline, deactivating CBL variant p.L493F alters domain orientation and is associated with multiple childhood cancers.

CBL is a mammalian gene encoding the protein CBL, which is an E3 ubiquitin-protein ligase involved in cell signaling and protein ubiquitination. Pathogenic variants in this gene have been implicated in a number of human cancers, particularly acute myeloid leukemia (AML). Here, we present a 5-year-old male patient with a history of AML, diffuse midline glioma, and left brain lesion with histiocytic features. A variant of uncertain significance (VUS): p.L493F was detected in his CBL gene via clinical evaluation. Protein modeling predicts this variant to be pathogenic. Details of the clinical evaluation and modeling assay are discussed.

A Cystic Renal Mass in the Setting of a Pneumothorax: More Than Meets the Eye?

DICER1 syndrome is a rare hereditary cancer predisposition syndrome that has relevance to pediatric urology providers due to its association with many various pediatric genitourinary malignancies. We describe the case of a pediatric patient who was eventually diagnosed with a pathogenic DICER1 germline variant after undergoing resection of a cystic nephroma and pleuropulmonary blastoma.

Germline predisposition to genitourinary rhabdomyosarcoma.

Multiple genetic conditions predispose to the development of rhabdomyosarcoma. Much of the literature on rhabdomyosarcoma in genetic syndromes does not sub-divide the location or the pathology of the sarcomas. Therefore, there are limited data on genitourinary specific associations with certain genetic syndromes. We summarize, here, the primary differential considerations for rhabdomyosarcoma of the genitourinary system. Primary considerations include DICER1 pathogenic variation, Li-Fraumeni syndrome, constitutional mismatch repair deficiency, mosaic variegated aneuploidy, neurofibromatosis type 1, Noonan syndrome, other RASopathies, Costello syndrome, and Beckwith-Wiedemann syndrome. Some conditions may present with specific pathological, clinical and/or family history features, but for others, the genitourinary tumor may be the only presenting sign at the time of diagnosis. Genetic evaluation with counseling and/or testing may help identify an underlying tumor predisposition. This manuscript serves as an introduction to germline considerations for children with genitourinary rhabdomyosarcoma.

DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies.

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma, and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing and surveillance and treatment recommendations. Attendees from North America, Europe, and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology, and clinical research. Recommendations are provided for genetic testing; prenatal management; and surveillance for DICER1-associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, and central nervous system tumors and gastrointestinal polyps. Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated. Clin Cancer Res; 24(10); 2251-61. ©2018 AACR.

Retinoblastoma and Neuroblastoma Predisposition and Surveillance.

Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. Clin Cancer Res; 23(13); e98-e106. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood.

Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1.

Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46-e53. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.