Signatures of copy number alterations in human cancer.

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

miR-34a is a tumor suppressor in zebrafish and its expression levels impact metabolism, hematopoiesis and DNA damage.

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation.

Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy.

At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals.

Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk.

A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53-and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.

Childhood cerebellar tumours mirror conserved fetal transcriptional programs.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.

Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs. METHODS: We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18 years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters. RESULTS: Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy. DISCUSSION: This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY.

Performance of the eHealth decision support tool, MIPOGG, for recognising children with Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin syndromes.

BACKGROUND: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation. METHODS: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period. RESULTS: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS. CONCLUSION: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS.

Maternal and childhood medical history and the risk of childhood brain tumours: a case-control study in Ontario, Canada.

BACKGROUND: Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child's early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs. METHODS: The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0-15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child's demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times. RESULTS: Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17-6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35-21.63) and 24-month (OR 6.04, 95% CI 2.06-17.70) lead time before diagnosis. No associations for other medications were found. CONCLUSIONS: This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted.

Hopes, concerns, satisfaction and regret in a precision medicine trial for childhood cancer: a mixed-methods study of parent and patient perspectives.

BACKGROUND: Paediatric precision oncology aims to match therapeutic agents to driver gene targets. We investigated whether parents and patients regret participation in precision medicine trials, particularly when their hopes are unfulfilled. METHODS: Parents and adolescent patients completed questionnaires at trial enrolment (T0) and after receiving results (T1). Parents opted-in to an interview at T1. Bereaved parents completed a questionnaire 6-months post-bereavement (T1B). We analysed quantitative data with R and qualitative data thematically with NVivo, before integrating all data for interpretation. RESULTS: 182 parents and 23 patients completed T0; 108/182 parents and 8/23 patients completed T1; 27/98 bereaved parents completed T1B; and 45/108 parents were interviewed. At enrolment, participants held concurrent hopes that precision medicine would benefit future children and their child. Participants expressed concern regarding wait-times for receipt of results. Most participants found the trial beneficial and not burdensome, including bereaved parents. Participants reported high trial satisfaction (median scores: parents: 93/100; patients: 80/100). Participants expressed few regrets (parent median scores: parents: 10/100; bereaved parents: 15/100; patient regret: 2/8 expressed minimal regret). CONCLUSIONS: Even when trial outcomes did not match their hopes, parents and patients rarely regretted participating in a childhood cancer precision medicine trial. These data are critical for integrating participants' views into future precision medicine delivery.

Genetic predisposition to cancers in children and adolescents.

PURPOSE OF REVIEW: Childhood cancer is rare, but it remains the leading cause of disease-related mortality among children 1-14 years of age. As exposure to environmental factors is lower in children, inherited genetic factors become an important player in the cause of childhood cancer. This review highlights the current knowledge and approach for cancer predisposition syndromes in children. RECENT FINDINGS: Current literature suggests that 10-18% of paediatric cancer patients have an underlying genetic susceptibility to their disease. With better knowledge and technology, more genes and syndromes are being discovered, allowing tailored treatment and surveillance for the probands and their families.Studies have demonstrated that focused surveillance can detect early malignancies and increase overall survival in several cancer predisposition syndromes. Various approaches have been proposed to refine early tumour detection strategies while minimizing the burden on patients and families. Newer therapeutic strategies are being investigated to treat, or even prevent, tumours in children with cancer predisposition. SUMMARY: This review summarizes the current knowledge about different cancer predisposition syndromes, focusing on the diagnosis, genetic counselling, surveillance and future directions.

TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report.

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.

Precision oncology for children: A primer for paediatricians.

Cancer is the leading cause of disease-related death in children, adolescents, and young adults beyond the newborn period in North America. Improving survival rates for patients with hard-to-cure cancer remains a challenge. One approach that has gained particular traction is 'precision oncology', whereby next-generation sequencing is used to identify genomic or transcriptomic changes that can help clarify the diagnosis, refine prognosis, define an underlying genetic cause, or identify a unique treatment target for a patient's cancer. In this primer, we provide a brief overview of the evolution of precision paediatric oncology, its current application to clinical oncology practice, and its future potential as a foundational approach to paediatric oncology care in Canada and around the world. We also address the many challenges and limitations inherent to the implementation of precision oncology as the standard of care, including ethical and economic considerations.

Childhood head trauma and the risk of childhood brain tumours: A case-control study in Ontario, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population-based and hospital-based case-control study of children 0 to 15 years with newly diagnosed CBTs from 1997 to 2003 recruited across Ontario through paediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, or head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research.

Diagnostic accuracy of imaging approaches for early tumor detection in children with Li-Fraumeni syndrome.

BACKGROUND: The Toronto protocol for cancer surveillance in children with Li-Fraumeni syndrome has been adopted worldwide. OBJECTIVE: To assess the diagnostic accuracy of the imaging used in this protocol. MATERIALS AND METHODS: We conducted a blinded retrospective review of imaging modalities in 31 pediatric patients. We compared imaging findings with the reference standards, which consisted of (1) histopathological diagnosis, (2) corresponding dedicated imaging or subsequent surveillance imaging or (3) clinical outcomes. We individually analyzed each modality's diagnostic performance for cancer detection and assessed it on a per-study basis for chest and abdominal regional whole-body MRI (n=115 each), brain MRI (n=101) and abdominal/pelvic US (n=292), and on a per-lesion basis for skeleton/soft tissues on whole-body MRI (n=140). RESULTS: Of 763 studies/lesions, approximately 80% had reference standards that identified 4 (0.7%) true-positive, 523 (85.3%) true-negative, 5 (0.8%) false-positive, 3 (0.5%) false-negative and 78 (12.7%) indeterminate results. There were 3 true-positives on whole-body MRI and 1 true-positive on brain MRI as well as 3 false-negatives on whole-body MRI. Sensitivities and specificities of tumor diagnosis using a worst-case scenario analysis were, respectively, 40.0% (95% confidence interval [CI]: 7.3%, 83.0%) and 38.2% (95% CI: 29.2%, 48.0%) for skeleton/soft tissues on whole-body MRI; sensitivity non-available and 97.8% (95% CI: 91.4%, 99.6%) for chest regional whole-body MRI; 100.0% (95% CI: 5.5%, 100.0%) and 96.8% (95% CI: 90.2%, 99.2%) for abdominal regional whole-body MRI; sensitivity non-available and 98.3% (95% CI: 95.3, 99.4) for abdominal/pelvic US; and 50.0% (95% CI: 2.7%, 97.3%) and 93.8% (95% CI: 85.6%, 97.7%) for brain MRI. CONCLUSION: Considerations for optimizing imaging protocol, defining criteria for abnormalities, developing a structured reporting system, and practicing consensus double-reading may enhance the diagnostic accuracy for tumor surveillance.

Paediatric atypical choroid plexus papilloma: is adjuvant therapy necessary?

INTRODUCTION: Choroid Plexus Tumours (CPTs) account for 1-4% of all brain tumours in children. Atypical choroid plexus papillomas (aCPPs) are a subset of these tumours, defined over a decade ago, yet no consensus exists on the optimal approach to their management. METHODS: We conducted a retrospective analysis of all patients treated for CPTs at the Hospital for Sick Children between January 1, 2000, and December 31, 2018, and focused on patients with aCPP. Data extracted from the patient records for analysis included: demographic and clinical features, radiological imaging, surgical and adjuvant therapies, key pathological features, immunohistochemical staining for TP53 and tumour karyotype. Six of seven aCPP samples were profiled using Illumina HumanMethylationEPIC arrays and the top 10,000 most variably methylated probes were visualized using tSNE. Copy number inferencing was also performed. RESULTS: Twenty-nine patients were diagnosed with CPT, seven of whom had a diagnosis of aCPP as confirmed by histological review. Methylation profiling demonstrated that aCPPs clustered with both choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). Complete resection of the tumour was pursued in all cases of aCPP and no patient received adjuvant therapy. All aCPP patients were alive at last follow up. CONCLUSIONS: This limited case series suggests that paediatric aCPP can be successfully managed with surgical resection alone, followed by a 'watch and wait' approach thus avoiding adjuvant therapies. A deeper understanding of the biology of aCPP is required to identify objective markers which can help provide robust risk stratification and inform treatment strategies.

Tumor surveillance for children and adolescents with cancer predisposition syndromes: The psychosocial impact reported by adolescents and caregivers.

PURPOSE: Individuals with cancer predisposition syndromes (CPS) are often followed in cancer screening programs, which aim to detect early stage tumors. While cancer surveillance has the potential to improve patient outcomes, its psychosocial impact is uncharacterized in the pediatric population. We examined the cancer surveillance experience from the perspectives of adolescents and parents of children at risk of developing cancer. PATIENTS AND METHODS: Using grounded theory and thematic analysis qualitative methodology, we conducted semi-structured interviews with parents and adolescents, separately. Interviews were transcribed verbatim and coded separately to derive overlapping and unique themes. RESULTS: We completed 20 semi-structured interviews (11 parents and nine adolescents). Positive experiences were related to feelings of reassurance and taking a proactive approach. Both adolescents and parents experienced worry, related to practical aspects of screening, and related to the reminder of cancer risk that manifests with surveillance appointments. This worry was cyclical, associated with appointments, and generally waned over time. Participants felt that the benefits of surveillance outweighed perceived challenges. Open communication with health care providers, and equipping parents/adolescents with vocabulary to discuss their diagnosis and care with others, were felt to be important for mitigating worries associated with cancer risk and surveillance. CONCLUSION: Parents and adolescents experience worry associated with surveillance for CPS, which may warrant regular psychosocial support, particularly during the first year following CPS diagnosis. Enhancing communication with the health care team and among and beyond immediate family members represents an additional important strategy to mitigate adverse experiences and perceptions.

Non-rhabdomyosarcoma soft tissue sarcomas diagnosed in patients at a young age. An overview of clinical, pathological, and molecular findings.

OBJECTIVE: Disease spectrum in pediatric sarcoma differs substantially from adults. We report a cohort of very young children with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) detailing their molecular features, treatment, and outcome. METHODS: We report features of consecutive children (age <2 years) with NRSTS (2000-2017). Archival pathological material was re-reviewed, with additional molecular techniques applied where indicated. RESULTS: Twenty-nine patients (16 females, 55%) were identified (median age 6 months; range 0-23). Most common diagnoses included infantile fibrosarcoma (IFS, n = 14, 48%), malignant rhabdoid tumor (MRT, n = 4, 14%), and undifferentiated sarcoma (n = 4, 14%). Twenty-seven of 29 (93%) had tumor molecular characterization to confirm diagnosis. Clinical presentation included a swelling/mass (n = 23, 79%). Disease extent was localized (n = 20, 69%), locoregional (n = 6, 21%), or metastatic (n = 3, 10%). Seventeen of 29 (59%) who underwent surgery achieved complete resection (R0). Other treatments included conventional chemotherapy (n = 26, 90%), molecularly targeted therapies (n = 3, 10%), and radiation (n = 5, 17%). At last follow-up (median 3 years; range 0.3-16.4), 23 (79%) were alive, disease-free and six (21%) had died of disease. All patients with IFS were alive and all those with MRT died. A cancer predisposition syndrome (CPS) was confirmed in three of 10 (30%) genetically tested patients. CONCLUSION: We recommend tumor molecular characterization in all young patients including evaluation for CPS to optimize treatment options and prognostication.

Clinical Outcomes of Children With Adrenocortical Carcinoma in the Context of Germline TP53 Status.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy of the adrenal cortex. This study characterizes a single-institution cohort of children treated for ACC, and explores the relationship between clinical outcomes of ACC and germline TP53 mutation status. We performed a retrospective chart review of 23 consecutive pediatric patients with ACC treated at The Hospital for Sick Children, Toronto, Canada, between 1977 and 2017. Clinical, biochemical, radiologic, pathologic, and genetic data were collected for each patient. ACC diagnosis followed a bimodal age distribution of 0 to 6 (n=17) and 12+ (n=6) years, with a female:male ratio of 3.6:1. Ten of 20 patients tested for germline TP53 status carried a pathogenic (9) or likely pathogenic (1) variant, including all but 1 male patient. Only 3 patients died of ACC-related causes, each 5 months post-diagnosis. When treated with resection and combination chemotherapy, carriers of germline TP53 mutations may respond more favorably than their wild-type counterparts. In addition, the survival of patients reported in our cohort with high-stage ACC was appreciably greater than previously described (100.0% for stage II, 50.0% for stage III, and 42.9% for stage IV), favoring aggressive intervention in these patient populations.

An eHealth decision-support tool to prioritize referral practices for genetic evaluation of patients with Wilms tumor.

Over 10% of children with Wilms tumor (WT) have an underlying cancer predisposition syndrome (CPS). Cognizant of increasing demand for genetic evaluation and limited resources across health care settings, there is an urgent need to rationalize genetic referrals for this population. The McGill Interactive Pediatric OncoGenetic Guidelines study, a Canadian multi-institutional initiative, aims to develop an eHealth tool to assist physicians in identifying children at elevated risk of having a CPS. As part of this project, a decisional algorithm specific to WT consisting of five tumor-specific criteria (age <2 years, bilaterality/multifocality, stromal-predominant histology, nephrogenic rests, and overgrowth features) and universal criteria including features of family history suspicious for CPS and congenital anomalies, was developed. Application of the algorithm generates a binary recommendation-for or against genetic referral for CPS evaluation. To evaluate the algorithm's sensitivity for CPS identification, we retrospectively applied the tool in consecutive pediatric patients (n = 180) with WT, diagnosed and/or treated at The Hospital for Sick Children (1997-2016). Odds ratios were calculated to evaluate the strengths of associations between each criterion and specific CPS subtypes. Application of the algorithm identified 100% of children with WT and a confirmed CPS (n = 27). Age <2 years, bilaterality/multifocality, and congenital anomalies were strongly associated with pathogenic variants in WT1. Presence of >1 overgrowth feature was strongly associated with Beckwith-Wiedemann syndrome. Stromal-predominant histology did not contribute to CPS identification. We recommend the incorporation of the WT algorithm in the routine assessment of children with WT to facilitate prioritization of genetic referrals in a sustainable manner.