Publications by authors named "David Malkin"

209 Publications

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

JCO Precis Oncol 2021 11;5. Epub 2021 Jan 11.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts.

Materials And Methods: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort.

Results: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (, ) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with fusion-negative RMS patients versus the patients with fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (, , , mismatch repair genes), rarely (, , , ), or never () reported in RMS. Numerous genes (, , mismatch repair) were on the ACMG Secondary Findings 2.0 list.

Conclusion: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.
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http://dx.doi.org/10.1200/PO.20.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169077PMC
January 2021

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

J Clin Oncol 2021 May 4:JCO2002636. Epub 2021 May 4.

Lebanese American University Medical Center-Rizk, Beirut, Lebanon.

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.

Patients And Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.

Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years.

Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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http://dx.doi.org/10.1200/JCO.20.02636DOI Listing
May 2021

Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children's Oncology Group ARAR0332 Protocol.

J Clin Oncol 2021 Apr 6:JCO2002871. Epub 2021 Apr 6.

Department of Oncology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Adrenocortical carcinoma (ACC) is a rare aggressive pediatric malignancy with distinct biology. Its treatment follows the principles developed for adults; pediatric-specific studies are scarce.

Patients And Methods: Prospective single-arm risk-stratified interventional study. Study objectives were (1) to describe the outcome of patients with stage I ACC treated with adrenalectomy alone; (2) to describe the outcome of stage II patients (completely resected > 200 cc or > 100 g) treated with adrenalectomy and retroperitoneal lymph node dissection; and (3) to describe the outcome of patients with stage III or IV treated with mitotane and chemotherapy.

Results: Between September 2006 and May 2013, 78 patients (77 eligible, 51 females) were enrolled. The 5-year event-free survival estimates for stages I (24 patients), II (15 patients), III (24 patients), and IV (14 patients) were 86.2%, 53.3%, 81%, and 7.1%, respectively. The corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively. On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, germline status, and presence of a somatic mutation were associated with outcome. On multivariable analysis, only stage and age were significantly associated with outcome. The probabilities of mitotane and chemotherapy feasibility events were 10.5% and 31.6%, respectively.

Conclusion: Outcome for children with stage I ACC is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III ACC have an excellent outcome combining surgery and chemotherapy. Patients with stage IV ACC are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one third of patients with advanced disease could not complete the scheduled treatment.
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http://dx.doi.org/10.1200/JCO.20.02871DOI Listing
April 2021

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

Pediatr Blood Cancer 2021 Aug 31;68(8):e29021. Epub 2021 Mar 31.

Department of Pediatrics, Division of Hematology-Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

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.
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http://dx.doi.org/10.1002/pbc.29021DOI Listing
August 2021

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

Pediatr Blood Cancer 2021 Aug 25;68(8):e29022. Epub 2021 Mar 25.

Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/pbc.29022DOI Listing
August 2021

The transcriptional landscape of Shh medulloblastoma.

Nat Commun 2021 03 19;12(1):1749. Epub 2021 Mar 19.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-21883-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819PMC
March 2021

Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition.

Cancer Discov 2021 Jun 9;11(6):1454-1467. Epub 2021 Feb 9.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for mutations ( = 10). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition and . Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1050DOI Listing
June 2021

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Cancer Discov 2021 May 18;11(5):1176-1191. Epub 2020 Dec 18.

Department of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223607PMC
May 2021

Nearly Half of Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children's Oncology Group.

JCO Precis Oncol 2020 2;4. Epub 2020 Oct 2.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Purpose: To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer.

Methods: The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively.

Results: Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP germline variant, of which 6 (46.2%) were confirmed to be de novo.

Conclusion: Apart from , we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP variants in our sample were de novo suggests universal screening for germline P/LP variants among pediatric patients with OS should be considered.
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http://dx.doi.org/10.1200/PO.20.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608506PMC
October 2020

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

J Pediatr Hematol Oncol 2021 Jul;43(5):e635-e641

Pediatrics, University of Toronto.

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.
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http://dx.doi.org/10.1097/MPH.0000000000001982DOI Listing
July 2021

Considerations for the use of circulating tumor DNA sequencing as a screening tool in cancer predisposition syndromes.

Pediatr Blood Cancer 2020 12 13;67(12):e28758. Epub 2020 Oct 13.

Division of Haematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Canada.

Liquid biopsy, specifically circulating tumor DNA (ctDNA) detection, has started to revolutionize the clinical management of patients with cancer by surpassing many limitations of traditional tissue biopsies, particularly for serial testing. ctDNA sequencing has been successfully utilized for cancer detection, prognostication, and assessment of disease response and evolution. While the applications of ctDNA analysis are growing, the majority of studies to date have primarily evaluated its use as a tool for tracking a known cancer, and in most cases at advanced stage. Herein, we discuss the potential application of ctDNA for surveillance and early cancer detection in patients with a cancer predisposition syndrome.
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http://dx.doi.org/10.1002/pbc.28758DOI Listing
December 2020

Cancer surveillance for individuals with Li-Fraumeni syndrome.

Eur J Hum Genet 2020 11 19;28(11):1481-1482. Epub 2020 Aug 19.

Division of Hematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1038/s41431-020-00709-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575605PMC
November 2020

Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome.

Nat Commun 2020 08 7;11(1):3945. Epub 2020 Aug 7.

Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy.

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.
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http://dx.doi.org/10.1038/s41467-020-17596-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414119PMC
August 2020

Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Department of Biomolecular Sciences, Università degli Studi di Urbino, 61032 Fano, Italy.

Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 () mutant-specific residual transcriptional activity scores () and used to stratify patients into two groups: transcriptionally and . The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the . In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had mutations. Ten patients with mutations showed better OS than carriers of other mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17-0.85, = 0.02). In the chemotherapy group, 41/62 (66%) patients had mutations, and the 11 carriers of mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17-5.95, = 0.02). VEGF-A mRNA expression levels were significantly increased in cases. Further studies are warranted to explore the effect of mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.
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http://dx.doi.org/10.3390/cancers12082049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465166PMC
July 2020

Tumour predisposition and cancer syndromes as models to study gene-environment interactions.

Nat Rev Cancer 2020 09 29;20(9):533-549. Epub 2020 May 29.

Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA.

Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular metabolism or other perturbations that cause DNA damage. Moreover, several environmental factors may damage the DNA, alter cellular metabolism or affect the ability of cells to interact with their microenvironment. While some environmental factors are well established as carcinogens, there remains a large knowledge gap of others owing to the difficulty in identifying them because of the typically long interval between carcinogen exposure and cancer diagnosis. DNA damage increases in cells harbouring mutations that impair their ability to correctly repair the DNA. Tumour predisposition syndromes in which cancers arise at an accelerated rate and in different organs - the equivalent of a sensitized background - provide a unique opportunity to examine how gene-environment interactions influence cancer risk when the initiating genetic defect responsible for malignancy is known. Understanding the molecular processes that are altered by specific germline mutations, environmental exposures and related mechanisms that promote cancer will allow the design of novel and effective preventive and therapeutic strategies.
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http://dx.doi.org/10.1038/s41568-020-0265-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104546PMC
September 2020

Li-Fraumeni Exploration Consortium Data Coordinating Center: Building an Interactive Web-Based Resource for Collaborative International Cancer Epidemiology Research for a Rare Condition.

Cancer Epidemiol Biomarkers Prev 2020 05 10;29(5):927-935. Epub 2020 Mar 10.

City of Hope National Medical Center, Duarte, California.

Background: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented.

Methods: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research.

Results: The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in . Data on cancer diagnoses are also available. Challenges and lessons learned are summarized.

Conclusions: The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications.

Impact: These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196512PMC
May 2020

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence.

Br J Cancer 2020 04 9;122(8):1231-1241. Epub 2020 Mar 9.

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

Background: Genome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist.

Methods: We analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits.

Results: A SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression.

Conclusions: These results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.
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http://dx.doi.org/10.1038/s41416-020-0764-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156685PMC
April 2020

"Balancing Expectations with Actual Realities": Conversations with Clinicians and Scientists in the First Year of a High-Risk Childhood Cancer Precision Medicine Trial.

J Pers Med 2020 Feb 14;10(1). Epub 2020 Feb 14.

School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, 2052, Australia.

Precision medicine is changing cancer care and placing new demands on oncology professionals. Precision medicine trials for high-risk childhood cancer exemplify these complexities. We assessed clinicians' ( = 39) and scientists' ( = 15) experiences in the first year of the PRecISion Medicine for Children with Cancer (PRISM) trial for children and adolescents with high-risk cancers, through an in-depth semi-structured interview. We thematically analysed participants' responses regarding their professional challenges, and measured oncologists' knowledge of genetics and confidence with somatic and germline molecular test results. Both groups described positive early experiences with PRISM but were cognisant of managing parents' expectations. Key challenges for clinicians included understanding and communicating genomic results, balancing biopsy risks, and drug access. Most oncologists rated 'good' knowledge of genetics, but a minority were 'very confident' in interpreting (25%), explaining (34.4%) and making treatment recommendations (18.8%) based on somatic genetic test results. Challenges for scientists included greater emotional impact of their work and balancing translational outputs with academic productivity. Continued tracking of these challenges across the course of the trial, while assessing the perspectives of a wider range of stakeholders, is critical to drive the ongoing development of a workforce equipped to manage the demands of paediatric precision medicine.
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http://dx.doi.org/10.3390/jpm10010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151613PMC
February 2020

Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

Cancer Med 2020 01 21;9(2):447-459. Epub 2019 Nov 21.

Department of Psychology, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.

Methods: Seventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.

Results: The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup.

Conclusions: By examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes.
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http://dx.doi.org/10.1002/cam4.2701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970040PMC
January 2020

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

Nature 2019 10 9;574(7780):707-711. Epub 2019 Oct 9.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
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http://dx.doi.org/10.1038/s41586-019-1650-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141958PMC
October 2019

Correction to: DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.

Clin Epigenetics 2019 Oct 21;11(1):144. Epub 2019 Oct 21.

Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.

After publication of the original article [1], authors have requested to add a 'J' as middle name for Richard Gilbertson. Hence, full name should be Richard J Gilbertson.
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http://dx.doi.org/10.1186/s13148-019-0737-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802296PMC
October 2019

DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.

Clin Epigenetics 2019 08 13;11(1):117. Epub 2019 Aug 13.

Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.

Background: Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs.

Methods: We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany.

Results: Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment.

Conclusions: We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.
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http://dx.doi.org/10.1186/s13148-019-0708-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692938PMC
August 2019

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Clin Genet 2019 11 6;96(5):461-467. Epub 2019 Aug 6.

Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.
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http://dx.doi.org/10.1111/cge.13613DOI Listing
November 2019

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group.

Cancer 2019 10 29;125(20):3514-3525. Epub 2019 Jul 29.

Dana-Farber Cancer Institute, Boston, and Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.
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http://dx.doi.org/10.1002/cncr.32351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948723PMC
October 2019

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

Int J Cancer 2020 02 30;146(4):1010-1017. Epub 2019 Jul 30.

Division of Hematology-Oncology, Montreal Children's Hospital, Department of Pediatrics, McGill University, Montreal, QC, Canada.

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.
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http://dx.doi.org/10.1002/ijc.32561DOI Listing
February 2020

Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma.

J Pathol 2019 11 28;249(3):319-331. Epub 2019 Aug 28.

Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, Canada.

Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5319DOI Listing
November 2019
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