The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations

Villani, Anita; Davidson, Scott; Kanwar, Nisha; Lo, Winnie; Li, Yisu; Cohen-Gogo, Sarah; Fuligni, Fabio; Edward, Lisa-Monique; Light, Nicholas; Layeghifard, Mehdi; Harripaul, Ricardo; Waldman, Larissa; Gallinger, Bailey; Comitani, Federico; Brunga, Ledia; Hayes, Robert E.; Anderson, Nathaniel D.; Yuki, Kyoko E.; Blay, Sasha; Johnstone, Brittney; Inglese, Cara; Hammad, Rawan; Goudie, Catherine; Shuen, Andrew Y.; Wasserman, Jonathan D.; Venier, Rosemarie E.; Eliou, Marianne; Lorenti, Miranda; Ryan, Carol Ann; Braga, Michael; Gloven-Brown, Meagan; Han, Jia-Jun; Montero, María; Spatare, Famida; Whitlock, James A.; Scherer, Stephen W.; Chun, Kathy; Somerville, Martin J.; Hawkins, Cynthia; Abdelhaleem, Mohamed; Ramaswamy, Vijay; Somers, Gino R.; Kyriakopoulou, Lianna; Shago, Mary; Morgenstern, Daniel A.; Tabori, Uri; Meyn, Stephen; Irwin, Meredith S.; Malkin, David

doi:10.1038/s43018-022-00474-y

Cited by 48 publications

(28 citation statements)

References 76 publications

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“…We next sought to investigate the role of TP53 mutations in shaping childhood cancer evolution by examining the clonality of somatic mutations. To do this we analysed the TP53 germline-mutant cohort alongside TP53 somatic-mutant (n = 15) and TP53-wildtype (n = 33) tumor samples, as part of the SickKids Cancer Sequencing (KiCS) childhood precision medicine program 27 . These tumors were selected to match the LFS tumor cohort.…”

Section: The Clonal Evolution Of Lfs Tumors Is Marked By a Large Clon...mentioning

confidence: 99%

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

et al. 2023

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Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

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Section: The Clonal Evolution Of Lfs Tumors Is Marked By a Large Clon...mentioning

confidence: 99%

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

et al. 2023

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“…Tumor-derived RNA from childhood cancer patients enrolled in an ongoing precision medicine program were sequenced (163 tumors/132 patients) 50 . OTTER was applied to this held-out validation cohort, and classifications were compared to the pathologists’ diagnosis (Supplementary Table 7a ).…”

Section: Resultsmentioning

confidence: 99%

Diagnostic classification of childhood cancer using multiscale transcriptomics

Comitani

Nash

Cohen-Gogo

et al. 2023

Nat Med

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The causes of pediatric cancers’ distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.

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“…The widespread interest in telehealth during the pandemic has also highlighted the importance of healthcare professionals' competency in its implementation [29,30]. Genomics and arti cial intelligence are expected to play a crucial role in predicting the prognosis of severe diseases, particularly cancer, and supporting clinical decision-making [31,32]. Mental health in children has gained increased attention during the pandemic, leading to proposed solutions utilizing various technologies [33,34].…”

Section: Discussionmentioning

confidence: 99%

Prioritizing Educational Initiatives on Emerging Technologies for Italian Pediatricians: bibliometric review and a survey

Tozzi

Gesualdo

Pandolfi

et al. 2023

Preprint

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Background Emerging technologies have demonstrated outstanding potential in improving healthcare, yet their full integration remains a challenge for all medical specialties, including pediatrics. To support the swift implementation of technologies, we identified the current trends through a bibliometric review, and we conducted a survey on Italian pediatricians to gauge educational needs and willingness to integrate technologies into clinical practice. Methods A working group of pediatricians representing various backgrounds designed and coordinated the study. To identify relevant topics for educational strategy development, we focused on virtual reality, telehealth, natural language processing, smartphone applications, robotics, genomics, and artificial intelligence. A bibliometric analysis limited to 2018-2023 was performed to identify trends and emerging applications within each topic. Based on the results, a questionnaire was developed and made available online to all Italian pediatricians. The results were analyzed through descriptive analysis and a multivariable logistic regression to explore associations between technology adoption and sociodemographic characteristics. Results A total of 3,253 publications were found, with Telehealth and Telemedicine having the highest number of publications and Natural Language Processing the lowest. The number of respondents to the online questionnaire was 1,540, predominantly medical doctors with over 20 years of experience working as family pediatricians. Telehealth had the highest level of knowledge (95.2%), followed by smartphone applications (89.1%) and genomics (63.2%). The greatest potential for increased use through education programs was projected for natural language processing (+43.1%), artificial intelligence (+39.6%), and virtual and mixed reality (+38.1%). Female respondents and older individuals were less likely to use emerging technologies. Hospital pediatricians and residents were more likely to use AI. Conclusions We developed a replicable strategy to identify emerging themes in medical technologies relevant to pediatrics and assess the educational needs of pediatricians. A significant gap still exists between current and potential usage of emerging technologies among Italian pediatricians although they showed a positive attitude towards implementing these technologies following specific education programs. The study highlights the need for comprehensive education programs on emerging technologies in pediatrics and recommends addressing gender and age disparities in technology adoption.

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The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations

Cited by 48 publications

References 76 publications

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

Diagnostic classification of childhood cancer using multiscale transcriptomics

Prioritizing Educational Initiatives on Emerging Technologies for Italian Pediatricians: bibliometric review and a survey

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