Several histopathological features are found more frequently in placentas from pregnancies complicated by fetal growth restriction (FGR), including villous infarction, maternal vascular changes and ...villous morphological alterations, although around one quarter of placentas associated with FGR lack any morphological abnormality on routine examination. Since similar changes may also affect clinically uncomplicated pregnancies, the positive predictive value of such findings for pathological FGR in an unselected case remains low. However, the pattern of placental pathologies varies with clinical subgroup. The combination of placental bed and parenchymal lesions in FGR with abnormal uterine artery Doppler velocimetry is essentially identical to preterm pre-eclampsia (PET), and there is an association between FGR with abnormal umbilical artery Doppler findings and lesions of fetal stem arteries and terminal villous hypovascularity. Conversely, placentas from pregnancies complicated by PET or FGR presenting at or near term have a significantly lower frequency of histological abnormalities compared to early-onset disease and absence of a distinctive biochemical profile. The histological placental findings in FGR are therefore varied, from morphologically unremarkable through to severe uteroplacental vasculopathy, with no single pathological feature associated with high sensitivity or specificity. Severe early-onset FGR, overlapping with severe early-onset PET, is mainly associated with features of impaired maternal uteroplacental perfusion secondary to defective extravillous trophoblast invasion, and its consequences. Late-onset FGR probably represents a more heterogeneous group with less characteristic histological changes. Future research using histopathological assessment of aggregated data from multiple studies into larger datasets with centralised pathology review will allow delineation of distinctive clinicopathological associations and further understanding of pathophysiology.
The transcription factor FOS has long been implicated in the pathogenesis of bone tumours, following the discovery that the viral homologue, v-fos, caused osteosarcoma in laboratory mice. However, ...mutations of FOS have not been found in human bone-forming tumours. Here, we report recurrent rearrangement of FOS and its paralogue, FOSB, in the most common benign tumours of bone, osteoblastoma and osteoid osteoma. Combining whole-genome DNA and RNA sequences, we find rearrangement of FOS in five tumours and of FOSB in one tumour. Extending our findings into a cohort of 55 cases, using FISH and immunohistochemistry, provide evidence of ubiquitous mutation of FOS or FOSB in osteoblastoma and osteoid osteoma. Overall, our findings reveal a human bone tumour defined by mutations of FOS and FOSB.
Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator ...Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.
Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital ...mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
The immune landscape of solid pediatric tumors Sherif, Shimaa; Roelands, Jessica; Mifsud, William ...
Journal of experimental & clinical cancer research,
06/2022, Letnik:
41, Številka:
1
Journal Article
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Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the ...pediatric counterpart.
We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome.
A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS.
We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults' tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid ...tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.
•There is remarkable diversity of intratumor genetic heterogeneity and evolutionary trajectories.•Gain of 1q is frequently heterogeneous and shows variable evolutionary timing.•11p15 CNNLOH is consistently an early event in Wilms tumorigenesis.•Rational biomarker-based treatment stratification in Wilms tumors requires multisampling.We have shown that Wilms tumor (WT), the commonest pediatric kidney cancer, shows a range of evolutionary trajectories. We also found that gain of the long arm of chromosome 1 (1q+) may occur both early or late in the evolution of WT. 1q+ is associated with a poorer outcome and is proposed for use in choosing patients for more intensive treatment, but we show that in order to detect it reliably, future trials require testing for this biomarker in multiple samples per tumor.
The gene expression analysis of formalin-fixed paraffin-embedded (FFPE) tissues is often hampered by poor RNA quality, which results from the oxidation, cross-linking and other chemical modifications ...induced by the inclusion in paraffin. Yet, FFPE samples are a valuable source for molecular studies and can provide great insights into disease progression and prognosis. With the advancement of genomic technologies, new methods have been established that offer reliable and accurate gene expression workflows on samples of poor quality. NanoString is a probe-based technology that allows the direct counting of the mRNA transcripts and can be applied to degraded samples. Here, we have tested 2 RNA extraction methods for FFPE samples, and we have performed a titration experiment to evaluate the impact of RNA degradation and RNA input on the gene expression profiles assessed using the NanoString IO360 panel. We have selected FFPE samples of different DV200 values and assessed them on the nCounter platform with 2 different amounts of input RNA. This study concludes that the nCounter is a robust and reliable platform to assess the gene expression of RNA samples with DV200 > 30%; its robustness and ease of use could be of particular benefit to clinical settings.
BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of ...anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance.
Spinal cord tumor presenting with neck stiffness Alassaf, Anood; Al Shami, Rana; Al Rayahi, Jehan ...
Journal of pediatric surgery case reports,
December 2021, 2021-12-00, 2021-12-01, Letnik:
75
Journal Article
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Three years old boy presented with recurrent severe abdominal pain. He was treated for constipation and the pain resolved. Later he developed a limitation of neck movements. Investigations revealed a ...spinal cord mass. After surgical resection, histopathology confirmed pilocytic astrocytoma. The authors urge clinicians to observe for early signs of spinal cord tumor in children presenting with unusual presentations such as abdominal pain. Early recognition of spinal cord tumors and immediate treatment will prevent life‐threatening complications and improve the prognosis.
520 The immune landscape of pediatric tumors Sherif, Shimaa; Roelands, Jessica; Mifsud, William ...
Journal for immunotherapy of cancer,
11/2020, Letnik:
8, Številka:
Suppl 3
Journal Article
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BackgroundIt is now well established that the immune system has a substantial role in controlling cancer growth and progression. Immunotherapy is quickly coming to the forefront of cancer ...treatment,however the implementation of immunotherapy in pediatric solid cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters1 using analytes extracted from gene expression data.MethodsWe performed single sample GeneSet Enrichment Analysis for 105 immune signatures previously described on 5pediatric tumors (410patients) from TARGET dataset1 to identify coherent signature modules. Then we clustered samples according to representative signatures1 and compared survival across clusters. We completed the analysis by analyzing the enrichment of immune subpopulations and the expression of the immune checkpoints. The degree of dysregulation of oncogenic pathways was also assessed. The performance of previously identified immune signatures as the Immunologic Constant of Rejection(2,3),which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy, was also checked within each tumor subtype.ResultsWe found 5main modules, in agreement with results obtained in adult solid tumors:Wound Healing,TGF-B signaling,IFN-G signaling, Macrophages and Lymphocytes (figure 1). These 5 modules clustered pediatric patients into 6 immune subtypes S1-S6 with distinct survival (S2vsS4,p=0.0044, adjusted for cancer type),S2 cluster has the best overall survival and characterized by low enrichment of wound healing signature, high Th1, low Th2 and high expression of HLA 1 and HLA2, while the opposite holds true for cluster S4 with the worst survival and highest enrichment of wound healing signature, high Th2, and low Th1.The S6 cluster is characterized by highest enrichment of lymphocyte signature, the highest expression of immune checkpoints accompanied by elevated expression of exhaustion markers, and an unpolarized immune response with high abundance of macrophages. Additionally, pan-cancer, the upregulation of WNT-Beta catenin pathway is associated with adverse outcome and lack of T-cell infiltration. In the per-cancer analysis, ICR is associated with better survival in osteosarcoma and with worse survival in Wilms’ tumors,similarly with what observed in adult kidney’s cancer despite the different embryological origin.Abstract 520 Figure 1Immune subtypes of pediatric solid tumorsA. Spearman Correlation matrix of 105 cancer immune signatures showing 5 main modules.B. Spearman’s correlation of the 105 cancer immune signatures, identifies separation of the 5 immune signatures in different clustersC. Distribution of cancer types within immune subtypes. The percentage of samples belonging to each tumor is shown in colors.D. Distribution of immune subtypes within TARGET pediatric tumors. The percentage of samples belonging to each immune subtype is shown in colors.E. Distributions of signature scores within the six immune subtypes (rows), with dashed line indicating the median.F. Kaplan-Meier OS curve for the 6 immune subtypes (S1-S6) showing different outcomes.ConclusionsWe demonstrated that pediatric solid cancers can be classified according to their immune disposition, unveiling unexpected similarity with adults’ tumors.Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune responsive tumors. This is the first pan-cancer immunogenomic analysis in children.ReferencesThorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018. 48(4):812–830.Roelands J, Hendrickx W, et al. ‘Oncogenic states dictate the prognostic and predictive connotations of intratumoral immune response.’ Journal for immunotherapy of cancer 2020;vol. 8:1.Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 2013;39:11–26.
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