Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers

Sartori, F.; Alaggio, Rita; Zanazzo, Giulio Andrea; Garaventa, Alberto; Cataldo, Andrea Di; Carli, Modesto; Rosolen, Angelo

doi:10.1002/cncr.21772

Cited by 32 publications

(44 citation statements)

References 111 publications

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“…The detection of RMS cells in PB and BM is thought to be of the utmost importance for the management of patients with this malignancy (13,14). RMS-specific translocation products PAX3/FOXO1 and PAX7/FOXO1 as markers for RMS cells are widely accepted owing to their absolute specificity for tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…In pediatric sarcomas, several works on Ewing's sarcoma (9)(10)(11)(12), rhabdomyosarcoma (RMS) (13,14), synovial sarcoma (15), and osteosarcoma (16) have suggested the possible use of cancer markers (especially translocation products) and tissue-specific markers for CTC detection. However, results of studies conducted on larger series of pediatric patients together with better standardization of techniques are necessary before they can be used for individual staging of patients.…”

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confidence: 99%

“…Patients with metastatic RMS have very poor prognosis and recurrences are common in advanced localized disease. Minimal residual disease (MRD)-CTCs in peripheral blood (PB) or disseminated to bone marrow (BM)-is a widespread feature of this neoplasia (13,14). MRD assessment is thought to be crucial for evaluation of the risk of metastasis and the appraisal of treatment efficacy.…”

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confidence: 99%

“…In this neoplasia, MRD has previously been studied by conventional and quantitative PCR (qPCR). The markers most used are muscle-specific transcription factors such as MYOD1 and MYOGENIN, and the RMS-specific chimeric transcripts PAX3/FOXO1 and PAX7/FOXO1 (13,14,22,23). Particularly in aRMS cases bearing translocation of PAX genes with FOXO1, the chimeric products PAX3/FOXO1 and PAX7/FOXO1 for MRD monitoring are highly specific for tumor cells, because these fusion genes are absent in the genome of normal cells.…”

mentioning

confidence: 99%

“…The detection of tissue-specific transcription factors by qRT-PCR is controversial owing to their possible residual expression, albeit extremely low, in control PB or BM that could give rise to false positives (17). Furthermore, the majority of RMS patients positive for MRD are only detected after a high number of PCR cycles (at high Ct values, corresponding to very low levels of the target template) when the qPCR reliability and reproducibility markedly decrease (13,14). For this reason, we postulate the convenience of the optimization of a flow cytometry-based method to detect RMS CTCs.…”

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confidence: 99%

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Optimization of rhabdomyosarcoma disseminated disease assessment by flow cytometry

et al. 2014

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Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. Circulating tumor cells in peripheral blood or disseminated to bone marrow, a concept commonly referred to as minimal residual disease (MRD), are thought to be key to the prediction of metastasis and treatment efficacy. To date, two MRD markers, MYOD and MYOGENIN, have been tested; however, MRD detection continues to be challenging mainly owing to the closeness of the detection limit and the discordance of both markers in some samples. Therefore, the addition of a third marker could be useful for more accurate MRD assessment. The PAX3 gene is expressed during embryo development in all myogenic precursor cells in the dermomyotome. As RMS cells are thought to originate from these muscle precursor cells, they are expected to be positive for PAX3. In this study, PAX3 expression was characterized in cancer cell lines and tumors, showing wide expression in RMS. Detection sensitivities by quantitative polymerase chain reaction (qPCR) of the previously proposed markers, MYOD and MYOGENIN, were similar to that of PAX3, thereby indicating the feasibility of its detection. Interestingly, the flow cytometry experiments supported the usefulness of this technique in the quantification of MRD in RMS using PAX3 as a marker. These results indicate that flow cytometry, albeit in some cases slightly less sensitive, can be considered a good approach for MRD assessment in RMS and more consistent than qPCR, especially owing to its greater specificity. Furthermore, fluorescence-activated cell sorting permits the recovery of cells, thereby providing material for further characterization of circulating or disseminated cancer cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Optimization of rhabdomyosarcoma disseminated disease assessment by flow cytometry

et al. 2014

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Clinical significance of circulating tumor cells and cell‐free DNA in pediatric rhabdomyosarcoma

et al. 2022

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Liquid biopsy analysis represents a powerful and noninvasive tool to uncover biomarkers for disseminated disease assessment and longitudinal monitoring of patients. Herein, we explored the value of circulating and disseminated tumor cells (CTC and DTC, respectively) and cell‐free DNA (cfDNA) in pediatric rhabdomyosarcoma (RMS). Peripheral blood and bone marrow samples were analyzed to detect and enumerate CTC and DTC, respectively. We used the epithelial cellular adhesion molecule (EpCAM)‐based CellSearch platform coupled with an automatic device to collect both EpCAM‐positive and EpCAM‐low/negative CTCs. The standard assay was implemented, including the mesenchymal marker desmin. For selected cases, we molecularly profiled primary tumors and liquid biopsy biomarkers using whole‐exome sequencing and droplet digital PCR, respectively. RMS patients with metastatic disease had a significantly higher number of CTCs compared to those with localized disease, whereas DTCs were detected independently of disease presentation. The use of the desmin marker remarkably increased the identification of CTCs and DTCs in RMS samples. Of note, CTC clusters were detected in RMS patients with disseminated disease. Further, cfDNA and CTC molecular features closely reflected the molecular makeup of primary tumors and informed of disease course.

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CIITA is silenced by epigenetic mechanisms that prevent the recruitment of transactivating factors in rhabdomyosarcoma cells

Londhe

Zhu

Abraham

et al. 2012

Intl Journal of Cancer

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Rhabdomyosarcomas (RMS) are highly malignant pediatric sarcomas. We have discovered that the gene encoding the major histocompatibilty complex class II transactivator, CIITA, is silenced in cells representing both major subtypes of RMS. Silencing of CIITA prevents the IFN-γ inducible expression of MHC class II genes in these cells. Overexpression of CIITA in these cells can restore MHC expression. We have found that IFN-γ signaling is intact in these cells, but pSTAT1 and IRF1 do not bind to the CIITA PIV promoter. The CIITA promoter is not hypermethylated in RD (ERMS) cells, but does show a modestly enhanced methylation status in SJRH30 (ARMS) cells. We have found that histone acetylation, which normally increases on the CIITA PIV promoter following IFN-γ treatment, is blocked in both types of RMS cells. In RD cells, treatment with a histone deacetylase inhibitor (TSA) reverses the silencing of CIITA. In SJRH30 cells, treatment with DNA methyltransferase inhibitors and TSA cooperatively restores CIITA expression. Surprisingly, we have also shown that the expression of two components of the immunoproteasome, which are embedded in the class II locus, is stimulated by IFN-γ in certain RMS cells in the absence of stimulation by CIITA. CIITA overexpression can also activate the expression of these genes, indicating that the immunoproteasome genes LMP2 and LMP7 can be activated by both CIITA dependent and CIITA independent pathways.

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Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers

Cited by 32 publications

References 111 publications

Optimization of rhabdomyosarcoma disseminated disease assessment by flow cytometry

Optimization of rhabdomyosarcoma disseminated disease assessment by flow cytometry

Clinical significance of circulating tumor cells and cell‐free DNA in pediatric rhabdomyosarcoma

CIITA is silenced by epigenetic mechanisms that prevent the recruitment of transactivating factors in rhabdomyosarcoma cells

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