ALK Expression Is a Novel Marker for the WNT-activated Type of Pediatric Medulloblastoma and an Indicator of Good Prognosis for Patients

Łastowska, Maria; Trubicka, Joanna; Niemira, Magdalena; Paczkowska-Abdulsalam, Magdalena; Karkucińska-Więckowska, Agnieszka; Kaleta, Magdalena; Drogosiewicz, Monika; Tarasińska, Magdalena; Perek-Polnik, Marta; Krętowski, Adam; Dembowska‐Bagińska, Bożenna; Grajkowska, Wiesława; Pronicki, Maciej; Matyja, Ewa

doi:10.1097/pas.0000000000000847

Cited by 15 publications

(20 citation statements)

References 19 publications

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“…In order to integrate more diagnostic markers and candidates for therapeutic targets of this tumor into one testing platform, we also investigated the correlation of several additional candidate signature genes with subgroups of MB. Some of these markers, such as ALK in the WNT group, TP53 , NMYC , and GLI1 in the SHH group, MYC in Group 3, and SNCAIP in Group 4, have been identified in various studies using different methods, which strongly supports the results from the NanoString assay in the current study . Furthermore, we identified several novel MB subgroup markers, including FGFR1 and PDGFRA in the WNT group and CCND1 in the SHH group.…”

Section: Discussionsupporting

confidence: 87%

“…Gene expression analysis was carried out using the classic MB subtyping gene CodeSet, which included 22 well known signature genes for different subgroups, as well as 11 additional tumor‐related genes. Six of the tumor‐related genes ( ALK , MYCN , TP53 , GLI1 , MYC , and SNCAIP ) have been reported to be related with different subtypes of this malignant brain tumor, based on various technical assays, and were integrated into the CodeSet here to improve the efficiency of clinical molecular testing as well as strengthen the subtyping fidelity of the NanoString platform . In addition, some candidates for therapeutic targets of this tumor, which were screened by our previous study (data not shown), were recruited in the current panel of genes, such as FGFR1 , PDGFRA , and CCND1 .…”

Section: Methodsmentioning

confidence: 99%

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SNCA, a novel biomarker for Group 4 medulloblastomas, can inhibit tumor invasion and induce apoptosis

Jiang

et al. 2018

Cancer Science

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Medulloblastoma (MB) is the most common malignant brain tumor in childhood. It contains at least four distinct molecular subgroups. The aim of this study is to explore novel diagnostic and potential therapeutic markers within each subgroup of MB, in particular within Group 4, the largest subgroup, to facilitate diagnosis together with gene therapy. One hundred and six MB samples were examined. Tumor subtype was evaluated with the NanoString assay. Several novel tumor related genes were shown to have high subgroup sensitivity and specificity, including PDGFRA,FGFR1, and ALK in the WNT group, CCND1 in the SHH group, and α‐synuclein (SNCA) in Group 4. Knockdown and overexpression assays of SNCA revealed the ability of this gene to inhibit tumor invasion and induce apoptosis. Methylation‐specific PCR and pyrosequencing analysis showed that epigenetic mechanisms, rather than DNA hypermethylation, might play the key role in the regulation of SNCA expression in MB tumors. In conclusion, we identify SNCA as a novel diagnostic biomarker for Group 4 MB. Some other subgroup signature genes have also been found as candidate therapeutic targets for this tumor.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

SNCA, a novel biomarker for Group 4 medulloblastomas, can inhibit tumor invasion and induce apoptosis

Jiang

et al. 2018

Cancer Science

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“…Two recently published studies based on NanoString method and 22-genes classifier have been employed for detection of four molecular groups in medulloblastoma and the results showed that a subset of tumors displayed expression of genes from both Group 3 and Group 4 signatures. Remarkably, these tumors were classified as Group 3 in a series by Li et al [ 8 ] but as Group 4 in our series by Łastowska et al [ 9 ]. Since Group 3 tumors are associated with a worse prognosis [ 2 , 4 , 5 ] it is very important that an individual tumor is classified correctly, as this may result in clinical consequences.…”

Section: Introductionmentioning

confidence: 53%

Medulloblastoma with transitional features between Group 3 and Group 4 is associated with good prognosis

et al. 2018

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Medulloblastoma, the most common malignant pediatric brain tumor, is a heterogeneous disease, with the existence of at least four molecular types: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 tumors. The latter two groups, which can be identified by an application of multi-gene expression or methylation profiling, show sometimes ambiguous categorization and are still classified for diagnostic reason as non-SHH/non-WNT medulloblastomas in updated WHO 2016 classification. In order to better characterize non-SHH/non-WNT tumors, we applied the method based on the Nanostring nCounter Technology, using the 26 genes codeset in 68 uniformly treated medulloblastoma patients. This allowed for identification of tumors, which shared common Group 3 and Group 4 gene signatures. We recognized three transcriptional groups within non-WNT/non-SHH tumors: Group 3, Group 4 and the Intermediate 3/4 Group. Group 3, in line with previously published results, showed poor prognosis with survival rate < 40%, frequent metastases, large cell/anaplastic pathology and presence of tumors with MYCC amplification. This is in contrast to patients from the Intermediate 3/4 Group who showed the best survival rate (100%). Overall and progression free survival were better for this group than for Group 3 (p = 0.001, for both) and Group 4 (p = 0.064 and p = 0.066, respectively). Our work supports the view that within the non-WNT/non-SHH tumors different risk groups exist and that the current two groups classifier may be not sufficient for proper clinical categorization of individual patients.

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“…New molecular categories of tumors discovered by DNA methylation profiling, CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR, are rare pediatric brain malignancies that have not yet been In this study, we applied a novel approach for the diagnosis of all four new entities using the NanoString nCounter Analysis System and multi-genes tumorspecific signatures. This method allows for analysis of degraded RNA, is therefore compatible with FFPE specimens and was previously successfully tested for detection of molecular subtypes in MBs [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…The only criterion for inclusion was the availability of tumor material. Only samples examined previously by NanoString method and diagnosed molecularly as MBs [12,13] were excluded from analysis. Analysis was performed on archive FFPE tumor material obtained at diagnosis and one relapsed sample.…”

Section: Patients and Tumor Materialsmentioning

confidence: 99%

Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes

Łastowska

Trubicka

Sobocińska

et al. 2020

acta neuropathol commun

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Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Altogether, 14 out of 187 (7.4%) high grade pediatric brain tumors were diagnosed with either of four new CNS categories. Histopathological examination of the tumors confirmed, that they demonstrate a spectrum of morphology mimicking other CNS high grade tumors. However, they also exhibit some suggestive histopathological and immunohistochemical features that allow for a presumptive diagnosis prior to molecular assessment. Clinical characteristics of patients corroborated with the previous findings for CNS EFT-CIC, CNS NB-FOXR2 and CNS HGNET-MN1 patients, with a favorable survival rate for the latter two groups. Among six CNS HGNE T-BCOR patients, three patients are long term survivors, suggesting possible heterogeneity within this molecular category of tumors. In summary, we confirmed the effectiveness of NanoString method using a single, multi-gene tumor specific signature and recommend this novel approach for identification of either one of the four newly described CNS tumor entities.

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ALK Expression Is a Novel Marker for the WNT-activated Type of Pediatric Medulloblastoma and an Indicator of Good Prognosis for Patients

Cited by 15 publications

References 19 publications

SNCA, a novel biomarker for Group 4 medulloblastomas, can inhibit tumor invasion and induce apoptosis

SNCA, a novel biomarker for Group 4 medulloblastomas, can inhibit tumor invasion and induce apoptosis

Medulloblastoma with transitional features between Group 3 and Group 4 is associated with good prognosis

Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes

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