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A 6-gene signature identifies four molecular subgroups of neuroblastoma

Artikel i vetenskaplig tidskrift
Författare Frida Abel
Daniel Dalevi
Maria Nethander
Rebecka Jörnsten
Katleen De Preter
Joëlle Vermuelen
Raymond Stallings
Per Kogner
John Maris
Staffan Nilsson
Publicerad i Cancer Cell International
Volym 11
Nummer/häfte 9
ISSN 1475-2867
Publiceringsår 2011
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik
Institutionen för matematiska vetenskaper, matematisk statistik
Språk en
Länkar dx.doi.org/10.1186/1475-2867-11-9
https://gup.ub.gu.se/file/77880
Ämnesord EXPRESSION-BASED CLASSIFICATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; TUMOR-SUPPRESSOR GENE; ACTIVATING MUTATIONS; ONCOLOGY GROUP; MESSENGER-RNA; COPY scigloo.NUMBER; ALK KINASE; AMPLIFICATION; PROGRESSION
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p < 0.05, Fisher's exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.

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