Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene

Ejeskär, Katarina; Aburatani, Hiroyuki; Abrahamsson, Jonas; Kogner, Per; Martinsson, Tommy

doi:10.1038/bjc.1998.297

Cited by 61 publications

(47 citation statements)

References 17 publications

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“…More recently, a study looking at 1p and 11q status by determining LOH has shown a strong prognostic impact of imbalanced 11q loss (Attiyeh et al, 2005). Chromosome 1p and 3p loss, as well as 2p gain, have also been associated with a higher risk of relapse (Caron et al, 1996;Ejeskar et al, 1998;Maris and Matthay, 1999;Spitz et al, 2003Spitz et al, , 2006. In this study, consistent with these previous observations, single genetic markers, including loss of 3p and 11q and gain of 2p and 17q, are all strong predictors of poor outcome.…”

Section: Discussionsupporting

confidence: 89%

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

et al. 2007

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Whereas neuroblastoma (NB) with MYCN amplification presents a poor prognosis, no single marker allows to reliably predict outcome in tumours without MYCN amplification. We report here an extensive analysis of 147 NB samples at diagnosis, without MYCN amplification, by chromosomal comparative genomic hybridisation (CGH), providing a comprehensive overview of their genomic imbalances. Comparative genomic hybridisation profiles showed gains or losses of entire chromosomes (type 1) in 71 cases, whereas partial chromosome gains or losses (type 2), including gain involving 17q were observed in 68 cases. Atypical profiles were present in eight cases. A type 1 profile was observed more frequently in localised disease (Po0.0001), and in patients of less than 12 months at diagnosis (Po0.0001). A type 2 genomic profile was associated with a higher risk of relapse in the overall population (logrank test; Po0.0001), but also in the subgroup of patients with localised disease (log-rank test, P ¼ 0.007). In multivariate analysis, the genomic profile was the strongest independent prognostic factor. In conclusion, the genomic profile is of prognostic impact in patients without MYCN amplification, making it a help in the management of low-stage NB. Further studies using higher-resolution CGH are needed to better characterise atypical genomic alterations.

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Section: Discussionsupporting

confidence: 89%

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

et al. 2007

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“…toma TSGs have been mapped by LOH studies to 1p36 (B35% in primary tumours show LOH), 11q23 (44%), 14q23 -qter (22%) and 3p (15%) (Ejeskar et al, 1998;Maris and Matthay, 1999). However, specific gene mutations have not been defined, although we did identify RASSF1A methylation in 55% of NBs and that CASP8 methylation occurs in B50% of tumours (Teitz et al, 2000;Astuti et al, 2001).…”

Section: Discussionmentioning

confidence: 68%

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

et al. 2004

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The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.

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“…In neuroblastoma samples, there was no correlation detected between BLU methylation status and N-myc amplification, 1 p deletion, 17q gain or survival (Table 1) (Ejeskar et al, 1998). However, lower stage neuroblastomas (stages I, II, IVS) were more frequently methylated for BLU compared to higher stage tumours (stages III, IV), P ¼ 0.025.…”

Section: Correlation Between Blu and Rassf1a Cpg Island Methylationmentioning

confidence: 93%

“…Our data suggest that in SCLC and neuroblastoma, RASSF1A and BLU methylations are unrelated events and not a manifestation of a regional alteration in epigenetic status, while in NSCLC there may be a regional methylation effect. Together, these data suggest a significant role for epigenetic inactivation of Introduction Allelic losses on the short arm of chromosome 3 are the most frequent genetic alterations detected in many sporadic human cancers, including lung, kidney, breast, ovary and neural crest-derived tumours (Ejeskar et al, 1998;Fullwood et al, 1999;Martinez et al, 2000Martinez et al, , 2001Wistuba et al, 2000;Maitra et al, 2001). Detailed studies on loss of heterozygosity (LOH) have identified several distinct 3p loci likely to contain tumour suppressor genes (TSGs), 3pl2, 3pl4, 3p21.3 and 3p25-26.…”

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confidence: 99%

Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers

et al. 2003

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Many distinct regions of 3p show frequent allelic losses in a wide range of tumour types. Previously, the BLU candidate tumour suppressor gene (TSG) encoded by a gene-rich critical deleted region in 3p21.3 was found to be inactivated rarely in lung cancer, although expression was downregulated in a subset of lung tumour cell lines. To elucidate the role of BLU in tumorigenesis, we analysed BLU promoter methylation status in tumour cell lines and detected promoter region hypermethylation in 39% lung, 42% breast, 50% kidney, 86% neuroblastoma and 80% nasopharyngeal (NPC) tumour cell lines. Methylation of the BLU promoter region correlated with the downregulation of BLU transcript expression in tumour cell lines. Expression was recovered in tumour cell lines treated with 5-aza 2-deoxycytidine. Exogenous expression of BLU in neuroblastoma (SK-N-SH) and NSCLC (NCI-H1299) resulted in reduced colony formation efficiency, in vitro. Furthermore, methylation of the BLU promoter region was detected in primary sporadic SCLC (14%), NSCLC (19%) and neuroblastoma (41%). As frequent methylation of the RASSF1A 3p21.3 TSG has also been reported in these tumour types, we investigated whether BLU and RASSF1A methylation were independent or related events. No correlation was found between hypermethylation of RASSF1A and BLU promoter region CpG islands in SCLC or neuroblastoma. However, there was association between RASSF1A and BLU methylation in NSCLC (P ¼ 0.0031). Our data suggest that in SCLC and neuroblastoma, RASSF1A and BLU methylations are unrelated events and not a manifestation of a regional alteration in epigenetic status, while in NSCLC there may be a regional methylation effect. Together, these data suggest a significant role for epigenetic inactivation of BLU in the pathogenesis of common human cancers and that methylation inactivation of BLU occurs independent of RASSF1A in SCLC and neuroblastoma tumours.

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Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene

Cited by 61 publications

References 17 publications

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers

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