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Genomic deletion and promoter methylation status of Hypermethylated in Cancer 1 (HIC1) in mantle cell lymphoma.

Stöcklein H, Hutter G, Kalla J, Hartmann E, Zimmermann Y, Katzenberger T, Adam P, Leich E, Höller S, Müller-Hermelink HK, Rosenwald A, Ott G, Dreyling M - J Hematop (2008)

Bottom Line: However, neither TP53 nor HIC1 deletions did affect survival of MCL patients.In most analyzed cases, no hypermethylation of the HIC1 exon 1A promoter was observed (17 out of 20, 85%).However, in MCL cell lines without HIC1-hypermethylation, the mRNA expression levels of HIC1 were nevertheless significantly reduced, when compared to reactive lymph node specimens, pointing to the occurrence of mechanisms other than epigenetic or genetic events for the inactivation of HIC1 in this entity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.

ABSTRACT
Mantle cell lymphomas (MCL), characterized by the t(11;14)(q13;q32), frequently carry secondary genetic alterations such as deletions in chromosome 17p involving the TP53 locus. Given that the association between TP53-deletions and concurrent mutations of the remaining allele is weak and based on our recent report that the Hypermethylated in Cancer 1 (HIC1) gene, that is located telomeric to the TP53 gene, may be targeted by deletions in 17p in diffuse large B-cell lymphoma (DLBCL), we investigated whether HIC1 inactivations might also occur in MCL. Monoallelic deletions of the TP53 locus were detected in 18 out of 59 MCL (31%), while overexpression of p53 protein occurred in only 8 out of 18 of these MCL (44%). In TP53-deleted MCL, the HIC1 gene locus was co-deleted in 11 out of 18 cases (61%). However, neither TP53 nor HIC1 deletions did affect survival of MCL patients. In most analyzed cases, no hypermethylation of the HIC1 exon 1A promoter was observed (17 out of 20, 85%). However, in MCL cell lines without HIC1-hypermethylation, the mRNA expression levels of HIC1 were nevertheless significantly reduced, when compared to reactive lymph node specimens, pointing to the occurrence of mechanisms other than epigenetic or genetic events for the inactivation of HIC1 in this entity.

No MeSH data available.


Related in: MedlinePlus

Chromosome 17p deletions in MCL. Whole arm deletion of chromosome 17p, including TP53 and HIC1, in 11/59 MCL (a), as indicated by fluorescence in situ hybridization using the TP53-specific probe RP11-199F11 (green) and the HIC1-specific probe RP11-667K14 (red) (b–c). Partial deletion of chromosome band 17p13.1 to 17p13.3 including only the TP53-locus in 7 out of 59 MCL (a), as seen by loss of one green signal (TP53) in contrast to two HIC1-signals (red) (d–e). Deletion of chromosomal band 17p13.3, including HIC1 without loss of TP53 in 7/59 MCL (a), as indicated by one HIC1-signal (red) instead of two TP53-signals (green; f–g)
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Fig1: Chromosome 17p deletions in MCL. Whole arm deletion of chromosome 17p, including TP53 and HIC1, in 11/59 MCL (a), as indicated by fluorescence in situ hybridization using the TP53-specific probe RP11-199F11 (green) and the HIC1-specific probe RP11-667K14 (red) (b–c). Partial deletion of chromosome band 17p13.1 to 17p13.3 including only the TP53-locus in 7 out of 59 MCL (a), as seen by loss of one green signal (TP53) in contrast to two HIC1-signals (red) (d–e). Deletion of chromosomal band 17p13.3, including HIC1 without loss of TP53 in 7/59 MCL (a), as indicated by one HIC1-signal (red) instead of two TP53-signals (green; f–g)

Mentions: The deletion status of HIC1 was examined in 59 MCL, using FISH with the HIC1 locus-specific probe RP11-667K14 (in 32 out of 59 fresh-frozen and leukemic blood samples) or LOH analysis with the microsatellite marker D17S831 (on DNA from 10/59 MCL samples extracted from leukemic blood) or by using both methods when appropriate material was available (in 17 out of 59 MCL). A monoallelic deletion of RP11-667K14 by FISH and/or loss of heterozygosity of D17S831 by LOH analysis was observed in 18 out of 59 cases (31%) (Table 1). Deletion of both the HIC1 and TP53 loci simultaneously occurred in only 11 of these MCL. By conventional cytogenetic analysis, a del(17p) was detected in 4 out of 11 MCL samples, indicating complete loss of chromosome 17p in these cases (Table 1, Fig. 1a–c).Fig. 1


Genomic deletion and promoter methylation status of Hypermethylated in Cancer 1 (HIC1) in mantle cell lymphoma.

Stöcklein H, Hutter G, Kalla J, Hartmann E, Zimmermann Y, Katzenberger T, Adam P, Leich E, Höller S, Müller-Hermelink HK, Rosenwald A, Ott G, Dreyling M - J Hematop (2008)

Chromosome 17p deletions in MCL. Whole arm deletion of chromosome 17p, including TP53 and HIC1, in 11/59 MCL (a), as indicated by fluorescence in situ hybridization using the TP53-specific probe RP11-199F11 (green) and the HIC1-specific probe RP11-667K14 (red) (b–c). Partial deletion of chromosome band 17p13.1 to 17p13.3 including only the TP53-locus in 7 out of 59 MCL (a), as seen by loss of one green signal (TP53) in contrast to two HIC1-signals (red) (d–e). Deletion of chromosomal band 17p13.3, including HIC1 without loss of TP53 in 7/59 MCL (a), as indicated by one HIC1-signal (red) instead of two TP53-signals (green; f–g)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2713485&req=5

Fig1: Chromosome 17p deletions in MCL. Whole arm deletion of chromosome 17p, including TP53 and HIC1, in 11/59 MCL (a), as indicated by fluorescence in situ hybridization using the TP53-specific probe RP11-199F11 (green) and the HIC1-specific probe RP11-667K14 (red) (b–c). Partial deletion of chromosome band 17p13.1 to 17p13.3 including only the TP53-locus in 7 out of 59 MCL (a), as seen by loss of one green signal (TP53) in contrast to two HIC1-signals (red) (d–e). Deletion of chromosomal band 17p13.3, including HIC1 without loss of TP53 in 7/59 MCL (a), as indicated by one HIC1-signal (red) instead of two TP53-signals (green; f–g)
Mentions: The deletion status of HIC1 was examined in 59 MCL, using FISH with the HIC1 locus-specific probe RP11-667K14 (in 32 out of 59 fresh-frozen and leukemic blood samples) or LOH analysis with the microsatellite marker D17S831 (on DNA from 10/59 MCL samples extracted from leukemic blood) or by using both methods when appropriate material was available (in 17 out of 59 MCL). A monoallelic deletion of RP11-667K14 by FISH and/or loss of heterozygosity of D17S831 by LOH analysis was observed in 18 out of 59 cases (31%) (Table 1). Deletion of both the HIC1 and TP53 loci simultaneously occurred in only 11 of these MCL. By conventional cytogenetic analysis, a del(17p) was detected in 4 out of 11 MCL samples, indicating complete loss of chromosome 17p in these cases (Table 1, Fig. 1a–c).Fig. 1

Bottom Line: However, neither TP53 nor HIC1 deletions did affect survival of MCL patients.In most analyzed cases, no hypermethylation of the HIC1 exon 1A promoter was observed (17 out of 20, 85%).However, in MCL cell lines without HIC1-hypermethylation, the mRNA expression levels of HIC1 were nevertheless significantly reduced, when compared to reactive lymph node specimens, pointing to the occurrence of mechanisms other than epigenetic or genetic events for the inactivation of HIC1 in this entity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.

ABSTRACT
Mantle cell lymphomas (MCL), characterized by the t(11;14)(q13;q32), frequently carry secondary genetic alterations such as deletions in chromosome 17p involving the TP53 locus. Given that the association between TP53-deletions and concurrent mutations of the remaining allele is weak and based on our recent report that the Hypermethylated in Cancer 1 (HIC1) gene, that is located telomeric to the TP53 gene, may be targeted by deletions in 17p in diffuse large B-cell lymphoma (DLBCL), we investigated whether HIC1 inactivations might also occur in MCL. Monoallelic deletions of the TP53 locus were detected in 18 out of 59 MCL (31%), while overexpression of p53 protein occurred in only 8 out of 18 of these MCL (44%). In TP53-deleted MCL, the HIC1 gene locus was co-deleted in 11 out of 18 cases (61%). However, neither TP53 nor HIC1 deletions did affect survival of MCL patients. In most analyzed cases, no hypermethylation of the HIC1 exon 1A promoter was observed (17 out of 20, 85%). However, in MCL cell lines without HIC1-hypermethylation, the mRNA expression levels of HIC1 were nevertheless significantly reduced, when compared to reactive lymph node specimens, pointing to the occurrence of mechanisms other than epigenetic or genetic events for the inactivation of HIC1 in this entity.

No MeSH data available.


Related in: MedlinePlus