Frequent chromosome arm 13q deletion in aggressive non-Hodgkin’s lymphoma

Wada, Makio; Okamura, Takuya; Okada, Masaki; Teramura, Masanao; Masuda, Michihiko; Motoji, Toshiko; Mizoguchi, Hideaki

doi:10.1038/sj.leu.2401395

Cited by 27 publications

(20 citation statements)

References 26 publications

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“…30,31 With regard to prognosis, Cuneo et al 45 found a significant association between 13q14 loss and shorter survival. This result was supported by Wada et al, 6 who found monoallelic loss of RB1 more frequently in aggressive NHL compared to indolent tumours. In our study, there was no significant association between survival and RB1 copy number or pRB expression.…”

Section: Discussionsupporting

confidence: 62%

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Proliferation-dependent expression and phosphorylation of pRB in B cell non-Hodgkin's lymphomas: dependence on RB1 copy number

et al. 2002

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Some studies have suggested that a significant fraction of nonHodgkin's lymphomas (NHL) do not express pRB protein, possibly due to deletions of RB1. We examined RB1/centromere 17 copy number by fluorescent in situ hybridisation, and pRB expression/phosphorylation by immunohistochemistry (IHC) and immunoblotting (IB) in 66 cases of B cell NHL. Thirteen cases had lost one RB1 copy relative to centromere 17 copy number and total DNA content. Case 458/88 had no RB1 copies. pRB levels were heterogeneous as assessed by IB (0.04-1.12 relative units), but all tumours, except for case 458/88, expressed pRB localised to the nucleus in Ͼ75% of the tumour cells by IHC. The fraction of phosphorylated pRB was correlated with pRB expression (r 2 = 0.56, P Ͻ 0.001). The 14 cases with loss of RB1 had lower pRB expression (median 0.25) than those without (median 0.48, P Ͻ 0.001), but a correlation with S phase fraction (r 2 = 0.43, P Ͻ 0.001; previously published data for tumour-specific S phase and apoptotic fractions) indicated that the variation in pRB expression was due to differences in proliferative activity. Furthermore, the regression lines for pRB expression vs S phase fraction were not different for the cases with or without loss of one RB1 copy (P = 0.5). Cases 154/88 (one RB1 copy) and 258/88 (two RB1 copies), in addition to case 458/88, had low expression of (hypophosphorylated) pRB (0.04, 0.08 and 0.04), despite their high S phase fractions (21%, 17% and 21%). There was no association between pRB expression/RB1 copy number and apoptotic fraction. Neither pRB expression nor loss of RB1 had prognostic value, but cases 154/88, 258/88, and 458/88 had short survival times (5, 3 and 46 months, respectively) compared to the others (median survival: 44 months, P = 0.03). It is suggested that pRB expression and function are normal in 63 of 66 NHL cases, including 12 of 13 lymphomas with loss of one RB1 allele.

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Section: Discussionsupporting

confidence: 62%

“…This aberration has been detected in all subclasses of lymphomas. [5][6][7] A target for the deletion has not yet been established. Originally, it was suggested that RB1, localised to this region, was the candidate tumour suppressor gene involved.…”

Section: Introductionmentioning

confidence: 99%

Proliferation-dependent expression and phosphorylation of pRB in B cell non-Hodgkin's lymphomas: dependence on RB1 copy number

et al. 2002

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“…In addition, we performed LOH studies that showed allelic imbalances of the 13q14 locus in 45% of the informative ALCL cases, confirming the FISH results. Using similar FISH methods, Wada and co-workers 39 also detected deletions of the 13q locus in 40% of aggressive lymphomas including one case of ALCL of T-cell lineage. Rosenwald and colleagues 40 also used FISH methods and reported allelic loss at 13q14 in 3 of 13 peripheral T-cell lymphomas.…”

Section: Discussionmentioning

confidence: 83%

Retinoblastoma Protein Is Frequently Absent or Phosphorylated in Anaplastic Large-Cell Lymphoma

Rassidakis

Lai

Herling

et al. 2004

The American Journal of Pathology

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The possible role of retinoblastoma protein (Rb) in the pathogenesis of anaplastic large-cell lymphoma (ALCL) is unknown. We investigated Rb protein expression, both total (phosphorylated and underphosphorylated) and active (underphosphorylated), in four anaplastic lymphoma kinase (ALK)-positive ALCL cell lines (Karpas 299, JB-6, SU-DHL1, and SR-786) by Western blot analysis, and in 67 ALCL tumors (30 ALK-positive, 37 ALK-negative) using immunohistochemical methods. We also used fluorescence in situ hybridization and polymerase chain reaction methods to assess for loss of heterozygosity of the rb gene. The findings were correlated with apoptotic rate assessed by the terminal dUTP nick-end labeling assay. Immunoblots showed high total Rb levels in Karpas 299, SU-DHL1 and SR-786 and relatively lower levels in and JB-6. Underphosphorylated Rb was negative or expressed at low levels in all cell lines. In ALCL tumors, total Rb was detected in 44 (66%) and absent in 23 (34%). The mean apoptotic rate was 3.2% in Rb-negative tumors compared with 2.7%, 2.2%, and 1.2% in tumors with <10%, 10 to 50%, and >50% Rb-positive cells, respectively (P ‫؍‬ 0.2, Kruskall-Wallis test). In a subset of 25 total

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“…These exons were identified using cDNA library screening (exons 1b, 3,4,[7][8][9] and RACE PCR (exons 5 and 6). The longest open reading frame of clone 1 is 297 bp,…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of the long arm of chromosome 13 (13q14.3) is however the commonest, with reported frequencies of 41-51%, 1-3 but 13q being also commonly deleted in a variety of other lymphoid and myeloid malignancies. [4][5][6][7][8][9] In the majority of cases, deletion of 13q14.3 is the sole cytogenetic abnormality 10,11 and approximately 10% of CLL patients show homozygous deletion at this locus. Consequently, the existence of a tumor suppressor gene within the deleted region at 13q14.3, involved in the pathogenesis of B cell CLL, has long been postulated.…”

Section: Introductionmentioning

confidence: 99%

Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia

et al. 2002

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Heterozygous and homozygous deletions of chromosome 13q14.3 are found in 50% of patients with B cell CLL, suggesting the presence of one or more tumour suppressor genes within the deleted region. To identify candidate genes from the region, we constructed a map of 13q14.3 using a combination of genomic and cDNA library screening. The incidence of deletions in CLL patients was 51.5% encompassing a 265 kb region of minimal deletion (RMD) telomeric to markers D13S319. Two CpG islands were identified within the RMD, the telomeric of which is fully methylated whilst the more centromeric is unmethylated. A novel transcript was identified within the RMD that represents an alternative splice version of Leu1. The nine exons of this transcript span a genomic of 436 kb with exon 1 of Leu1 being the common first exon. The remaining exons were shown to be more frequently deleted than Leu1 itself. All splice forms of this transcript were detectable by RT-PCR but Leu1 detected the most abundant message on Northern blotting. Sequence analysis failed to reveal inactivating mutations in patients with heterozygous deletion of 13q14.3, although a polymorphic T to A variant was identified within exon 1 of Leu1 in leukemic and normal controls. As no mutations have been detected for Leu1 or any other transcript so far described, we cannot exclude the existence of control elements within the RMD that may regulate expression of genes lying in this region.

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Frequent chromosome arm 13q deletion in aggressive non-Hodgkin’s lymphoma

Cited by 27 publications

References 26 publications

Proliferation-dependent expression and phosphorylation of pRB in B cell non-Hodgkin's lymphomas: dependence on RB1 copy number

Proliferation-dependent expression and phosphorylation of pRB in B cell non-Hodgkin's lymphomas: dependence on RB1 copy number

Retinoblastoma Protein Is Frequently Absent or Phosphorylated in Anaplastic Large-Cell Lymphoma

Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia

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