Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma

Grønbæk, Kirsten; Brown, Peter de Nully; Møller, Michael; Nedergaard, Trine; Ralfkiær, Elisabeth; Möller, Peter; Zeuthen, Jesper; Guldberg, Per

doi:10.1038/sj.leu.2401901

Cited by 68 publications

(15 citation statements)

References 66 publications

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“…The 3 patients with the shortest survival times also harbored deletions of the INK4a/ARF locus, which is a strong negative prognostic factor in DLBCL. 29 One sample taken at relapse showed concomitant mutation of ATM, mutation of TP53, and deletion of ARF, and this patient survived only 1 month after biopsy. Although the size of the sample is small, these data suggest that the low median survival time in patients with ATM-mutated DLBCLs is at least in part due to the relatively high frequency of concurrent ARF deletions in this group, and that ATM mutation in itself may not be associated with a particularly poor outcome.…”

Section: Clinical Featuresmentioning

confidence: 89%

“…Mutations in the TP53 gene (exons 2-11) and deletions of the INK4a/ARF locus (exons 1␤ and 2) had been previously determined in most of the DLBCL and FL cases. 29 The remaining cases were analyzed as described. 29,30 The entire coding sequence and all splice sites of the ATM gene (exons 4-65) 31 were scanned for mutations using a combination of polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE).…”

Section: Dna Isolation Mutation Analysis and Direct Sequencingmentioning

confidence: 99%

“…29 The remaining cases were analyzed as described. 29,30 The entire coding sequence and all splice sites of the ATM gene (exons 4-65) 31 were scanned for mutations using a combination of polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE). The melting characteristics of each exonic region were calculated by means of the MELT87 computer algorithm, 32 and appropriate GC-and AT-clamps were included in the PCR primers to modulate the melting properties into a 2-domain profile.…”

Section: Dna Isolation Mutation Analysis and Direct Sequencingmentioning

confidence: 99%

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ATM mutations are associated with inactivation of theARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

Grønbæk

Worm²,

Ralfkiær³

et al. 2002

Blood

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The ATM serine-threonine kinase plays a central role in the cellular response to DNA damage. Germ-line mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with predisposition to lymphoma and acute leukemia. Moreover, somatic ATM mutations have been identified in T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. In this study, the entire ATM coding sequence was examined in genomic DNA from 120 lymphoid neoplasms. Novel mutations and mutations implicated in cancer and/or A-T were found in 9 of 45 diffuse large B-cell lymphomas (DLBCLs), 2 of 24 follicular lymphomas, and 1 of 27 adult acute lymphoblastic leukemias, whereas no such mutations were detected among 24 peripheral T-cell lymphomas. The mutational spectrum consisted of 2 nonsense mutations, 1 mutation affecting RNA splicing, and 10 missense variants. Most of these mutations were associated with loss or mutation of the paired ATM allele, consistent with biallelic inactivation of ATM. Of the 9 DLBCLs with ATM mutations, 7 also carried TP53 mutations and/or deletions of the INK4a/ARF locus (P ‫؍‬ .003). The ATM 735C>T substitution previously considered a rare normal variant was found to be 5.6 times more frequent in individuals with DLBCL than in random individuals (P ‫؍‬ .026), suggesting that it may predispose to B-cell lymphoma. Our data suggest that ATM mutations contribute to the development of DLBCL, and that ATM and the ARFp53 tumor suppressor pathway may cooperate in the pathogenesis of this malignancy.

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Section: Clinical Featuresmentioning

confidence: 89%

Section: Dna Isolation Mutation Analysis and Direct Sequencingmentioning

confidence: 99%

Section: Dna Isolation Mutation Analysis and Direct Sequencingmentioning

confidence: 99%

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ATM mutations are associated with inactivation of theARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

Grønbæk

Worm²,

Ralfkiær³

et al. 2002

Blood

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“…4,38,50,51 However, it has been suggested that concomitant inactivation of the RB1 and p53 pathways leads to additional growth advantage and aggressiveness in NHL. 52,53 Aberrations in the RB1 pathway leading to loss of G 1 restriction point control are traditionally thought to be mutually exclusive, eg tumours with inactivating RB1 mutations in general show no elevation in cyclin D1 expression. 54,55 Twelve of the 13 MCL cases in this study (excluding case 67/92), and SLL case 339/89 showed (over)expression of cyclin D1 caused by a t (11;14) translocation (all of the others were negative; unpublished results).…”

Section: Discussionmentioning

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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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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“…61 The identification of prognostic markers in DLCL has clinical implications. Patients with DLCL with low expression of E2F-1 or p16…”

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confidence: 99%

Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A

et al. 2000

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In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P ‫؍‬ 0.006). Cyclin D3 overexpression and p16 INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P ‫؍‬ 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk ‫؍‬ 6.9; P ‫؍‬ 0.0037) and p16 INK4Ainactivation (relative risk ‫؍‬ 3.3; P ‫؍‬ 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16 INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma. Leukemia (2000) 14, 898-904.

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Concurrent disruption of p16INK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin's lymphoma

Cited by 68 publications

References 66 publications

ATM mutations are associated with inactivation of theARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

ATM mutations are associated with inactivation of theARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

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

Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A

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