p53 Mutations in B-Cell Chronic Lymphocytic Leukemia

Aims. Chronic lymphocytic leukemia (CLL) is the most common adult leukemia with a very heterogeneous course. Progress in molecular genetic characterization of CLL has confirmed the prognostic role of unbalanced chromosomal abnormalities currently defined by molecular cytogenetic methods: conventional karyotyping and FISH. However, a significant percentage of genomic abnormalities escapes routine investigation due to the limitations of these methods. It is presently clear that some of these aberrations have impact on prognosis and disease progression. Methods. We examined copy number changes in the tumor genomes of 50 CLL patients using bacterial artificial chromosome (BAC) and/or oligonucleotide array platforms. We compared the results of arrayCGH with those obtained by FISH and conventional cytogenetics and evaluated their clinical importance. Results. A total of 111 copy number changes were detected in 43 patients (86%) with clonal abnormalities present in at least 23% of the cells. Moreover, 14 patients (28%) were found to have 39 genomic changes that had not been detected by standard cytogenetic and/or FISH analyses. These included possibly prognostically important recurrent 2p and 8q24 gains. The most frequent unbalanced changes involved chromosomes 18, 7, 3, 9 and 17. We also determined the minimal deleted region on chromosome 6q in 7 cases by chromosome 6/7 specific array. Conclusions. The results showed that a subset of potentially significant genomic aberrations in CLL is being missed by the current routine techniques. Further, we clearly demonstrated the robustness, high sensitivity and specificity of the arrayCGH analysis as well as its potential for use in routine screening of CLL.

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“…26,27 ), miR-15a/16-1 and RB1 genes at the 13q14 region [28][29][30] , TP53 gene at 17p13 (ref. 31,32 ) and trisomy 12 / gain of 12q (ref. 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…5,15,16,19,32,36 and 50) with 6q loss detected by FISH or arrayCGH were successfully subjected to 32K tiling path chromosome 6 arrayCGH to more precisely define the smallest commonly deleted region (SCDR). We confirmed that the SCDR included 6q21q32 comprising a 1.4 Mb region (Figure 2).…”

Section: Loss Of 6q and Determination Of The Smallest Commonly Deletementioning

confidence: 99%

Array-based karyotyping in chronic lymphocytic leukemia (CLL) detects new unbalanced abnormalities that escape conventional cytogenetics and CLL FISH panel

Urbánková¹,

Papajík²,

Plachy³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…The p53 protein is involved in cell apoptosis, so dysregulation of the p53 gene leads to prolonged cell survival. Therefore, deletions or mutations are associated with MDR independent drug resistance, advanced stage disease, a significantly worse prognosis (median survival 32 months) and an excess of prolymphocytes (Gaidano et al ., 1991; El Rouby et al ., 1992; Fenaux et al ., 1992; El Rouby et al ., 1993; Gandini et al ., 1994; Wattel et al ., 1994; Dohner et al ., 1995; Amiel et al ., 1997; Lens et al ., 1997; Dohner et al ., 2000). Combined genetic and molecular studies show that structural abnormalities of 17p are often associated with molecular mutations of the other p53 allele.…”

Section: Chromosome 17mentioning

confidence: 99%

Molecular abnormalities in B-cell chronic lymphocytic leukaemia

Fegan¹

2001

Clinical &Amp; Laboratory Haematology

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Chronic lymphocytic leukaemia is the commonest adult leukaemia, however the pathogenesis is largely unknown. Since the 1980s specific chromosomal abnormalities have been identified, of which the commonest are deletions of chromosomes 6q, 11q23, 13q14 and 17q13 and trisomy 12. The search for the responsible oncogenes at these sites has proved to be extremely frustrating. There are many oncogenes at 11q23 but the exact gene(s) responsible have yet to be identified. Germline abnormalities of the ATM gene occur in about 18% of patients compared to a normal population carriage of 0.5% but not all studies agree that ATM is the gene responsible. Unfortunately, despite the identification of various minimally deleted regions and the full sequencing of 13q14 no oncogenes have been identified. All original studies suggested the presence of a autosomally recessive tumour suppressor gene at this site but more recent studies suggest this may not be the case and the pathogenesis is more complex than first thought. Similarly, no genes have been identified at 6q or on chromosome 12. We know that the p53 tumour suppressor gene at 17p13 is an important prognostic indicator but it occurs in a minority of patients (about 15%), usually in patients with advanced disease, and therefore probably is not of aetiological importance.

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A unique spectrum of p53 mutations in B‐cell chronic lymphocytic leukemia distinct from that of other lymphoid malignancies

Newcomb

Rouby

Thomas

1995

Molecular Carcinogenesis

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The spectrum and pattern of p53 mutations detected in 42 cases of B-cell chronic lymphocytic leukemia (B-CLL) were analyzed, and several interesting features were noted. Codon 209 in the p53 gene may be a new hot-spot for p53 mutation in B-CLL disease. Four of the 42 (10%) reported B-CLL p53 mutations occurred at codon 209 versus none in 214 cases of other lymphoid malignancies screened for p53 mutations (P = 0.0006). Transversion mutations predominated at codon 273 rather than the transition mutations that are known to occur at this CpG site. Four of six (67%) B-CLL cases had transversions at codon 273 compared with two of 17 (12%) of all other lymphoid tumors examined (P = 0.02). In addition, over 65% of the p53 mutations detected in B-CLL showed a strand bias for p53 mutations on the untranscribed DNA strand. This feature of DNA strand bias is notable in cancers of the lung, esophagus, and head and neck, which may result from high exposure to carcinogens. This spectrum of p53 mutations in B-CLL together with the high frequency of transversion mutations and DNA strand bias may implicate environmental carcinogens associated with p53 gene damage in some B-CLL patients.

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p53 Mutations in B-Cell Chronic Lymphocytic Leukemia

Cited by 7 publications

References 9 publications

Array-based karyotyping in chronic lymphocytic leukemia (CLL) detects new unbalanced abnormalities that escape conventional cytogenetics and CLL FISH panel

Array-based karyotyping in chronic lymphocytic leukemia (CLL) detects new unbalanced abnormalities that escape conventional cytogenetics and CLL FISH panel

Molecular abnormalities in B-cell chronic lymphocytic leukaemia

A unique spectrum of p53 mutations in B‐cell chronic lymphocytic leukemia distinct from that of other lymphoid malignancies

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