Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis of additional cytogenetic abnormalities detected by interphase fluorescence<b><i>in situ</i></b>hybridisation and array-based comparative genomic hybridisation

Rudenko, Hannah; Else, Monica; Dearden, Claire; Brito‐Babapulle, Vasantha; Jones, Chris; Dexter, Tim; Fenwick, Kerry; Mackay, Alan; Ashworth, Alan; Matutes, Estella; González, David; Catovsky, Daniel; Morgan, Gareth J.

doi:10.1080/10428190802345902

Cited by 13 publications

(11 citation statements)

References 40 publications

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“…In addition, an increased expression of CD38, ZAP-70, and unmutated IGHV was reported in 17p- cases, which agrees with the poor prognosis of this group of patients [31, 66, 67]. Other studies have demonstrated a significant correlation between 17p- and 4p-, 18p-, 20p-, or chromosome 8 alterations (8p- or 8q+) [30, 68]. Thus, TP53 mutation/17p- is correlated with a higher genetic complexity.…”

Section: Cytogenetic Aberrations With Known Prognostic Valuesupporting

confidence: 76%

Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We Go

Puiggros

Blanco

Espinet

2014

BioMed Research International

125

122

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Chromosomal abnormalities in chronic lymphocytic leukemia (CLL) are detected in up to 80% of patients. Among them, deletions of 11q, 13q, 17p, and trisomy 12 have a known prognostic value and play an important role in CLL pathogenesis and evolution, determining patients outcome and therapeutic strategies. Standard methods used to identify these genomic aberrations include both conventional G-banding cytogenetics (CGC) and fluorescence in situ hybridization (FISH). Although FISH analyses have been implemented as the gold standard, CGC allows the identification of chromosomal translocations and complex karyotypes, the latest associated with poor outcome. Genomic arrays have a higher resolution that allows the detection of cryptic abnormalities, although these have not been fully implemented in routine laboratories. In the last years, next generation sequencing (NGS) methods have identified a wide range of gene mutations (e.g., TP53, NOTCH1, SF3B1, and BIRC3) which have improved our knowledge about CLL development, allowing us to refine both the prognostic subgroups and better therapeutic strategies. Clonal evolution has also recently arisen as a key point in CLL, integrating cytogenetic alterations and mutations in a dynamic model that improve our understanding about its clinical course and relapse.

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Section: Cytogenetic Aberrations With Known Prognostic Valuesupporting

confidence: 76%

Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We Go

Puiggros

Blanco

Espinet

2014

BioMed Research International

125

122

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“…Previous retrospective studies based on FISH, comparative genomic hybridization (aCGH) and SNP array identified 2p gain as a recurrent alteration in CLL associated with advanced Binet stage, UM status of IGHV gene and 17p13 deletion [12,[14][15][16][17][18][19][20][21][22]24,[39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

et al. 2012

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Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P 5 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 3 10 24 ) and CD38 (P < 1 3 10 24 ) and ZAP-70 positive expression (P 5 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P 5 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P 5 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 88:24-31, 2013. V

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“…It has, therefore, been suggested that alternative therapies may be needed to manage those patients with a TP53 defective pathway, as traditional therapies such as the use of fludarabine and cyclophosphamide have been found ineffective (Catovsky et al , 2007; Grever et al , 2007). Similarly, inferior response to treatment and low rate of overall and progression‐free survival were found to be characteristics of CLL patients with a high percentage of TP53 ‐deleted cells in their peripheral blood (Rudenko et al , 2008). Finally, in a study that analyzed a series of cell cycle regulatory proteins including CDKN1A (also called p21 Waf1 ), p27 Kip2 , retinoblastoma (Rb) and cyclin D1 in relation to TP53 in CLL and its transformed disease state, Richter syndrome, it was found that the pattern of overexpression of TP53 and under‐expression of CDKN1A was significantly associated with TP53 mutations.…”

Section: Tp53 Status and Its Prognostic Value In Lymphoid Malignanciesmentioning

confidence: 99%

The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target

2009

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SummaryThe tumour suppressor TP53 (previously termed p53) mediates a pathway that is considered to be one of the most important mechanisms in the maintenance of genomic stability. The function of TP53 can be abrogated by genomic deletion, mutation, or deregulation of upstream and downstream participants in the TP53 pathway. While aberrations of TP53 are widely prevalent in non-haematological malignancies (over 60%), they are present in much lower frequency in haematological malignancies (<20%). Nevertheless, in those cases where TP53 function or expression is aberrant, correlation with inferior clinical outcome (such as overall survival and progression or transformation) has generally been strong. In this review, we focus our discussion on the relationship between TP53 and lymphoid malignancies as defined by the World Health Organization. Specifically, we examine the prevalence of TP53 aberrations and their prognostic significance in various types of lymphoid cancer. Next, we discuss the various mechanisms of TP53 inactivation. Finally, we summarize progress in the use of recent therapeutic modalities that target TP53.

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Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis of additional cytogenetic abnormalities detected by interphase fluorescencein situhybridisation and array-based comparative genomic hybridisation

Cited by 13 publications

References 40 publications

Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We Go

Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We Go

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target

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