ATM and TP53 mutations show mutual exclusivity but distinct clinical impact in mantle cell lymphoma patients

Marečková, Andrea; Malčíková, Jitka; Tom, Nikola; Pál, Karol; Radová, Lenka; Schwartz, David A.; Janíková, Andrea; Moulis, Mojmír; Šmardová, Jana; Křen, Leoš; Mayer, Jiřı́; Trbušek, Martin

doi:10.1080/10428194.2018.1542144

Cited by 24 publications

(27 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With this methodology, 100% sensitivity was reached, but with an overall lower accuracy of 79%. It is known that patients with MCL are molecularly diverse, 31 with TP53 aberrations being one of the strongest risk factors. 3 Thus, IHC analysis of p53 can serve multiple purposes.…”

Section: Discussionmentioning

confidence: 99%

p53 is associated with high‐risk and pinpointsTP53missense mutations in mantle cell lymphoma

et al. 2020

View full text Add to dashboard Cite

Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapybased treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients with TP53 missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 and TP53 status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression and TP53 mutations on survival (hazard ratio of 3Á1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.

show abstract

Section: Discussionmentioning

confidence: 99%

p53 is associated with high‐risk and pinpointsTP53missense mutations in mantle cell lymphoma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The ATM gene encodes a 370-kDa ATM protein, which is a member of the PI-3 protein kinase family and is essential for DNA processing, the cell cycle and telomere length regulation [ 81 ]. Notably, 11q deletion and/or ATM mutation, in cooperation with cyclin D1, consistently represent the most frequent oncogenic event in MCL [ 82 ]. This response is closely related to the activation (stabilization) of TP53 mediated by ATM.…”

Section: Atm Defectsmentioning

confidence: 99%

“…Indeed, in MCL, 26% of cases contain TP53 mutation/deletion, 56% contain ATM alteration and 10% contain both genetic changes [ 35 ]. Mareckova and colleagues revealed the mutual exclusivity of ATM and TP53 mutations in MCL [ 82 ]. Due to limited information on the clinical impact of ATM mutations on MCL and although ATM has been repeatedly proven to be the most commonly mutated gene, followed by CDKN2A and TP53, the latest publications consistently show no statistically significant difference in the OS of patients with wild-type vs. mutated ATM, which is in sharp contrast to TP53 defects [ 3 , 83 ].…”

Section: Atm Defectsmentioning

confidence: 99%

Progress in molecular feature of smoldering mantle cell lymphoma

Jiang

Desai

2021

Exp Hematol Oncol

View full text Add to dashboard Cite

Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid tumors. However, it sometimes displays indolent behavior in patients and might not necessitate treatment at diagnosis; this has been described as “smoldering MCL” (SMCL). There are significant differences in the diagnosis, prognosis, molecular mechanisms and treatments of indolent MCL and classical MCL. In this review, we discuss the progress in understanding the molecular mechanism of indolent MCL to provide insights into the genomic nature of this entity. Reported findings of molecular features of indolent MCL include a low Ki-67 index, CD200 positivity, a low frequency of mutations in TP53, a lack of SOX11, normal arrangement and expression of MYC, IGHV mutations, differences from classical MCL by L-MCL16 assays and MCL35 assays, an unmutated P16 status, few defects in ATM, no NOTCH1/2 mutation, Amp 11q gene mutation, no chr9 deletion, microRNA upregulation/downregulation, and low expression of several genes that have been valued in recent years (SPEN, SMARCA4, RANBP2, KMT2C, NSD2, CARD11, FBXW7, BIRC3, KMT2D, CELSR3, TRAF2, MAP3K14, HNRNPH1, Del 9p and/or Del 9q, SP140 and PCDH10). Based on the above molecular characteristics, we may distinguish indolent MCL from classical MCL. If so, indolent MCL will not be overtreated, whereas the treatment of classical MCL will not be delayed.

show abstract

“…For example, the mutual exclusivity of ATM and TP53 mutations in mantle cell lymphoma patients was associated with significantly reduced overall survival. 38 Thus, it is necessary to comprehensively identify and analyze co‐occurring or mutually exclusive events of mutations to enhance the understanding of tumorigenesis and improve the treatment strategies for precision medicine.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic heterogeneity of driver gene mutations reveals novel mutual exclusivity and improves exploration of functional associations

et al. 2021

View full text Add to dashboard Cite

show abstract

ATM and TP53 mutations show mutual exclusivity but distinct clinical impact in mantle cell lymphoma patients

Cited by 24 publications

References 57 publications

p53 is associated with high‐risk and pinpointsTP53missense mutations in mantle cell lymphoma

p53 is associated with high‐risk and pinpointsTP53missense mutations in mantle cell lymphoma

Progress in molecular feature of smoldering mantle cell lymphoma

Transcriptomic heterogeneity of driver gene mutations reveals novel mutual exclusivity and improves exploration of functional associations

Contact Info

Product

Resources

About