Elsevier

Annals of Diagnostic Pathology

Volume 41, August 2019, Pages 38-42
Annals of Diagnostic Pathology

Original Contribution
TP53 mutations are common in mantle cell lymphoma, including the indolent leukemic non-nodal variant

https://doi.org/10.1016/j.anndiagpath.2019.05.004Get rights and content

Highlights

  • TP53 mutations are common in both the classical and leukemic non-nodal variant MCL.

  • TP53 mutations may be clonal or subclonal in MCL.

  • Subclonal TP53 mutations were more common in L-MCL.

  • In L-MCL it may serve as a useful biomarker for early detection of clonal expansion.

Abstract

Introduction

Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm, but clinically indolent subtypes are also recognized. Data on the utility of mutation profiling in the context of routine workup and its role in risk-stratification of MCL patients are limited. In this study, we describe the mutational landscape and clinicopathologic correlates of a series of MCL cases at a single-institution setting.

Methods

Samples from 26 patients with MCL were evaluated by NGS using DNA extracted from peripheral blood (PB) or bone marrow (BM). Evaluation of extent of PB or BM involvement was performed using flow cytometry immunophenotyping.

Results

The study group included 17 (65%) men and 9 (35%) women with a median age of 65 years (range, 50–94). Twenty-one (81%) patients had nodal MCL (N-MCL) and 5 (19%) had the “leukemic variant” (L-MCL). Mutated genesincluded TP53 (35%), ATM (27%), CARD11 (10%); and FBXW7, NOTCH1, SPEN, BIRC3 (~5% each). Most mutations were clonal in nature. Ten unique TP53 mutations were identified in 9 samples, including 3 L-MCL cases. There was no difference in the frequency of TP53 mutations between L-MCL and N-MCL groups (p = 0.3), but TP53 mutations were subclonal in 2/3 L-MCL cases. Identification of clonal TP53 alterations in L-MCL patients prompted initiation of therapy despite low tumor burden.

Conclusions

TP53 is commonly mutated in MCL. TP53 mutations may be clonal or subclonal. Seemingly indolent L-MCL may harbor subclonal TP53 mutations which may serve as a useful biomarker for prognostication, therapeutic planning, follow-up monitoring, and early detection of clonal expansion.

Introduction

Mantle cell lymphoma (MCL) has been long considered an aggressive mature B-cell lymphoma, derived from CD5 positive naïve B cells, with most patients ultimately relapsing and succumbing to disease despite intensive therapy [1,2]. MCL is caused by juxtaposition of CCND1 located at chromosome 11q13 with the promoter region of IGH at chromosome 14q32 resulting in overexpression of cyclin D1. The CCND1-IGH translocation is a disease defining genetic abnormality and is believed to be the primary oncogenic event in MCL [3], although rare cases of chronic lymphocytic leukemia with acquisition of CCND1-IGH have been described [4]. This translocation is detected in >90% of MCL cases and is usually detected by conventional karyotyping or fluorescence in situ hybridization [5,6]. However, studies using conventional cytogenetics, comparative genomic hybridization and other methods have shown the presence of many other chromosomal alterations in MCL [[7], [8], [9]]. In this regard, MCL is considered to be a genetically heterogeneous mature B cell neoplasm with many secondary chromosomal changes, likely resulting primarily from marked chromosomal instability [3,10,11].

More recently, a subset of MCL cases has been identified that shows mostly an indolent clinical course even without therapeutic intervention [7,12,13]. The 2016 update of the World Health Organization (WHO) classification of lymphoid neoplasms recognizes two indolent variants of mantle cell lymphoma: in situ mantle cell neoplasia and so-called non-nodal leukemic variant of mantle cell lymphoma (L-MCL) [5]. L-MCL shows a number of differences compared with nodal mantle cell lymphoma including frequently hypermutated immunoglobulin heavy chain variable region (IGHV), a less complex genome, and absence of SOX11 expression [12,14,15]. L-MCL frequently expresses surface CD200, which is usually absent in conventional nodal mantle cell lymphoma (N-MCL) [16]. The presence of secondary molecular changes, including alterations in CDK4, INK4a, TP53, RB1 and ATM, are significantly more common in the N-MCL compared with L-MCL [17,18]. While MCL is generally considered to be incurable and is associated with poor prognosis in most patients, precise prediction of clinical outcome and prognosis of MCL patients is challenging due to disease heterogeneity [19,20].

TP53 mutations occur in approximately 5–11% of MCL cases and are associated with an unfavorable clinical outcome and poor response to conventional chemotherapy regimens [21]. Earlier studies have shown that MCL has a unique mutational profile with prognostic implications [22,23]; however, data on the utility of mutation profiling using next-generation sequencing (NGS) in the context of routine clinical workup and its role in risk-stratification of MCL patients, are limited. In this study, we describe the mutational landscape and clinicopathologic correlates of a series of MCL cases at a single-institution setting.

Section snippets

Study group

This study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center and was carried out in accord with the Declaration of Helsinki. We performed an electronic query of our departmental archives for patients diagnosed with MCL –with available next generation sequencing data. A total of 26 cases were identified. Clinical, laboratory and imaging data were obtained from electronic medical records.

Histologic evaluation

The diagnosis of MCL was established and cases were further

Clinical and laboratory findings

A total of 26 MCL patients were included in this study: 21 (81%) had N-MCL and 5 (19%) had L-MCL. All the patients had BM and/or PB involvement. There were 17 men (65%, 15 N-MCL and 2 L-MCL) and 9 women (35%, 6 N-MCL and 3 L-MCL). The median age for the entire patient cohort was 65 years (range, 50–94) at initial diagnosis. The median age at the time of diagnosis was 64 years (range, 50–94) and 71 years (range, 53–86) for N-MCL and L-MCL, respectively. For the entire cohort, the median absolute

Discussion

Mantle cell lymphoma is considered an aggressive mature B-cell lymphoma with relatively short overall survival (OS) of <3 years and a high risk of relapse in most patients [3,25,26]. Patients with MCL are typically treated with intensive chemoimmunotherapy regimens at the time of diagnosis [27,28]. However, indolent forms of MCL have been identified and recently the WHO classification officially recognized two indolent subtypes of MCL, the non-nodal leukemic variant [5,6] and the in situ

Acknowledgements

All authors have contributed to this work. Their contribution is as follows:

Conception and design: AS, SL, JDK.

Provision of study materials or patients: CYO, RKS, CCY, SH, LJM, SL.

Collection and assembly of data: AS, CYO, KPP, ZZ, MJR, JKD, SL.

Data analysis and interpretation: AS, KPP, RKS, CCY, MJR, RL, SL.

Manuscript writing: AS, LJM, SL.

Final approval of manuscript: all authors.

Compliance with ethical standards

Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors.

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

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