Molecular Subsets of Mantle Cell Lymphoma Defined by the <i>IGHV</i> Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features

Navarro, Alba; Clot, Guillem; Royo, Cristina; Jares, Pedro; Hadzidimitriou, Anastasia; Agathangelidis, Andreas; Bikos, Vasilis; Darzentas, Nikos; Papadaki, Theodora; Salaverría, Itziar; Pinyol, Magda; Puig, Xavier; Palomero, Jara; Vegliante, Maria Carmela; Amador, Virgina; Martínez‐Trillos, Alejandra; Štefančíková, Lenka; Wiestner, Adrian; Wilson, Wyndham H.; Pott, Christiane; Calasanz, Marı́a José; Trim, Nicola; Erber, Wendy N.; Sander, Birgitta; Ott, German; Rosenwald, Andreas; Colomer, Dolors; Giné, Eva; Siebert, Reiner; López‐Guillermo, Armando; Stamatopoulos, Kostas; Beà, Sı́lvia; Campo, Elı́as

doi:10.1158/0008-5472.can-12-1615

Cited by 231 publications

(196 citation statements)

References 43 publications

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“…Such an aggressive feature relates to a high number of recurrent secondary chromosomal aberrations and different molecular mechanisms causing gene deregulation. The transcription factor SOX11 (SRY [sex determining region Y]-box 11) has been found aberrantly expressed in most aggressive MCL patients, being considered a reliable biomarker in this pathology [2]. This gene is commonly associated with embryonic neurogenesis and tissue remodeling, and is not expressed under normal conditions in any adult normal tissue [3].…”

Section: Introductionmentioning

confidence: 99%

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

et al. 2016

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Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.

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Section: Introductionmentioning

confidence: 99%

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

et al. 2016

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“…Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6,7). This favorable behavior has been associated with IGHV-mutated (8,9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.…”

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confidence: 99%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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361

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Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6, 7). This favorable behavior has been associated with IGHV-mutated (8, 9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

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“…Иницијални догађај се одиграва у пре-B ћелијама коштане сржи и праћен је кретањем у два правца молекуларних измена 12,13 . Ове ћелије су генетски стабилне, СОX11 експресија је негативна или ниска и тумор има тенденцију дисеминације у периферну крв и слезину.…”

Section: уводunclassified

Primary mantle cell lymphoma of tonsil: Case report

Knežević¹

2017

Opsta med

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СажетакУвод. Mantle cell lymphoma је редак подтип B-ћелијског лимфома. Обухвата 4%-6% свих нехочкинских лимфома (NHL). Чешћи је код старијих мушкараца у односу на друге подтипове лимфома; средња старост оболелих је 65 година. Примарни тонзиларни лимфом чини мање од 1% малигнитета главе и врата.Циљ рада. Указати на значај ране и тачне дијагнозе и благовременог лечења малигних болести.Метод. Mantle cell лимфом. Мултислајсна компјутеризована томографија (MSCT) врата, грудног коша и горњег абдомена: лева тонзила је промера 28 mm x 32 mm, у дужини 36 mm, лобулараних контура, хетерогене структуре, асиметрично сужава попречни лумен дисајног стуба на 7 mm. Патолошки увећани лимфни нодуси промера 10 mm до 15 mm субмандибуларно и лево парајугуларно. У плућном паренхиму нема патолошких промена. Нема увећаних лимфних нодуса у абдомену и ретроперитонеалном простору. Абдоминални органи у физиолошким границама. Биопсија коштане сржи: нема знакова лимфопролиферативног обољења. Хемалошки конзилијум: NHL Mantle cell lymphoma CS IIAE. Хемотерапија по протоколу: циклофосфамид, доксорубицин, винкристин и преднизолон (CHOP), ординирано шест циклуса. Лева тонзила се после другог циклуса хемотерапије смањила а пацијенту је било олакшано дисање и узимање хране; терапију примио до краја, јавља се на редовне контроле. Kључне речи:примарна здравствена заштита, дијагноза, генетика, општа медицина, лимфом.

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Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features

Cited by 231 publications

References 43 publications

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Primary mantle cell lymphoma of tonsil: Case report

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