On the way towards a ‘CLL prognostic index’: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort

Cortese, Diego; Sutton, Lesley Ann; Cahill, Nicola; Smedby, Karin E.; Geisler, Christian H.; Gunnarsson, R; Juliusson, Gunnar; Mansouri, Larry; Rosenquist, Richard

doi:10.1038/leu.2013.333

Cited by 74 publications

(81 citation statements)

References 18 publications

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“…[32][33][34][35][36][37] That said, 32% (176/557) of cases analyzed concerned M-CLL, subset #2 (n=98) (mixed SHM profile) and subset #4 (n=78), and the complete absence of MYD88 mutations amongst these cases implies that mutations within MYD88 are absent from M-CLL assigned to major stereotyped subsets.…”

Section: Myd88 Mutationsmentioning

confidence: 99%

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

et al. 2016

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We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

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Section: Myd88 Mutationsmentioning

confidence: 99%

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

et al. 2016

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“…This case displayed a prominently nodular growth pattern and cytology that appeared much more consistent with a diagnosis of nodal marginal zone lymphoma with plasmacytic differentiation. MYD88 L265P has also been described in a small percentage of chronic lymphocytic leukemia/small lymphocytic lymphoma, 15,21,25,26,40,41 emphasizing that MYD88 mutation status alone clearly cannot be used to define lymphoplasmacytic lymphoma. The MYD88 L265P abnormality has also been reported in a small percentage of cases diagnosed as extranodal marginal zone lymphoma, 19,20 although distinction between extranodal marginal zone lymphoma with plasmacytic differentiation and an extranodal lymphoplasmacytic lymphoma may be somewhat arbitrary, and the prior studies included insufficient clinical or histologic information to completely exclude extranodal lymphoplasmacytic lymphoma.…”

Section: F Hamadeh Et Almentioning

confidence: 99%

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

et al. 2015

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The diagnosis of lymphoplasmacytic lymphoma is often challenging, especially in extramedullary tissues where the differential diagnosis includes nodal marginal zone lymphoma, splenic marginal zone lymphoma, or other small B-cell neoplasms with plasmacytic differentiation. The MYD88 L265P mutation has been recently identified in 490% of bone-marrow-based lymphoplasmacytic lymphoma, but the incidence of this abnormality and corresponding morphologic correlates in nodal lymphoplasmacytic lymphoma have not been established. We analyzed 87 cases of extramedullary lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, unclassifiable splenic B-cell lymphomas, nodal marginal zone lymphoma with plasmacytic differentiation, and chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation for MYD88 L265P. Eighteen cases (21%) were positive, including 9/9 (100%) lymphoplasmacytic lymphomas with classic histologic features, 5/12 (42%) cases that met 2008 WHO criteria for lymphoplasmacytic lymphoma but with atypical morphologic features, 3/15 (20%) cases initially considered nodal marginal zone lymphoma with plasmacytic differentiation, and 1/6 (17%) unclassifiable splenic B-cell lymphomas. The presence of MYD88 L265P was associated with IgM paraprotein (Po0.001) and a trend for bone marrow involvement (P ¼ 0.09). Each of 44 splenectomy-defined splenic marginal zone lymphomas (19 with plasmacytic differentiation) and the chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation were negative for the mutation. Morphologic re-review with knowledge of MYD88 mutation status and all available clinical features suggested all MYD88 mutated cases were consistent with lymphoplasmacytic lymphoma (either classic or variant histology), except for one case which remained most consistent with nodal marginal zone lymphoma with plasmacytic differentiation. These results demonstrate the importance of MYD88 mutational analysis in better defining lymphoplasmacytic lymphoma as a relatively monomorphic small B-cell lymphoma with plasmacytic differentiation that may show total nodal architectural effacement and follicular colonization. Cases previously considered lymphoplasmacytic lymphoma that are more polymorphous and are often associated with histiocytes should no longer be included in the lymphoplasmacytic lymphoma category. Clinicopathologic review suggests that although MYD88 mutated non-lymphoplasmacytic lymphoma small B-cell neoplasms exist, they are very uncommon.

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“…In CLL, besides TP53 and ATM mutations, which are both known to confer poor prognosis, recent high-throughput NGS studies have revealed recurrent mutations within NOTCH1, SF3B1, and BIRC3 for example, that were reported to be associated with poor clinical outcome with higher frequencies in relapsing/treatment-refractory CLL and in Richter's syndrome. 48,[69][70][71][72][73][74][75][76][77][78][79] More recent studies have also identified additional gene mutations that may confer a worse outcome in CLL, e.g. NKFBIE, EGR2, and RPS15, although they have been studied less.…”

Section: Genes With Prognostic Potentialmentioning

confidence: 99%

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

Rosenquist

Rosenwald

et al. 2016

Haematologica

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On the way towards a ‘CLL prognostic index’: focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort

Cited by 74 publications

References 18 publications

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

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