Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

Marina Parry; Matthew J.J. Rose-Zerilli; Viktor Ljungström; Jane Gibson; Jun Wang; Renata Walewska; Helen Parker; Anton Parker; Zadie Davis; Anne Gardiner; Neil McIver-Brown; Christina Kalpadakis; Aliki Xochelli; Achilles Anagnostopoulos; Claudia Fazi; D. Gonzalez de Castro; Claire Dearden; Guy Pratt; Richard Rosenquist; Margaret Ashton-Key; Francesco Forconi; Andrew Collins; Paolo Ghia; Estella Matutes; Gerassimos Pangalis; Kostas Stamatopoulos; David Oscier; Jonathan C. Strefford

doi:10.1158/1078-0432.CCR-14-2759

Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

Marina Parry, Matthew J.J. Rose-Zerilli, Viktor Ljungström, Jane Gibson, Jun Wang, Renata Walewska, Helen Parker, Anton Parker, Zadie Davis, Anne Gardiner, Neil McIver-Brown, Christina Kalpadakis, Aliki Xochelli, Achilles Anagnostopoulos, Claudia Fazi, D. Gonzalez de Castro, Claire Dearden, Guy Pratt, Richard Rosenquist, Margaret Ashton-KeyFrancesco Forconi, Andrew Collins, Paolo Ghia, Estella Matutes, Gerassimos Pangalis, Kostas Stamatopoulos, David Oscier, Jonathan C. Strefford

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

122 Citations (Scopus)

Abstract

Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.

Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.

Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).

Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

Original language	English
Pages (from-to)	4174-4183
Number of pages	10
Journal	Clinical Cancer Research
Volume	21
Issue number	18
DOIs	https://doi.org/10.1158/1078-0432.CCR-14-2759
Publication status	Published - Sept 2015

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Parry, M., Rose-Zerilli, M. J. J., Ljungström, V., Gibson, J., Wang, J., Walewska, R., Parker, H., Parker, A., Davis, Z., Gardiner, A., McIver-Brown, N., Kalpadakis, C., Xochelli, A., Anagnostopoulos, A., Fazi, C., Gonzalez de Castro, D., Dearden, C., Pratt, G., Rosenquist, R., ... Strefford, J. C. (2015). Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing. Clinical Cancer Research, 21(18), 4174-4183. https://doi.org/10.1158/1078-0432.CCR-14-2759

@article{1dde82f780e3476c9af38480f601d95e,

title = "Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing",

abstract = "Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. ",

author = "Marina Parry and Rose-Zerilli, {Matthew J.J.} and Viktor Ljungstr{\"o}m and Jane Gibson and Jun Wang and Renata Walewska and Helen Parker and Anton Parker and Zadie Davis and Anne Gardiner and Neil McIver-Brown and Christina Kalpadakis and Aliki Xochelli and Achilles Anagnostopoulos and Claudia Fazi and {Gonzalez de Castro}, D. and Claire Dearden and Guy Pratt and Richard Rosenquist and Margaret Ashton-Key and Francesco Forconi and Andrew Collins and Paolo Ghia and Estella Matutes and Gerassimos Pangalis and Kostas Stamatopoulos and David Oscier and Strefford, {Jonathan C.}",

year = "2015",

month = sep,

doi = "10.1158/1078-0432.CCR-14-2759",

language = "English",

volume = "21",

pages = "4174--4183",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "18",

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Parry, M, Rose-Zerilli, MJJ, Ljungström, V, Gibson, J, Wang, J, Walewska, R, Parker, H, Parker, A, Davis, Z, Gardiner, A, McIver-Brown, N, Kalpadakis, C, Xochelli, A, Anagnostopoulos, A, Fazi, C, Gonzalez de Castro, D, Dearden, C, Pratt, G, Rosenquist, R, Ashton-Key, M, Forconi, F, Collins, A, Ghia, P, Matutes, E, Pangalis, G, Stamatopoulos, K, Oscier, D & Strefford, JC 2015, 'Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing', Clinical Cancer Research, vol. 21, no. 18, pp. 4174-4183. https://doi.org/10.1158/1078-0432.CCR-14-2759

TY - JOUR

T1 - Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

AU - Parry, Marina

AU - Rose-Zerilli, Matthew J.J.

AU - Ljungström, Viktor

AU - Gibson, Jane

AU - Wang, Jun

AU - Walewska, Renata

AU - Parker, Helen

AU - Parker, Anton

AU - Davis, Zadie

AU - Gardiner, Anne

AU - McIver-Brown, Neil

AU - Kalpadakis, Christina

AU - Xochelli, Aliki

AU - Anagnostopoulos, Achilles

AU - Fazi, Claudia

AU - Gonzalez de Castro, D.

AU - Dearden, Claire

AU - Pratt, Guy

AU - Rosenquist, Richard

AU - Ashton-Key, Margaret

AU - Forconi, Francesco

AU - Collins, Andrew

AU - Ghia, Paolo

AU - Matutes, Estella

AU - Pangalis, Gerassimos

AU - Stamatopoulos, Kostas

AU - Oscier, David

AU - Strefford, Jonathan C.

PY - 2015/9

Y1 - 2015/9

N2 - Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

AB - Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

U2 - 10.1158/1078-0432.CCR-14-2759

DO - 10.1158/1078-0432.CCR-14-2759

M3 - Article

SN - 1078-0432

VL - 21

SP - 4174

EP - 4183

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 18

ER -

Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

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