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Sutton, Lesley Ann
Alternative names
Publications (10 of 30) Show all publications
Mundt, F., Merrien, M., Nygren, L., Sutton, L. A., Christensson, B., Wahlin, B. E., . . . Wasik, A. M. (2019). Expression of GNAZ, encoding the G alpha(z) protein, predicts survival in mantle cell lymphoma. British Journal of Haematology, 185(4), 708-712
Open this publication in new window or tab >>Expression of GNAZ, encoding the G alpha(z) protein, predicts survival in mantle cell lymphoma
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2019 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 185, no 4, p. 708-712Article in journal (Refereed) Published
Abstract [en]

Mantle cell lymphoma (MCL), a malignancy of B-lymphocytes, has a poor prognosis. It is thus necessary to improve the understanding of the pathobiology of MCL and identify factors contributing to its aggressiveness. Our studies, based on Affymetrix data from 17 MCL biopsies, real-time quantitative polymerase chain reaction data from 18 sorted primary MCL cells and 108 MCL biopsies compared to non-malignant tissue, reveals that GNAZ expression predicts poor clinical outcome of MCL patients (Cox regression, P = 0 center dot 014) and lymphocytosis (Mann-Whitney, P = 0 center dot 011). We show that GNAZ translates to G alpha(z) protein - a signalling molecule within the G-protein coupled receptor network. Our findings suggest that GNAZ/G alpha(z) contribute to the MCL pathobiology.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
mantle cell lymphoma, G-protein coupled receptors, G-proteins, prognosis, lymphocytosis
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-383841 (URN)10.1111/bjh.15810 (DOI)000467276100010 ()30788840 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved
Baliakas, P., Moysiadis, T., Hadzidimitriou, A., Xochelli, A., Jeromin, S., Agathangelidis, A., . . . Stamatopoulos, K. (2019). Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia. Haematologica, 104(2), 360-369
Open this publication in new window or tab >>Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 2, p. 360-369Article in journal (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to first -treatment and a treatment probability at Five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or ST3B1 mutations were associated with the shortest time-to-First treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2019
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377215 (URN)10.3324/haematol.2018.195032 (DOI)000457460800032 ()30262567 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Polychronidou, E., Kalamaras, I., Agathangelidis, A., Sutton, L. A., Yan, X.-J., Bikos, V., . . . Tzovaras, D. (2018). Automated shape-based clustering of 3D immunoglobulin protein structures in chronic lymphocytic leukemia. BMC Bioinformatics, 19, Article ID 414.
Open this publication in new window or tab >>Automated shape-based clustering of 3D immunoglobulin protein structures in chronic lymphocytic leukemia
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2018 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, article id 414Article in journal (Refereed) Published
Abstract [en]

Background: Although the etiology of chronic lymphocytic leukemia (CLL), the most common type of adult leukemia, is still unclear, strong evidence implicates antigen involvement in disease ontogeny and evolution. Primary and 3D structure analysis has been utilised in order to discover indications of antigenic pressure. The latter has been mostly based on the 3D models of the clonotypic B cell receptor immunoglobulin (BcR IG) amino acid sequences. Therefore, their accuracy is directly dependent on the quality of the model construction algorithms and the specific methods used to compare the ensuing models. Thus far, reliable and robust methods that can group the IG 3D models based on their structural characteristics are missing. Results: Here we propose a novel method for clustering a set of proteins based on their 3D structure focusing on 3D structures of BcR IG from a large series of patients with CLL. The method combines techniques from the areas of bioinformatics, 3D object recognition and machine learning. The clustering procedure is based on the extraction of 3D descriptors, encoding various properties of the local and global geometrical structure of the proteins. The descriptors are extracted from aligned pairs of proteins. A combination of individual 3D descriptors is also used as an additional method. The comparison of the automatically generated clusters to manual annotation by experts shows an increased accuracy when using the 3D descriptors compared to plain bioinformatics-based comparison. The accuracy is increased even more when using the combination of 3D descriptors. Conclusions: The experimental results verify that the use of 3D descriptors commonly used for 3D object recognition can be effectively applied to distinguishing structural differences of proteins. The proposed approach can be applied to provide hints for the existence of structural groups in a large set of unannotated BcR IG protein files in both CLL and, by logical extension, other contexts where it is relevant to characterize BcR IG structural similarity. The method does not present any limitations in application and can be extended to other types of proteins.

Keywords
CLL protein clustering, 3D protein descriptors, descriptor fusion
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-373247 (URN)10.1186/s12859-018-2381-1 (DOI)000454362600006 ()30453883 (PubMedID)
Funder
EU, Horizon 2020, 692298
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
Malcikova, J., Tausch, E., Rossi, D., Sutton, L. A., Soussi, T., Zenz, T., . . . Pospisilova, S. (2018). ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia—update on methodological approaches and results interpretation. Leukemia, 32(5), 1070-1080
Open this publication in new window or tab >>ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia—update on methodological approaches and results interpretation
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2018 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 5, p. 1070-1080Article, review/survey (Refereed) Published
Abstract [en]

In chronic lymphocytic leukemia (CLL), TP53 gene defects, due to deletion of the 17p13 locus and/or mutation(s) within the TP53 gene, are associated with resistance to chemoimmunotherapy and a particularly dismal clinical outcome. On these grounds, analysis of TP53 aberrations has been incorporated into routine clinical diagnostics to improve patient stratification and optimize therapeutic decisions. The predictive implications of TP53 aberrations have increasing significance in the era of novel targeted therapies, i.e., inhibitors of B-cell receptor (BcR) signaling and anti-apoptotic BCL2 family members, owing to their efficacy in patients with TP53 defects. In this report, the TP53 Network of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) presents updated recommendations on the methodological approaches for TP53 mutation analysis. Moreover, it provides guidance to ensure that the analysis is performed in a timely manner for all patients requiring treatment and that the data is interpreted and reported in a consistent, standardized, and accurate way. Since next-generation sequencing technologies are gaining prominence within diagnostic laboratories, this report also offers advice and recommendations for the interpretation of TP53 mutation data generated by this methodology.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:uu:diva-358110 (URN)10.1038/s41375-017-0007-7 (DOI)000431769800003 ()29467486 (PubMedID)
Funder
EU, Horizon 2020, 692298; 644906; LQ1601German Research Foundation (DFG), SFB1074Swedish Cancer SocietySwedish Research Council, FNBr 65269705; FM MU ROZV/24/LF/2016
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Agathangelidis, A., Ljungström, V., Scarfo, L., Fazi, C., Gounari, M., Pandzic, T., . . . Ghia, P. (2018). Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations. Haematologica, 103(5), 865-873
Open this publication in new window or tab >>Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations
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2018 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 5, p. 865-873Article in journal (Refereed) Published
Abstract [en]

Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-356089 (URN)10.3324/haematol.2017.177212 (DOI)000431396200029 ()29449433 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyEU, European Research Council
Available from: 2018-07-19 Created: 2018-07-19 Last updated: 2018-07-19Bibliographically approved
Agathangelidis, A., Sutton, L. A., Hadzidimitriou, A., Tresoldi, C., Langerak, A. W., Belessi, C., . . . Ghia, P. (2018). Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation. Journal of Visualized Experiments (141), Article ID e57787.
Open this publication in new window or tab >>Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
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2018 (English)In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 141, article id e57787Article in journal (Refereed) Published
Abstract [en]

During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data.

Place, publisher, year, edition, pages
JOURNAL OF VISUALIZED EXPERIMENTS, 2018
Keywords
Cancer Research, Issue 141, Chronic lymphocytic leukemia (CLL), somatic hypermutation (SHM), immunoglobulin, immunoglobulin heavy variable (IGHV), complementarity determining region 3 (CDR3), International ImMunoGene Tics information system (IMGT)
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-376902 (URN)10.3791/57787 (DOI)000456469400033 ()30531723 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationEU, Horizon 2020Swedish Cancer Society
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-02-12 Created: 2019-02-12 Last updated: 2019-02-12Bibliographically approved
Baliakas, P., Mattsson, M., Hadzidimitriou, A., Minga, E., Agathangelidis, A., Sutton, L. A., . . . Stamatopoulos, K. (2018). No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy [Letter to the editor]. Haematologica, 103(4), E158-E161
Open this publication in new window or tab >>No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy
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2018 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 4, p. E158-E161Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2018
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-356894 (URN)10.3324/haematol.2017.182634 (DOI)000428242100006 ()29269523 (PubMedID)
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved
Xochelli, A., Baliakas, P., Kavakiotis, I., Agathangelidis, A., Sutton, L. A., Minga, E., . . . Stamatopoulos, K. (2017). Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes. Clinical Cancer Research, 23(17), 5292-5301
Open this publication in new window or tab >>Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 17, p. 5292-5301Article in journal (Refereed) Published
Abstract [en]

Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.  

Keywords
B-cell receptors, gene mutational status, antigen receptors, CD38 expression, genomic aberrations, sequence-analysis, I-antigen, immunoglobulin, antibodies, dna
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-334402 (URN)10.1158/1078-0432.CCR-16-3100 (DOI)000409037300034 ()28536306 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-11Bibliographically approved
Bhoi, S., Mansouri, L., Castellano, G., Sutton, L. A., Papakonstantinou, N., Queiros, A., . . . Rosenquist, R. (2017). DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?. Paper presented at 22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN. Haematologica, 102(Suppl. 2), 68-68, Article ID P244.
Open this publication in new window or tab >>DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?
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2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 68-68, article id P244Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377412 (URN)000404127001140 ()
Conference
22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Young, E., Noerenberg, D., Mansouri, L., Ljungström, V., Frick, M., Sutton, L. A., . . . Damm, F. (2017). EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia, 31(7), 1547-1554
Open this publication in new window or tab >>EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1547-1554Article in journal (Refereed) Published
Abstract [en]

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-314928 (URN)10.1038/leu.2016.359 (DOI)000404745300009 ()27890934 (PubMedID)
Note

E.Y. and D.N. contributed equally to this study as joint first authors.

R.R. and F.D. contributed equally as joint senior authors.

Available from: 2017-02-07 Created: 2017-02-07 Last updated: 2017-09-28Bibliographically approved
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