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Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
LA. Sutton, E. Young, P. Baliakas, A. Hadzidimitriou, T. Moysiadis, K. Plevova, D. Rossi, J. Kminkova, E. Stalika, LB. Pedersen, J. Malcikova, A. Agathangelidis, Z. Davis, L. Mansouri, L. Scarfò, M. Boudjoghra, A. Navarro, AF. Muggen, XJ. Yan, F....
Jazyk angličtina Země Itálie
Typ dokumentu časopisecké články
Free Medical Journals od 1994
Freely Accessible Science Journals od 1994
PubMed Central od 2009
Europe PubMed Central od 2009
Open Access Digital Library od 1994-01-01
ROAD: Directory of Open Access Scholarly Resources od 1996
Odkazy
PubMed
27198719
DOI
10.3324/haematol.2016.141812
Knihovny.cz E-zdroje
- MeSH
- chronická lymfatická leukemie genetika metabolismus mortalita MeSH
- cytogenetické vyšetření MeSH
- frekvence genu MeSH
- genová přestavba B-lymfocytů MeSH
- geny pro imunoglobuliny MeSH
- hypervariabilní oblasti genetika MeSH
- imunoglobuliny - vazebný region genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- mutace * MeSH
- nádorové biomarkery * MeSH
- prognóza MeSH
- receptory antigenů B-buněk genetika metabolismus MeSH
- těžké řetězce imunoglobulinů genetika MeSH
- variabilní oblast imunoglobulinu genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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).
1st Department of Propaedeutic Medicine University of Athens Greece
Cancer Sciences Faculty of Medicine University of Southampton UK
Department of Haematology Royal Bournemouth Hospital Bournemouth UK
Department of Hematology Rigshospitalet Copenhagen Denmark
Department of Immunology Erasmus MC University Medical Center Rotterdam The Netherlands
Hematology Department and University Pierre et Marie Curie Hopital Pitie Salpetriere Paris France
Hematology Department Nikea General Hospital Piraeus Greece
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