Τίτλος:
Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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). © 2016 Ferrata Storti Foundation.
Συγγραφείς:
Sutton, L.-A.
Young, E.
Baliakas, P.
Hadzidimitriou, A.
Moysiadis, T.
Plevova, K.
Rossi, D.
Kminkova, J.
Stalika, E.
Pedersen, L.B.
Malcikova, J.
Agathangelidis, A.
Davis, Z.
Mansouri, L.
Scarfò, L.
Boudjoghra, M.
Navarro, A.
Muggen, A.F.
Yan, X.-J.
Nguyen-Khac, F.
Larrayoz, M.
Panagiotidis, P.
Chiorazzi, N.
Niemann, C.U.
Belessi, C.
Campo, E.
Strefford, J.C.
Langerak, A.W.
Oscier, D.
Gaidano, G.
Pospisilova, S.
Davi, F.
Ghia, P.
Stamatopoulos, K.
Rosenquist, R.
the European Research Initiative on CLL
Περιοδικό:
Haematologica-the hematology journal
Εκδότης:
Ferrata Storti Foundation
Λέξεις-κλειδιά:
B lymphocyte receptor; immunoglobulin; myeloid differentiation factor 88; Notch1 receptor; peptides and proteins; protein p53; complementarity determining region; immunoglobulin heavy chain; immunoglobulin structure; immunoglobulin variable region; lymphocyte antigen receptor; tumor marker, Article; chronic lymphatic leukemia; cytogenetics; fluorescence in situ hybridization; gene mutation; human; major clinical study; sequence analysis; single nucleotide polymorphism; trisomy; chromosome analysis; chronic lymphatic leukemia; complementarity determining region; female; gene frequency; gene rearrangement; genetics; immunoglobulin gene; immunoglobulin structure; immunoglobulin variable region; male; metabolism; mortality; mutation; prognosis, Biomarkers, Tumor; Complementarity Determining Regions; Cytogenetic Analysis; Female; Gene Frequency; Gene Rearrangement, B-Lymphocyte; Genes, Immunoglobulin; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Joining Region; Immunoglobulin Variable Region; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mutation; Polymorphism, Single Nucleotide; Prognosis; Receptors, Antigen, B-Cell
DOI:
10.3324/haematol.2016.141812
