@article{Lesley-Ann Sutton_Emma Young_Panagiotis Baliakas_Anastasia Hadzidimitriou_Theodoros Moysiadis_Karla Plevova_Davide Rossi_Jana Kminkova_Evangelia Stalika_Lone Bredo Pedersen_Jitka Malcikova_Andreas Agathangelidis_Zadie Davis_Larry Mansouri_Lydia Scarfò_Myriam Boudjoghra_Alba Navarro_Alice F. Muggen_Xiao-Jie Yan_Florence Nguyen-Khac_Marta Larrayoz_Panagiotis Panagiotidis_Nicholas Chiorazzi_Carsten Utoft Niemann_Chrysoula Belessi_Elias Campo_Jonathan C. Strefford_Anton W. Langerak_David Oscier_Gianluca Gaidano_Sarka Pospisilova_Frederic Davi_Paolo Ghia_Kostas Stamatopoulos_Richard Rosenquist_2016, place={Pavia, Italy}, title={Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors}, volume={101}, url={https://haematologica.org/article/view/7798}, DOI={10.3324/haematol.2016.141812}, abstractNote={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 (<em>BIRC3, MYD88, NOTCH1, SF3B1</em> and <em>TP53</em>) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of <em>NOTCH1</em> 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 (<em>P</em><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 <em>NOTCH1</em> mutations were found to carry few (if any) <em>SF3B1</em> mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, <em>SF3B1</em> mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within <em>TP53</em>, 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 <em>MYD88</em> mutations, whereas <em>BIRC3</em&gt; 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).}, number={8}, journal={Haematologica}, author={Lesley-Ann Sutton and Emma Young and Panagiotis Baliakas and Anastasia Hadzidimitriou and Theodoros Moysiadis and Karla Plevova and Davide Rossi and Jana Kminkova and Evangelia Stalika and Lone Bredo Pedersen and Jitka Malcikova and Andreas Agathangelidis and Zadie Davis and Larry Mansouri and Lydia Scarfò and Myriam Boudjoghra and Alba Navarro and Alice F. Muggen and Xiao-Jie Yan and Florence Nguyen-Khac and Marta Larrayoz and Panagiotis Panagiotidis and Nicholas Chiorazzi and Carsten Utoft Niemann and Chrysoula Belessi and Elias Campo and Jonathan C. Strefford and Anton W. Langerak and David Oscier and Gianluca Gaidano and Sarka Pospisilova and Frederic Davi and Paolo Ghia and Kostas Stamatopoulos and Richard Rosenquist}, year={2016}, month={Jul.}, pages={959-967} }