Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

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Authors	SUTTON Lesley-Ann YOUNG Emma BALIAKAS Panagiotis HADZIDIMITRIOU Anastasia MOYSIADIS Theodoros PLEVOVÁ Karla ROSSI Davide KMÍNKOVÁ Jana STALIKA Evangelia PEDERSEN Lone Bredo MALČÍKOVÁ Jitka AGATHANGELIDIS Andreas DAVIS Zadie MANSOURI Larry SCARFO Lydia BOUDJOGHRA Myriam NAVARRO Alba MUGGEN Alice F. YAN Xiao-Jie NGUYEN-KHAC Florence LARRAYOZ Marta PANAGIOTIDIS Panagiotis CHIORAZZI Nicholas NIEMANN Carsten Utoft BELESSI Chrysoula CAMPO Elias STREFFORD Jonathan C. LANGERAK Anton W. OSCIER David GAIDANO Gianluca POSPÍŠILOVÁ Šárka DAVI Frederic GHIA Paolo STAMATOPOULOS Kostas ROSENQUIST Richard
Year of publication	2016
Type	Article in Periodical
Magazine / Source	Haematologica
MU Faculty or unit	Central European Institute of Technology
Citation
web	http://www.haematologica.org/content/101/8/959.full.pdf+html
Doi	http://dx.doi.org/10.3324/haematol.2016.141812
Field	Oncology and hematology
Keywords	ANTIGEN RECEPTORS; GENOMIC ABERRATIONS; EXPRESSION PROFILES; SF3B1; SELECTION; TP53; CLL; SUBGROUPS; INDICATE; PATTERNS
Description	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).
Related projects:	CEITEC - Central European Institute of Technology