Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

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Authors	KAUFMAN Matthew YAN Xiao-Jie LI Wentian GHIA Emanuela M LANGERAK Anton W RASSENTI Laura Z BELESSI Chrysoula KAY Neil E DAVI Frederic BYRD John C POSPÍŠILOVÁ Šárka BROWN Jennifer R CATHERWOOD Mark DAVIS Zadie OSCIER David MONTILLO Marco TRENTIN Livio ROSENQUIST Richard GHIA Paolo BARRIENTOS Jacqueline C KOLITZ Jonathan E ALLEN Steven L RAI Kanti R STAMATOPOULOS Kostas KIPPS Thomas J NEUBERG Donna CHIORAZZI Nicholas
Year of publication	2022
Type	Article in Periodical
Magazine / Source	Frontiers in Oncology
MU Faculty or unit	Faculty of Medicine
Citation
Web	https://www.frontiersin.org/articles/10.3389/fonc.2022.897280/full
Doi	http://dx.doi.org/10.3389/fonc.2022.897280
Keywords	chronic lymphocytic leukemia; CLL; somatic mutations; immunoglobulin variable domain; prognosis
Description	Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc <= 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
Related projects:	Comprehensive prognostic and predictive panel for chronic lymphocytic leukemia: a next-generation sequencing tool suitable for clinical practice and study of genetic architecture behind the disease progress