Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
Year: 2022
Type: article
Study design: Observational Study
Abstract: 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.
Source: Frontiers in Oncology
Authors: Matthew Kaufman, Xiao-Jie Yan, Wentian Li, Emanuela M. Ghia, Anton W. Langerak, Laura Z. Rassenti, Chrysoula Belessi, Neil E. Kay, Frederic Davi, John C. Byrd, Sarka Pospisilova, Jennifer R. Brown, Mark Catherwood, Zadie Davis, David Oscier, Marco Montillo, Livio Trentin, Richard Rosenquist, Paolo Ghia, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kanti R. Rai, Kostas Stamatopoulos, Thomas J. Kipps, Donna Neuberg, Nicholas Chiorazzi
Institutions: Northwell Health, Feinstein Institute for Medical Research, University of California San Diego, Moores Cancer Center, Erasmus MC, General Hospital of Nikea, Mayo Clinic, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, University of Cincinnati, Masaryk University, University Hospital Brno, Dana-Farber Cancer Institute, Belfast City Hospital, Royal Bournemouth Hospital, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, University of Padua, Azienda Ospedale - Università Padova, Karolinska Institutet, IRCCS Ospedale San Raffaele, Hofstra University, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Centre for Research and Technology Hellas
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Celgene, TG Therapeutics, Sunesis, MEI Pharma, Agios Pharmaceuticals, BeiGene, Argenx, Verastem Oncology, European Commission, Cancerfonden, Ministerstvo Zdravotnictví Ceské Republiky, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Radiumhemmets Forskningsfonder, MorphoSys, National Institutes of Health, Genentech, Sanofi Genzyme, Pharmacyclics, Juno Therapeutics, Feinstein Institutes for Medical Research, National Cancer Institute, Janssen Pharmaceuticals
OpenAlex ID: W4285040801