Work

Relationship among three common hematological premalignant conditions

Year: 2023

Type: article

Abstract: Monoclonal B-cell lymphocytosis (MBL), monoclonal gammopathy of undetermined significance (MGUS), and clonal hematopoiesis (CH) are all asymptomatic hematological conditions characterized by clonal expansion of blood cells [ 1 , 2 ]. These conditions are notably associated with increased risk of hematologic cancers. Each condition has an annual progression rate of ~1–2%/year, with MBL progressing to chronic lymphocytic leukemia (CLL) [ 3 ] or lymphoid malignancies [ 4 ], MGUS progressing mostly to multiple myeloma (MM) [ 5 ], and CH progressing predominately to myeloid neoplasms [ 2 ]. Additionally, these premalignant conditions (or a particular subtype of them) are associated with adverse outcomes, including increased risk of infections [ 6 , 7 , 8 ] and reduced overall survival [ 2 , 4 , 5 ]. Known risk factors for these conditions are limited but include aging [ 4 , 9 ] and common inherited variants [ 10 , 11 , 12 ]. The prevalence of each of these conditions has been established, ranging from 5–25% overall, with particular subtypes having varying prevalence rates [ 2 , 4 , 9 ]. However, little is known about their co-occurrence. One hospital-based cohort of ~1500 non-hematological patients screened for MBL and MGUS found no significant association between them [ 13 ]. Another study of 777 subjects enrolled in the Monzino 80-plus cohort found no significant association between MGUS and CH [ 14 ]. Herein, we investigate the co-occurrence of MBL with MGUS and with CH, along with the associations between them and the prevalence of all three conditions. This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center, and participants provided written informed consent. Study participants were a cross-sectional sample from the Mayo Clinic Biobank who were recruited between 2009–2016 from general medical practice clinics, randomly selected from participants who had no prior history of hematological cancers, 40 years or older, and provided a biospecimen needed for MBL and MGUS screening [ 4 ]. For a more representative cohort, we included participants who resided predominantly from counties surrounding Mayo Clinic and therefore who typically receive their general medical care at Mayo Clinic. CH screening was conducted on a subset of these individuals and were selected based on MBL status (a case-control study comprised of 330 individuals with MBL and 588 age- and sex-matched individuals without MBL). The methods used for MBL screening [ 4 , 7 ] and MGUS screening [ 9 ] have been previously published. For CH, peripheral blood DNA was used to sequence the coding regions from 42 CH-related genes (Supplementary Table 1 ) using the Illumina HiSeq 4000. The average coverage depth was >1000x. Somatic mutations were called using MuTect2. Variants were excluded if the number of reads supporting variant alleles was <8, variant allele fraction (VAF) was <0.01, gnomAD allele frequency was ≥0.005, more than 80% of the variant reads came from a single strand, or the VAF did not deviate from 50% at a p value of at least 0.00001 unless reported in COSMIC at least 10 times. Loss-of-function variants (nonsense, frameshift, and consensus splice sites) and missense variants, classified as pathogenic or likely pathogenic, were used to identify individuals with CH. Different laboratory technicians performed each premalignant screening assay, thus were blinded to the results of the other screening assays. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) using R (version 3.6.2). All analyses were adjusted for age and sex; in addition, association analyses between CH and MGUS were also adjusted for MBL status.

Source: Leukemia

DOI: 10.1038/s41375-023-01914-z