Differential Distribution Of Recurrent Gene Mutations
Baliakas P, Hadzidimitriou A, Sutton L et al.
Key Points:
- Study aimed to confirm and extend observation that different CLL subsets with distinct stereotyped B-cell
- Receptor immunoglobulins display distinct genetic makeup, differential modes of immune signaling and eventually determine clinical aggressiveness
- Cases sub-classified into subsets: (i) unmutated IGHV genes (U-CLL): #1, n=72; #3, n=25; #5, n=11; #6, n=22; #7, n=37; #8, n=20; (ii) mutated IGHV genes (M-CLL): #4, n=32; #77, n=12; #148, n=20; and, (iii) subset #2 (IGHV3-21, variable mutational status), n=57
- Mutations in MYD88 and BIRC3 genes relatively rare, with no clear bias to any subset
- Single mutation in TP53 gene identified in 80 M-CLL subset cases
- Among U-CLL subsets and clinically aggressive subset #2, TP53 mutations enriched in subsets #3 & #7 (>10%), #1 (9%) and #99; NOTCH1 mutations exhibited increased frequency in subsets #1 (28%) and #8 (25%), intermediate frequency (9%) in subset #2, lower frequencies in subsets #3 (8%), #5 (10%) and #7 (3%); SF3B1 mutations significantly enriched in subsets #2 (47.6%), #3 (40%) and #7 (25%)
- All the differences in subsets statistically significant.
Implications:
- Differential modes of immune signaling in context of subset-biased antigen-IG interactions may be associated with acquisition and/or selection of certain genomic aberrations in various stereotyped subsets and eventually determining underlying clinical aggressiveness through distinct mechanisms
- Sequence similarities between different subsets (e.g. #1 and #99) likely reflect similar pathobiology, underscoring relevance of molecular sub-classification of CLL based on BcR stereotypy.
View the original abstract on the ASH website.
