DISTINCT FREQUENCY AND PROFILES OF TP53 GENE MUTATIONS IN CLL SUBGROUPS WITH DISTINCT ANTIGEN RECEPTORS: EVIDENCE FOR ANTIGEN-DRIVEN SELECTION OF GENOMIC ABERRATIONS

Background:

In CLL, mutations of the TP53 gene negatively impact on patient outcome and are strongly associated with deletion of chromosome 17p and unmutated IGHV genes (U-CLL).

Aims:

Here we sought to explore the distribution and spectrum of TP53 mutations with regards to immunogenetic features in a series of 1160 patients intentionally selected for belonging to prognostically adverse immunogenetic CLL subgroups.

Methods:

We investigated (i) U-CLL and/or (ii) cases expressing the IGHV3-21 gene, especially in stereotyped B cell receptors (BcRs) assigned to subset #2 with variable IGHV mutational status. For this reason, only 49/1160 (4.2%) cases of the cohort carried mutated IGHV genes (M-CLL; germline identity, GI, <98%). The remaining cases (1111/1160, 95.8%) concerned U-CLL; of these, 271 (24.4%) and 840 (75.6%) cases expressed IGHV genes with 98-99.9% and 100% GI, respectively. For the purposes of the present study, we particularly focused on missense TP53 mutations in DNA binding motifs (DBMs), described to be associated with a markedly adverse prognosis.

Results:

Overall, 206 cases (17.8%) were found to carry TP53 mutations; 99/206 (48%; or 8.5% of the entire cohort) carried mutations in DBMs. The high frequency of mutations can be explained by the composition of the present cohort which essentially consisted of prognostically adverse immunogenetic subgroups. As expected, TP53 mutations (all types as well as mutations in DBMs) were significantly more frequent in cases with del(17p) vs. all other aberrations in the hierarchical model (P<0.0001). Association analyses regarding immunogenetic features concerned the following: (1) somatic hypermutation (SHM) status. The frequency of all types of TP53 mutations was significantly higher in cases expressing IGHV genes with GI=100% vs. GI=98-99.9% (19.6% vs 13.6%; P=0.02). (2) IGHV gene repertoire. Among U-CLL cases, significant differences in the incidence of TP53mutations in general and mutations in DBMs in particular (P=0.03 for both) were identified in cases utilizing different IGHV genes: in particular, there were more than 20% TP53-mutated cases in the IGHV1-69, IGHV1-3, IGHV3-30 and IGHV4-39 groups, thus contrasting the IGHV5-51 (7%) and, especially, the IGHV3-21 group (4%). (3) BcR stereotypy. In addition to subset #2 (n=66 cases, variable SHM status), several other wellcharacterized subsets were represented in the present cohort (all concerning UCLL), including #1 (n=61), #8 (n=15) (both already documented as poor-prognostic) as well as five subsets utilizing the IGHV1-69 gene albeit with distinct VH CDR3 motifs, namely #3 (n=16), #5 (n=14), #6 (n=25) and #7 (n=44). TP53 mutation frequencies varied significantly (P=0.01) between these subsets, ranging from 0% in subset #5 to 25% in subset #3; of note, these subsets have previously been reported to exhibit distinct prognosis (shorter time-to-first-treatment in #3). The two largest subsets, namely #1 and #2 had TP53 mutation frequencies of 14.8% and 6% respectively. Differences were more pronounced (P=0.008) concerning TP53 mutation frequencies in DBMs.

Summary / Conclusion:

We demonstrate markedly different incidence and spectra of TP53 mutations, especially missense mutations in DBMs, in different stereotyped CLL subsets. These findings confirm and significantly extend recent reports by us and others that certain BcR stereotypes are linked to distinct profiles of genomic aberrations. On these grounds, antigen-driven, BcR-mediated selection can be proposed as a possible mechanism for the acquisition of genomic aberrations in CLL.

Supported by MSM0021622430, NT13493, NT13519, FR-TI2/254

Abstrakta v časopise Haematologica 2013, Suppl1

Online Program